ESMO LYMPHOMAS by Infomedica

www.esmo.org

edited by

Michele Ghielmini Silvia Montoto

lymphomas e s s e n t i a l s forc l i n i c i a n s

Michele Ghielmini Silvia Montoto

lymphomas e s s e n t i a l s forc l i n i c i a n s

lymphomas

edited by

Michele Ghielmini & Silvia Montoto

Reed-Sternberg cell

e s s e n t i a l s fo r c l i n i c i a n s

‘Lymphomas’ is one of the most feared subjects for medical students and training doctors sitting an exam. It is frequently regarded as a difficult one, highly complicated, continuously changing, and almost reserved for experts. The aim of this book is to transform learning on lymphomas into an easy and enjoyable experience by using a very visual and didactic format that recalls a PowerPoint presentation, with plenty of images, succinct comments, speech bubbles on the pictures, and revision questions. This book is mainly addressed to junior doctors taking their first steps in this field or preparing for their exams, but it is also suitable for general oncologists or hematologists who are no lymphoma specialists but want to keep updated on this topic and to enjoy it while doing so.

1980

1990

2000

2010

total nodal

regional nodal

involved field

involved node

1.0 – 0.9 – 0.8 – 0.7 – 0.6 – 0.5 –

A B

0.4 –

0.3 –

0.2 – 0.1 – 0– 0 12 Time (months)

ESMO Press · ISBN 978-88-906359-2-2

ESMO Press

ESMOEssentials_LymphomasOK.indd 1

9 788890 635922

A: 4xABVD + 30 GY IF-RT B: 4xABVD + 20 Gy IF-RT C: 2xABVD + 30 GY IF-RT D: 2xABVD + 20 Gy IF-RT

ISBN 978-88-906359-2-2

ESMO Press

108

120

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The distribution of this material is supported by an educational grant from Millennium: The Takeda Oncology Company. Millennium: The Takeda Oncology Company has not influenced the content of this publication.

CM16 ESMO Lymphomas Inside front1 1

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Lymphomas Essentials for Clinicians

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CM16 ESMO Lymphoma Booklet v21.i2 2

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Lymphomas Essentials for Clinicians

Edited by

Michele Ghielmini Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland

Silvia Montoto Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK

ESMO Press

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First published in 2012 by ESMO Press

ÂŠ 2012 European Society for Medical Oncology

All rights reserved. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission of the publisher or in accordance with the provisions of the Copyright, Designs, and Patents Act 1988 or under the terms of any license permitting limited copying issued by the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA (www.copyright. com/ or telephone 978-750-8400). Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe.

This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission and sources are indicated. Reasonable efforts have been made to publish reliable data and information, but the authors and publisher cannot assume responsibility for the validity of all materials or for the consequence of their use.

Although every effort has been made to ensure that drug doses and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publishers nor the authors can be held responsible for errors or for any consequences arising from the use of information contained herein. For detailed prescribing information on the use of any product or procedure discussed herein, please consult the prescribing information or instructional material issued by the manufacturer.

A CIP record for this book is available from the British Library.

ISBN: 978-88-906359-2-2

For orders, corporate sales, foreign rights, and reprint permissions, please contact: ESMO Head Office Guidelines and Publishing Department Via Luigi Taddei 4 6962 Viganello-Lugano Switzerland Tel: +41 (0) 91 973 1900 Email: publishing@esmo.org www.esmo.org

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Contents Preface

vii

Contributors

viii

Abbreviations

Acknowledgments

A. What every oncologist/hematologist should know 1. The immune system A Davies

2. Diagnosing lymphomas D Soldini & L Mazzucchelli

3. The WHO lymphoma classification A Carvajal-Cuenca & E Campo

4. Staging and response assessment in lymphoma patients A Borra & A Gallamini

5. Common treatments for lymphoma D Rodriguez-Abreu & M Provencio

6. Diffuse large B-cell lymphoma A Chiappella & U Vitolo

7. Follicular lymphoma AA Moccia & M Ghielmini

8. Chronic lymphocytic leukemia / small lymphocytic lymphoma S Norin & E Kimby

9. Mantle cell lymphoma T Weiglein & M Dreyling

10. Extranodal marginal zone lymphoma of MALT type F Bertoni & E Zucca

11. Peripheral T-cell lymphomas MB Pedersen & F dâ&#x20AC;&#x2122;Amore

12. Hodgkin lymphoma DA Eichenauer & A Engert

B. More advanced knowledge 13. Etiology and epidemiology L Costas & S de Sanjose

14. History of lymphoma classification M Ponzoni & AJM Ferreri

15. Molecular biology of lymphomas FE Cotter

16. New drugs and novel treatment strategies G Hess

17. Cutaneous lymphoma R Willemze

18. Peripheral T-cell lymphomas (extranodal) V Ballova

19. Non-MALT marginal zone lymphomas C Montalban

Contents CM16 ESMO Lymphoma Booklet v21.i5 5

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20. Lymphoplasmacytic lymphoma / WaldenstrĂśmâ&#x20AC;&#x2122;s macroglobulinemia E Kastritis & MA Dimopoulos

101

21. Burkitt lymphoma and lymphoblastic lymphoma MA Fridrik

105

22. Extranodal lymphomas AJM Ferreri & M Ponzoni

109

23. Lymphomas in the immunocompromised patient S Montoto

113

Appendices 1. WHO Classification of Lymphomas

117

2. Prognostic indices

118

3. Selected treatment schedules

119

Image sources

124

Index

126

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Preface ESMO has decided to publish a series of booklets devoted to “Essentials for Clinicians” about specific tumors or tumor groups. The editors have taken on the difficult task of preparing the first of these, which should serve also as a template for those to follow. We have to admit we were distinctly skeptical when we first heard about the project. First of all, we thought that in the era of e-learning it was difficult to imagine how such an endeavor could easily squeeze between, on the one hand, the multitude of guidelines and, on the other, some very excellent standard textbooks. Our skepticism was even greater since the editors had not only to create the template for this series, but to do so with nothing less than the malignant lymphomas, a very complex group of neoplasias encompassing at least three dozen different entities with a wide variety of pathological patterns. We are delighted to recognize today that the result of their endeavor is astonishing: they have devised a novel format, which is very modern, including the impression of looking like a PowerPoint presentation. The book is also very interactive: at the end of each page the reader can check, thanks to a couple of questions, whether he/she has understood the most important points and, concluding each chapter, there is additionally a brief, but complete, summary as well as selective further critical readings, should they be needed. Without doubt, a highly comprehensive account of the essential features of the malignant lymphomas and their management can be found in this reader-friendly booklet. ESMO is now very fortunate to have a magnificent template for the preparation of the next “Essentials for Clinicians”. Professor Andrew Lister London, UK

Professor Franco Cavalli Bellinzona, Switzerland

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Contributors V Ballova Oncological Clinic, Hematology Department, National Oncologic Institute, Bratislava, Slovakia F Bertoni Division of Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland A Borra Haematology Department and BMT Unit, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy E Campo Department of Pathology, Hospital Clinic, University of Barcelona, Barcelona, Spain A Carvajal-Cuenca Department of Pathology, Hospital San Juan de Dios, University of Costa Rica, San José, Costa Rica A Chiappella Hematology 2, Città della Salute e della Scienza, San Giovanni Battista Hospital and University, Torino, Italy L Costas Unit of Infections and Cancer, Cancer Epidemiology Research Programme, IDIBELL, Catalan Institute of Oncology, Barcelona, Spain FE Cotter Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK F d’Amore Department of Hematology, Aarhus University Hospital, Aarhus, Denmark A Davies Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK MA Dimopoulos Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece M Dreyling Department of Medicine III, Klinikum der Universität München, Campus Grosshadern, München, Germany DA Eichenauer First Department of Internal Medicine, University Hospital Cologne; German Hodgkin Study Group (GHSG), University Hospital Cologne, Cologne, Germany A Engert First Department of Internal Medicine, University Hospital Cologne; German Hodgkin Study Group (GHSG), University Hospital Cologne, Cologne, Germany AJM Ferreri Unit of Lymphoid Malignancies, Division of Onco-Hematological Medicine, Department of Onco-Hematology, San Raffaele Scientific Institute, Milan, Italy MA Fridrik Department of Internal Medicine 3, Center for Hematology and Medical Oncology, Linz, Austria A Gallamini Haematology Department and BMT Unit, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy M Ghielmini Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland

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G Hess Department of Hematology, Oncology and Pneumology, University Medical School of the Johannes Gutenberg-Universität, Mainz, Germany E Kastritis Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece E Kimby Division of Hematology, Department of Medicine at Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden L Mazzucchelli Istituto Cantonale di Patologia, Locarno, Switzerland AA Moccia Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland C Montalban Department of Internal Medicine, Hospital Ramón y Cajal, Madrid, Spain S Montoto Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK S Norin Division of Hematology, Department of Medicine at Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden MB Pedersen Department of Hematology, Aarhus University Hospital, Aarhus, Denmark M Ponzoni Unit of Lymphoid Malignancies, Division of Onco-Hematological Medicine, Department of Onco-Hematology, Pathology Unit, San Raffaele Scientific Institute, Milano, Italy M Provencio Medical Oncology Department, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain D Rodriguez-Abreu Medical Oncology Department, Hospital Universitario Insular de Gran Canaria, Las Palmas de Gran Canaria, Spain S de Sanjose Unit of Infections and Cancer, Cancer Epidemiology Research Programme, IDIBELL, Catalan Institute of Oncology, Barcelona; CIBER Epidemiologia y Salud Pública, Madrid, Spain D Soldini Istituto Cantonale di Patologia, Locarno, Switzerland U Vitolo Hematology 2, Città della Salute e della Scienza, San Giovanni Battista Hospital and University, Torino, Italy T Weiglein Department of Medicine III, Klinikum der Universität München, Campus Grosshadern, München, Germany R Willemze Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands E Zucca Division of Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

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Abbreviations Ab Antibody Ag Antigen AIHA Autoimmune hemolytic anemia Ara-C Cytarabine ASCT Autologous stem cell transplantation BBB Blood-brain barrier BCR B-cell receptor BM Bone marrow CD Cluster of differentiation CNS Central nervous system CRP C-reactive protein CSF Cerebrospinal fluid CT Computed tomography DFS Disease-free survival DXM Dexamethasone EBER Epstein-Barr early RNA EBV Epstein-Barr virus EFS Event-free survival EOT End of treatment FDG F-18-Fluorodeoxyglucose FFS Failure free survival FISH Fluorescence in situ hybridization FPE Fixed paraffin embedded G-CSF Granulocyte-colony stimulating factor GI Gastrointestinal HAART Highly active antiretroviral therapy HD High dose HDT High-dose therapy IFN Interferon Ig Immunoglobulin IHC Immunohistochemistry IPI International prognostic index IPS International prognostic score ISH In situ hybridization LN Lymph node LP Lumbar puncture LT Lymphoid tissue MGUS Monoclonal gammopathy of undetermined significance MM Multiple myeloma MoAb Monoclonal antibodies MTX Methotrexate neg Negative NF-kappaB Nuclear factor-kappaB OS Overall survival PB peripheral blood PBSC Peripheral blood stem cell PCR Polymerase chain reaction PET Positron emission tomography PFS Progression free survival pos positive PS Performance status RIC reduced-intensity conditioning regimen RR response rate RT Radiotherapy SUV Standardized uptake volume TCR T-cell receptor TTP Time to progression WBRT Whole brain radiotherapy

AITL Angioimmunoblastic T-cell lymphoma ALCL Anaplastic large cell lymphoma BL Burkitt lymphoma CBCL Cutaneous B-cell lymphoma CLL Chronic lymphocytic leukemia CTCL Cutaneous T-cell lymphoma DLBCL Diffuse large B-cell lymphoma EATL Enteropathy associated T-cell lymphoma FL Follicular lymphoma HSTL Hepatosplenic T-cell lymphoma LL Lymphoblastic lymphoma LPL Lymphoplasmacytic lymphoma MCL Mantle cell lymphoma MZL Marginal zone lymphoma NLPHL Nodular lymphocyte-predominant Hodgkin lymphoma PTCL Peripheral T-cell lymphoma SPTCL Subcutaneous panniculitis-like T-cell lymphoma

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Acknowledgments The editors would like to thank the members of the ESMO Publishing Working Group and Educational Steering Committee for their support of this initiative. The editors wish to thank Dr Keith McGregor and Claire Bramley of ESMO for their support in the preparation of this publication. We also thank Dr Carvajal-Cuenca, Dr Campo, and Dr Soldini, who reviewed the pathological content of the chapters. Michele Ghielmini and Silvia Montoto

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What every oncologist/hematologist should know

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The immune system

The immune response The immune system comprises two arms functioning cooperatively to provide a comprehensive protective response: the innate and the adaptive immune system. The innate immune system is primitive, does not require the presentation of an antigen, and does not lead to immunological memory.

Innate immunity (rapid response)

Adaptive immunity (slow response) Dendritic cell

Mast cell

B cell

Macrophage γδ T cell

T cell

Natural killer cell

Basophil

Complement protein

Its effector cells are neutrophils, macrophages, and mast cells, reacting within minutes to hours with the help of complement activation and cytokines (CK).

Natural killer T cell

Eosinophil Granulocytes

Antibodies CD4+ T cell

CD8+ T cell

Neutrophil

B-lymphocytes B-cell receptor

epitope antigen

T-lymphocytes T-cell receptor

epitope

The adaptive immune response is provided by the lymphocytes, which precisely recognize unique antigens (Ag) through cell-surface receptors. Receptors are obtained in billions of variations through cut and splicing of genes and subsequent negative selection: self-recognizing lymphocytes are eradicated. Immunological memory after an Ag encounter permits a faster and heightened state of response on a subsequent exposure.

MHC

Lymphocytes develop in primary lymphoid tissue (bone marrow [BM], thymus) and circulate towards secondary lymphoid tissue (lymph nodes [LN], spleen, MALT). The Ag reach the LN carried by lymphocytes or by dendritic cells. Lymphocytes enter the LN from blood transiting through specialized endothelial cells. The Ag is processed within the LN by lymphocytes, macrophages, and other immune cells in order to mount a specific immune response.

Tonsils and adenoids

Lymph nodes Lymphatic vessels Thymus

Lymph nodes Spleen Peyer’s patches Appendix Bone marrow

Lymph nodes Lymphatic vessels

REVISION QUESTIONS 1. Which are the effector cells of the innate immune system? 2. Which cells are responsible for immune memory? 3. In which anatomical structure are the antigens processed by lymphocytes?

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Immunoglobulins and B-cell development The lymphocytes developed in the BM (B cells) have as their final task the production of Ag-specific immunoglobulins (Ig), which function as antibodies (Ab). Ig are proteins secreted by or present on the surface of B cells, assembled from identical couples of heavy (H) and light (L) chains. The highly variable N terminal regions are the Ag-binding portion (Fab fragment). The constant domains interact with the Fc receptors on the effector cells.

There are 5 classes of Ig: M, G, A, E, and D, distinguished by different heavy chains. B cells can change the class of Ig produced: class switch.

In the rest of the cells in the body (not B cells), the genes encoding for the H and L chains of the Ig are distributed in many segments so that they cannot be expressed.

Before being capable of producing Ag-specific Ig, B cells must undergo a number of transformations, first in the BM and subsequently in the LNs.

These gene segments must be rearranged within the chromosome in the B cells so the final gene structure allows the expression of a functional protein. The first stages of B-cell development occur in the BM, where pro-B cells first rearrange the Ig H chain gene to become a pre-B cell. Pre-B cells continue this somatic recombination process by rearranging the L chain to become an immature B cell, expressing IgM on their surface.

Pro-B

Rag + H DJ L -

Pre-B

B cell

plasma cell

+ VDJ -

- VDJ VJ

VDJ VJ

REVISION QUESTIONS 1. What are the Fab and the Fc portions of an immunoglobulin? 2. What distinguishes a pre-B from a pro-B from an immature B cell? 3. What is meant with the term â&#x20AC;&#x153;somatic recombinationâ&#x20AC;??

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B-cell diversity In B cells the variable regions of the Ig L chains are encoded by the random joining of one of many variable (V) and joining (J) segment genes. In addition to the above, for the H chain gene, a diversity (D) gene must also be rearranged. The result of this random process is the expression on any individual naive B-cell surface of a unique Ig with Ag specificity: the B-cell receptor (BCR).

Naive B cells exit the BM and circulate between blood, LN, and secondary lymphoid tissue in search of an Ag that will match the randomly determined BCR.

Light zone

Dark zone

When naive B cells encounter an antigen within the germinal center (GC) of a LN they undergo further variation and selection. Binding of an Ag to the BCR, with the help of T cells and antigen-presenting cells (APC), initiates an Agdependent germinal center reaction.

In the peripheral dark zone of the GC, rapidly dividing B cells (centroblasts, CB) introduce random mutations in the H and L chains (somatic hypermutation). In the central light zone, CBs mature to centrocytes (CC) and are selected for affinity with the help of follicular helper T cells and dendritic cells. High-affinity CC mature to either plasma cells or memory B cells and leave the GC. They may undergo Ig class switch by changing the Ig H chain.

REVISION QUESTIONS 1. What are the phases of B-cell development and where do they take place? 2. How is the diversity of immunoglobulin specificity derived? 3. What is meant by â&#x20AC;&#x153;somatic hypermutationâ&#x20AC;??

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T cells and NK cells T lymphocytes arise in the BM but soon migrate to the thymus, where they mature to express the Ag-binding T-cell receptor (TCR) on their membrane. The TCR is a dimer composed of 2 chains, usually Îą and Î˛. Similar to the BCR, each one of these chains includes a variable and a constant domain. T cells are able to recognize Ag (through their TCR) only when the Ag is bound to a major histocompatibility complex (MHC) molecule.

After migrating to the secondary lymphoid organs, naive T cells are exposed to Ag which bind to the TCR. TCR activation induces proliferation and differentiation. T cells mature to distinct T-helper (Th) and T-cytotoxic (Tc) populations characterized by expression of CD4 and CD8, respectively. There are 2 classes of MHC molecules: class I and class II. Th recognizes Ag in the context of class II MHC, whereas Tc recognizes Ag bound to class I MHC.

Activated Th cells divide and produce a clone of effector cells, which in turn secrete CK, activating other components of the immune response. Once activated, Tc induce apoptosis of dysfunctional cells (i.e. infected) by enzymatic or signaling processes. Natural killer (NK) cells have a similar function.

NK do not require MHC expression to recognize target cells

Memory T cells are produced after Ag exposure. They remain quiescent and provide an enhanced response after repeated exposure to the Ag.

REVISION QUESTIONS 1. What is the structure of the T-cell receptor? 2. How can T-helper and T-cytotoxic cells be easily distinguished? 3. What is the main function of cytotoxic T cells?

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Immune system activity Cytokines (CK) are low molecular weight proteins that play a key role in the induction and regulation of the immune response. Produced by a variety of cells, their actions are mediated through their respective receptors; they exert autocrine, paracrine, and endocrine effects. CK regulate the intensity and duration of both the innate and adaptive immune response.

The various individual facets of the immune response interact in a complex fashion to result in a coordinated response. Following a rapid response by the cells of the innate system, the cells of the adaptive immune system recognize Ag, expanding and activating effectors. APC, present throughout the body, internalize and process Ag, displaying part of it on their surface bound to a class II MHC molecule.

This way APC carry cargos of foreign Ag to lymphoid organs, where they are recognized by Th cells which initiate the adaptive response.

Generation of oxidants Immunomodulation Reduced damage to host from inflammatory response

All aspects of the adaptive response are initiated and controlled by T cells. They recruit immunological effector mechanisms by direct contact or through CK. Antibodies may cause direct cytotoxicity by activation of the complement cascade or by recruiting effector cells (NK, macrophages, etc) that cause cell death.

Opsonization

Direct antimicrobial activity

Antibody-dependent cell cytotoxicity

Activation of complement

Virus and toxin neutralization

REVISION QUESTIONS 1. What are cytokines and how do they exert their function? 2. What is the role of the antigen-presenting cells? 3. What mechanisms are employed by antibodies to result in dysfunctional cell death?

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Summary: The immune system • Cells of the primitive innate immune system and the antigen-specific adaptive immune system act as a cooperative network to bring about a coordinated and tightly regulated immune response to foreign antigens • The former uses a limited pattern of recognition molecules and, although it retains no memory, is able to mount a rapid response • The latter recognizes a huge diversity of different specific antigens and elicits a response that is highly specific and retains memory • Diversity and antigen specificity in both the TCR and BCR result from somatic recombination and the random splicing of a selected number of gene segments • When naive B cells encounter an antigen, further antigen specificity is added by somatic hypermutation in the germinal center of secondary lymphoid organs • Only the most avidly antigen-binding cells mature to become either antibody-producing plasma cells or memory B cells • Antibodies may switch to different classes with differing effector functions and tissue locations while retaining the same antigen specificity in their variable regions • In response to antigen, T cells differentiate to effector T cells that may augment the immune response, cytotoxic T cells that destroy altered self-cells, or regulatory T cells • Cytokines regulate the immune response by autocrine, paracrine, and endocrine mechanisms • Cooperative interactions of both facets of the immune response result in efficient effector mechanisms that clear foreign antigen with residual immunological memory

Further Reading Fugmann SD, Lee AI, Shockett PE, Villey IJ, Schatz DG. The RAG proteins and V(D)J recombination: complexes, ends, and transposition. Annu Rev Immunol 2000;18:495–527. Goldsby RA, Kindt TJ, Osborne BA. Kuby Immunology. Sixth edition. New York: W.H. Freeman and Company; 2012. Helbert M. Flesh and Bones of Immunology. Edinburgh: Mosby Elsevier; 2006. Jaffe ES, Harris NL, Stein H, et al. Introduction and overview of the classification of lymphoid neoplasm. In: Swerdlow SH, Campo E, Harris NL, et al (Eds). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Fourth edition. Lyon: International Agency for Research on Cancer, 2008; 158–166. Klein U, Dalla-Favera R. Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol 2008; 8:22–33. Kracker S, Durandy A. Insights into the B cell specific process of immunoglobulin class switch recombination. Immunol Lett 2011; 138:97–103. Mucida D, Cheroutre H. The many face-lifts of CD4 T helper cells. Adv Immunol 2010; 107:139–152. Parham P. The Immune System. Second edition. New York: Garland Science Publishing; 2005. Rathmell JC, Thompson CB. The central effectors of cell death in the immune system. Annu Rev Immunol 1999; 17:781–828. Sun JC, Lanier LL. NK cell development, homeostasis and function: parallels with CD8 T cells. Nat Rev Immunol 2011; 11:645–657.

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Diagnosing lymphomas

Introduction â&#x20AC;&#x201C; Cytology and histology Pathology (derived from logos, study, and pathos, suffering) is a discipline devoted to study the changes associated with disease in cells, tissues, and organs.

Cytology is the last resort if there is no other way to obtain appropriate tissue

When lymphoma is suspected, the affected biological tissue is examined, both microscopically and with aid of immunophenotypic and, optionally, genetic studies. Excisional biopsies of lymphoid tissue are preferred to needle-core biopsies or cytology-based analysis as they generally allow higher diagnostic accuracy.

Excisional biopsy

Needle core biopsy

Cytology smear

Cytological preparations can be obtained from touch and scrape imprints of fresh material or from fine-needle aspirates (FNA). Slides are either fixed (alcohol or formalin) or air-dried. These are then stained, usually with Wright-Giemsatype staining (e.g. Diff-Quick) or Papanicolaou. In addition to morphological examination, cytological material allows immunophenotypic studies (flow cytometry, immunocytochemistry) and genetic studies.

Histology requires fresh biopsy material to be submitted to the pathologist. If possible, a portion is frozen for immunophenotypic and genetic studies.

Tissue sample

Paraffin block

Specimens are sectioned by pathologists in slices for fixation, usually in buffered formalin. After processing, paraffin-embedded material is cut in 2 Âľm sections. Sections are stained with hematoxylin-eosin (HE) for morphological assessment. Other useful stains: Giemsa, periodic acid-Schiff (PAS), Gomori.

REVISION QUESTIONS 1. How is pathology defined? 2. What is the best material for an accurate lymphoma diagnosis? 3. Which stains are commonly used in cytology and histology?

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Histopathology and cytology of lymphoid tissue Lymphoid tissues (LT) are divided into primary LT (bone marrow [BM] and thymus) and secondary LT (lymph nodes [LN], mucosa-associated LT, spleen).

Afferent lymphatics

Paracortex

Efferent lymphatic

Secondary LT present B-cell rich and T-cell rich areas (in LN: cortex and paracortex). Plasma cell-rich area, fibrous capsule, and sinuses further characterize LN. In reactive conditions, each component can be increased or diminished, which leads to an alteration of the whole structure.

Small cells in small lymphocytic lymphoma

Large cells in diffuse large B-cell lymphoma

Cortex

Vein Artery Medulla Capsule Medullary cords

Subcapsular sinus

Hodgkin cell with inflammatory background

Follicles

Trabeculum

Histology of lymphoma: the neoplastic cell population effaces the structure of LT, at least focally. Occasionally, it impinges on the non-neoplastic LT. In addition, the neoplastic cell population shows signs of invasion (e.g. tissue surrounding LT, vessel walls) and cytological atypia (cell size, nuclear morphology). Once a diagnosis of malignancy is made, the lymphoma has to be classified according to growth pattern and cytological features, with the aid of ancillary studies.

Cytological specimens may be of value in special situations, as for staging or in case of relapse, being rapid, accurate, and safe. For the initial diagnosis of lymphoma, however, confirmation with ancillary studies (immunophenotypic and genetic studies) is required. In contrast to reactive conditions, cytological specimens of neoplastic LN show limited range of maturation of the neoplastic cells. Small cells in small lymphocytic lymphoma

Large cells in diffuse large cell lymphoma

Hodgkin cell with inflammatory background

REVISION QUESTIONS 1. Recapitulate the structure of a non-neoplastic lymph node. 2. Which are the three key histological characteristics of a neoplastic LN? 3. When would you try to obtain a cytological sample instead of a histological sample?

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Immunophenotype – Immunohistochemistry and flow cytometry Immunohistochemistry (IHC) represents the most important method for immunophenotyping lymphocytes on fixed paraffin-embedded (FPE) material. It allows the visualization of an antigen (Ag) by means of primary monoclonal or polyclonal antibodies (Ab) and a detection system. Monoclonal primary Ab specific for the same Ag are assigned cluster of differentiation (CD) numbers at International Leukocyte Typing Workshops. Plasma cell myeloma CD38+

Lymphoma Mature B-cell lymphomas CLL/SLL Mantle cell lymphoma Follicular lymphoma Burkitt lymphoma Mature T- and NK-cell lymphomas Peripheral T-cell lymphoma Anaplastic large cell lymphoma Angioimmunoblastic T-cell lymphoma Extranodal NK/T-cell lymphoma, nasal type Hodgkin lymphomas (HL) Classical HL Nodular lymphocytic predominant HL

Characteristic antigen CD20, CD79a, CD5, CD23 CD20, CD79a, CD5, CyclinD1 CD20, CD79a, Bcl2, CD10, Bcl6 CD20, CD79a, CD10, Bcl6 CD2, CD3, CD4>CD8 CD2, CD30, ALK, CD4>CD8, EMA CD2, CD3, CD5, CD4>CD8 CD2, CD56 CD15, CD30 CD20 (weak), CD79a (weak), CD45

IHC staining requires a careful correlation with the morphological findings to define lineage and immunophenotype of the neoplastic cells. Staining for immunoglobulin (Ig) light chain κ and λ is useful in B-cell lymphomas (BCL) to assess clonality (light chain restriction). In T-cell lymphomas (TCL), staining for CD4 and CD8 is relevant. In addition, the aberrant or lost expression of a specific Ag may be suggestive for lymphoma (such as aberrant CD5 expression in CLL or loss of CD7 in TCL).

Kappa

In this quadrant each dot represents a single cell expressing both CD20 and CD10

Lambda

Flow cytometry represents an alternative technique to IHC for immunophenotyping lymphocytes. Importantly, it requires fresh tissue to produce cell suspensions. Cells are incubated with multiple fluorochrome-labeled Ab and passed through a laser light beam in the fluorescence-activated cell sorting (FACS) machine. When the light beam hits the fluorochrome it produces a photon which, detected by a sensor, results in a “dot” representing each individual cell on the scattergram.

These cells are CD10 and CD20 neg

Follicular lymphoma: co-expression of CD10 and CD20

REVISION QUESTIONS 1. Why is IHC very useful in the diagnostic procedures for lymphomas? 2. Which are the most important lineage-specific markers? 3. What are the advantages of flow cytometry over IHC?

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Molecular diagnostics â&#x20AC;&#x201C; Cytogenetics and FISH (fluorescence in situ hybridization) Conventional cytogenetics requires dividing cells. In contrast, FISH is a commonly used alternative molecular method applicable on fresh and FPE tissue.

Genetic abnormality

Oncogene

Lymphoma

t(8;14)(q24;q32)

MYC

BL, DLBCL

t(8;22)(q24;q11)

MYC

BL, DLBCL

Fluorophore-labeled DNA probes hybridize to specific DNA sequences. They are used to detect non-random chromosomal translocations in lymphoma.

t(8;2)(q24;p12)

MYC

BL, DLBCL

t(14;18)(q32;q21)

BCL2

FL, DLBCL

t(11;14)(q13;q32)

CCND1 (Cyclin D1)

MCL

t(11;18)(q21;q21)

API2-MALT fusion gene

MALT lymphoma

Translocation results either in the juxtaposition of a gene with a regulatory region (e.g. Ig) or in the fusion of two genes encoding a chimeric protein.

t(14;18)(q32;q21)

MALT1

MALT lymphoma

t(3;14)(p14.1;q32)

FOXP1

MALT lymphoma

t(1;14)(p22.1;q32)

BCL10

MALT lymphoma

t(2;5)(p23;q35)

NPM-ALK fusion gene

ALCL ALK+

t(1;2)(q25;p23)

TPM3-ALK fusion gene

ALCL ALK+

In lymphomas, two FISH strategies are commonly used: break-apart (or split-signal) and dual-color dual-fusion strategy. FISH with break-apart strategy is used to detect rearrangements in the investigated gene, without knowing the partner involved in the translocation. In case of gene rearrangement, 1 red and 1 green signal indicate translocation and juxtaposed probes represent the normal chromosome.

FISH with dual-color dual-fusion strategy is used to detect the presence of a reciprocal translocation between the investigated gene and a known partner. In case of translocation, both gene sequences are rearranged: 2 juxtaposed probes (translocation), 1 red and 1 green signal (normal chromosomes) are visualized. FISH on interphase nuclei requires tailored handling procedures and interpretation of FISH results should be performed by trained personnel.

REVISION QUESTIONS 1. What is the advantage of FISH over conventional cytogenetics? 2. Which are the two most important FISH strategies in lymphomas? 3. Using the break-apart method, what information do you obtain by detecting a separation of the two probes?

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Molecular diagnostics – in situ hybridization, polymerase chain reaction (PCR), others Hodgkin lymphoma

In situ hybridization (ISH) uses labeled probes (complementary DNA or RNA strands) to localize specific DNA or RNA sequences in tissue specimens. In situ studies for Ig light chain κ and λ are useful in the diagnosis of BCL, when IHC gives high background or light-chain proteins are not expressed. Epstein-Barr early RNA (EBER) in situ is the most sensitive method to detect an EBV infection (e.g. in Hodgkin and angioimmunoblastic T-cell lymphoma).

EBER

Reactive lymph node

Malignant lymphoma

EBV-LMP by IHC

PCR is a very sensitive method to detect clonality on fresh or FPE material. It can also be used to detect specific chromosomal translocations. PCR enables detection of rearrangements in the Ig gene in BCL and of the T-cell receptor (TCR) gene in TCL, therefore suggesting clonality.

Normal B cell populations will have a broad variety (several peaks in the diagram) of IGH rearranged DNA fragment sizes

B lymphoid neoplasia will have a predominant rearranged IGH segment (one peak)

Clonality should be assessed only if specimens are highly suspicious for lymphoma. As results can be misleading, priority must be given to morphology/IHC.

Columns represent patients

Rows represent gene

DNA microarrays are collections of DNA spots (gene chips) used to measure simultaneously the expression of a large number of genes. Gene expression profiling studies can be of prognostic value and have led to the discovery of new entities (class discovery). DNA microarrays and other high throughput technologies are not currently used on a routine basis, but may improve our knowledge of lymphomas.

Overexpressed genes are highlighted in red Underexpressed genes are highlighted in blue

REVISION QUESTIONS 1. What are the main applications of ISH? 2. When are clonality studies by PCR indicated? 3. How should one interpret a result of clonality for Ig or TCR obtained by PCR?

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Summary • Lymphoma diagnosis requires microscopic examination of biological material • The sample of choice should be a tissue sample for histology • In special cases (when it is difficult to obtain a biopsy) cytological samples can be an option • When specimens are suspicious for lymphoma, ancillary studies are required • Immunophenotypic characterization of the specimen (immunohistochemistry, FACS) is necessary for a correct diagnosis • Immunohistochemistry is performed on cytological and histological fixed material • Flow cytometry is a very useful technique in the diagnosis of lymphoma, but requires fresh material • FISH represents the most widely used cytogenetic technique for lymphoma diagnosis • FISH allows visualization of chromosomal translocations associated with specific lymphomas • High throughput technologies, although not used in routine diagnosis, allow study of the expression of large numbers of genes and/or proteins

Further Reading Fletcher CDM. Diagnostic Histopathology of Tumors. Third edition. Philadelphia: Elsevier Health Sciences, 2007. Gorczyca W. Cytogenetics, FISH and Molecular Testing in Hematologic Malignancies. Boca Raton, FL: Taylor and Francis, 2008. Ioachim HL, Medeiros LJ. Ioachim’s Lymph Node Pathology. Fourth edition. Philadelphia: Lippincott Williams & Wilkins, 2008. Jaffe ES, Harris NL, Vardiman J, Campo E, Arber DM. Hematopathology E-Book. Philadelphia: Elsevier Health Sciences, 2011. Koss LG, Melamed MR. Koss’ Diagnostic Cytology and Its Histopathologic Basis. Philadelphia: Lippincott Williams & Wilkins, 2006. Kumar V, Abbas AK, Aster J. Robbins and Cotran Pathologic Basis of Disease. Eighth edition. Philadelphia: Elsevier, 2009. Radbruch A. (Ed). Flow Cytometry and Cell Sorting. Berlin: Springer, 2000. Rosai J. Rosai and Ackerman’s Surgical Pathology. Tenth edition. E-Book. Philadelphia: Elsevier Health Sciences, 2011. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: International Agency for Research on Cancer, 2008. Tubbs RR, Stoler MH. Cell and Tissue Based Molecular Pathology E-Book. Philadelphia: Elsevier Health Sciences, 2009.

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The who lymphoma classification

Basic principles The lymphoma classification accepted as the reference is the WHO 2008. It builds a common language and conceptual framework for professionals involved in the field. This classification recognizes non-overlapping entities with well-defined pathological and clinical features. It is therefore biologically sound and clinically useful. Each entity has its specific clinical evolution: some diseases are incurable but evolving slowly (as FL) while others are clinically aggressive but curable (as DLBCL).

Lymphomas as malignant counterparts of specific stages of lymphocyte maturation

The WHO Lymphoma Classification Malignant Lymphomas as Disease Entities â&#x20AC;˘ Non-overlapping (mutually exclusive) â&#x20AC;˘ Stratified according to cell lineage Epidemiology Etiology Pathogenesis Clinical presentation Evolution Prognostic parameters Therapy

Morphology Phenotype Genetic Molecular

The WHO classification integrates all these features and allows further characterization of each entity

Lymphoma entities are considered to be the malignant counterpart of a specific stage of lymphocyte differentiation. The postulated normal counterpart of MCL, as an example, is usually a peripheral B cell of the mantle zone, mostly of naive pregerminal center type. A basic concept of the WHO 2008 classification is the distinction of neoplasms derived from precursor cells (blasts) from neoplasms derived from mature cells.

Specific genetic abnormalities are included as defining features in some entities, e.g. t(11;14) in MCL, ALK rearrangements in ALCL, ALK+, and are very common in others, e.g. t(14;18) in FL.

The role of t(14;18) in follicular lymphoma Germinal center B cell Follicular lymphoma

In FL, the t(14;18) translocation (BCL2/IGH) causes the permanent activation of the bcl-2 protein and, thus, inhibition of apoptosis. The bcl-2 protein blocks the intrinsic (mitochondrial) apoptosis pathway by inhibiting the activation of pro-apoptotic proteins (caspases).

Germinal center B cells switch off expression of bcl-2 permitting apoptosis of those B cells expressing low affinity antibodies

bcl-2 overexpression: apoptosis is inhibited so the cell can survive external aggression

REVISION QUESTIONS 1. What are the basic principles of the WHO classification for lymphoid neoplasms? 2. Which lymphomas are presumed to derive from a germinal center B cell? 3. Explain the role of the BCL2 rearrangement in follicular lymphoma.

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Cytological and histological diagnostic criteria Cytological features are a mainstay in classification. An important tumor cell characteristic is the cell size: DLBCL is composed of sheets of large B cells.

Cytology

Examples of small B-cell lymphomas include CLL/ SLL, MCL, FL, and marginal zone lymphoma (MZL). T-cell lymphomas are characterized by a heterogeneous population of small, medium-sized, and large neoplastic T cells.

Nodular

Pseudonodular

CLL/SLL

DLBCL

Small cell

Large cell

The histological architecture of the tumor is also an important feature for the diagnosis. For example, FL shows most frequently a nodular growth pattern. Another morphological clue for the diagnosis is the relationship of the tumor cells to the normal tissues, such as lymphoepithelial lesions in MALT lymphoma.

DLBCL

Burkitt Lymphoma

Diffuse

Starry sky

Distinct bone marrow (BM) infiltration patterns are commonly associated with certain lymphomas: paratrabecular B cells suggest infiltration by FL.

The importance of the microenvironment in the pathogenesis and evolution of lymphomas is being increasingly recognized. In HL, the malignant cells (Reed-Sternberg cells) are surrounded by a background of T cells, eosinophils, neutrophils, and histiocytes. HL is associated with over-production of cytokines and chemokines, resulting in the abundant microenvironment of non-neoplastic inflammatory cells and fibrosis.

Nodular Sclerosis Classical Hodgkin Lymphoma

REVISION QUESTIONS 1. How does cytology help in distinguishing different lymphoma entities? 2. Which are the main growth patterns of lymphoid neoplasms? 3. Does the non-neoplastic microenvironment play a role in lymphoma pathogenesis?

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Immunophenotypic criteria for diagnosis The stage of differentiation of lymphocytes may be recognized by their different pattern of surface antigen expression (immunophenotype).

Bone marrow Pre-BCR

Pro-B

Mature na誰ve B

Germinal center

Memory B (marginal zone)

Plasma cell

CD10

PAX5 CD20 bcl-6 IRF4/MUM1

BCR, B-cell receptor SHM, somatic hypermutation Tdt, terminal deoxynucleotidyl transferase , IGH@ rearrangement , IGL rearrangement , Rearranged IGH@ and IGL

T reg

Th1

CD2/CD5 CD3 surface CD4 CD8

Tdt, terminal deoxynucleotidyl transferase , Germline T-cell receptor (TCR) genes , Rearranged TCR

Immature B

CD79a

CD10

CD1a

Cytoplasmic and secreted immunoglobulins

CD10 CD19

TdT

CD4/CD8

TdT

CD34

CD3 cytoplasmic

Pre-B

bcl-6

FOXP3

CD57

CD25

PD1

Aberrant or loss of expression of CD markers is an immunophenotypic feature suggesting the diagnosis of lymphoid neoplasms.

Th2

CD138

TdT, CD10, and CD34 are expressed by B- and T-cell lymphoblasts and thus may be useful in recognizing lymphoblastic neoplasias.

Peripheral lymphoid tissues

CD10 CD7

SHM and class switch

CD34

CD10 and bcl-6 are expressed by centrocytes and centroblasts and are positive in germinal center-derived lymphomas, such as FL.

Pro- Subcapsular Cortical Cortical Medullary Peripheral Follicular thymocyte thymocyte thymocyte thymocyte thymocyte T cell T helper

CD79a and PAX5 are B-cell markers expressed at the early stage of heavy chain gene rearrangements. CD20 appears later with the light chain rearrangement.

Thymus

Peripheral lymphoid tissues BCR M

Th7

Follicular T-helper cells express CD10, bcl-6, CD57, and PD1. Angioimmunoblastic T-cell lymphoma arises from follicular T-helper cells. CD3, CD2, CD5, and CD7 recognize virtually all mature T cells and are useful in the diagnostic work-up of T-cell lymphomas.

Loss of T-cell markers: T-cell lymphoma

Peripheral T-cell lymphomas usually have an aberrant T-cell phenotype such as loss of T-cell markers, double expression of CD4/CD8, or double negative T cells. Several B-cell lymphomas such as MCL and CLL/SLL show aberrant expression of CD5, a T-cell marker.

Peripheral T-cell lymphoma

CD7 is the most frequent T-cell marker lost in T-cell lymphomas

REVISION QUESTIONS 1. List three typical markers of B cells. 2. Name two B-cell lymphomas that typically express the T-cell marker CD5. 3. Do normal T cells express both CD4 and CD8 at the same time?

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Genetic criteria for diagnosis Genetic criteria are part of the WHO 2008 classification. Furthermore, some entities are defined by a specific genetic abnormality. In contrast, some genetic abnormalities, while characteristic of one entity, are not specific (such as MYC, CCND1, or BCL2 rearrangements).

Mantle cell lymphoma

Genetic analysis allows the identification of a subset of B-cell lymphomas with concomitant MYC and BCL2 rearrangement and a very poor prognosis.

Some genetic aberrations may be recognized by immunohistochemistry (IHC)

Cyclin D1

FISH (fluorescence in situ hybridization) studies are important for the identification of these specific gene rearrangements. MYC rearrangement, t(8;14), demonstrated by FISH in the neoplastic cells. The tumor cells also had the t(14;18) and BCL2 rearrangement (double hit)

Currently, FISH studies may help in the diagnosis of FL (BCL2), MCL (CCND1), MALT lymphomas (MALT1), BL (MYC), and DLBCL (BCL2, MYC, and BCL6). B- and T-cell clonality can be determined by PCR (polymerase chain reaction) in fresh or paraffinembedded tissues.

B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma

A monoclonal rearrangement of the Ig heavy chain or Tcell receptor genes proves clonality. This is shown by a single peak in the PCR analysis.

B- and T-cell clonality FR3-IGH

These studies may be helpful in the differential diagnosis between some lymphomas and reactive processes. The study of phenotypic and genetic features to define entities led to the identification of intracellular signaling pathways that may be targets for therapy.

FR1-IGH

DLBCL TCR-GAMMA POLYCLONAL

REVISION QUESTIONS 1. Why are genetic features included in the WHO 2008 classification? 2. What does â&#x20AC;&#x153;double hit lymphomaâ&#x20AC;? mean? 3. In which cases is B- and T-cell clonality determination helpful for diagnosis?

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Emerging concepts and provisional entities Limited clonal lymphoid expansions with certain morphological, phenotypic, and molecular features of overt lymphoma are increasingly recognized. These lesions have very limited potential for histological or clinical progression and should therefore not be considered nor treated as lymphoma.

bcl-2 is strongly positive in the neoplastic cells that are confined to the germinal center

Monoclonal B-cell lymphocytosis (MBL), “in situ” follicular lymphoma-like, and “in situ” MCL-like lesions are examples of these early lymphoid lesions.

“in situ” Follicular Lymphoma

Clinical aspects such as age are also becoming a defining feature of some entities, i.e. EBV+ DLBCL of the elderly or pediatric-type follicular lymphoma. Specific immunodeficiency-associated lymphoproliferative disorders are also distinguished, as in HIV+ or organ-transplanted patients. The WHO recognizes the relevance of the anatomical site (such as CNS, skin, spleen, bone) in the identification of specific lymphoma entities. Primary DLBCL of the CNS

Two borderline categories have been created for cases with features intermediate between DLBCL and HL or between DLBCL and BL.

CD30

Borderline categories allow welldefined entities to be kept pure and borderline cases to be studied separately. In WHO 2008 provisional entities are categories for which there is insufficient evidence to define a distinct disease and need more studies to be validated.

Sheet-like growth of pleomorphic cells in a fibrotic stroma. Tumor cells express Hodgkin markers and B-cell transcription factors

CD20

CD15

OCT-2

PAX-5

REVISION QUESTIONS 1. What is the clinical and biological significance of early lymphoid lesions? 2. Which are the main emerging concepts included in the WHO 2008 classification? 3. Why are borderline categories included in the WHO 2008 classification?

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Summary: The who lymphoma classification • Lymphomas are non-overlapping diseases stratified according to cell lineage • Lymphoma entities are considered to be the malignant counterpart of a specific stage of lymphocyte differentiation • Cytology, growth pattern, and microenvironment are important morphological features for the diagnosis of lymphoid neoplasms • Lymphocytes may be recognized by their different immunophenotype • Aberrant or loss of expression of lymphoid markers are features suggesting the diagnosis of lymphoid neoplasms • The inclusion of phenotypic and genetic features in the diagnosis of lymphoid neoplasms has led to the identification of pathways that may be targets for therapy • Early lymphoid lesions are clonal lymphoid expansions with limited potential for progression • Age, site, and other clinical features are defining concepts of some entities • Borderline categories include cases with intermediate features between two entities • Provisional entities include cases with distinct features but which are not yet fully validated

Further Reading Calvo KR, Traverse-Glehen A, Pittaluga S, et al. Molecular profiling provides evidence of primary mediastinal large B-cell lymphoma as a distinct entity related to classic Hodgkin lymphoma: implications for mediastinal gray zone lymphomas as an intermediate form of B-cell lymphoma. Adv Anat Pathol 2004; 11:227–238. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 2011; 117:5019–5032. Carbone A, Gloghini A, Aiello A, Testi A, Cabras A. B-cell lymphomas with features intermediate between distinct pathologic entities. From pathogenesis to pathology. Hum Pathol 2010; 41:621–631. Carvajal-Cuenca A, Sua LF, Silva NM, et al. In situ mantle cell lymphoma: clinical implications of an incidental finding with indolent clinical behavior. Haematologica 2012; 97:270–278. de Leval L, Hasserjian RP. Diffuse large B-cell lymphomas and Burkitt lymphoma. Hematol Oncol Clin North Am 2009; 23:791–827. Jegalian AG, Eberle FC, Pack SD, et al. Follicular lymphoma in situ: clinical implications and comparisons with partial involvement by follicular lymphoma. Blood 2011; 118:2976–2984. Kluin P, Schuuring E. Molecular cytogenetics of lymphoma: where do we stand in 2010? Histopathology 2011; 58:128–144. Küppers R. The biology of Hodgkin’s lymphoma. Nat Rev Cancer 2009; 9:15–27. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: International Agency for Research on Cancer, 2008. Vose J, Armitage J, Weisenburger D; International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2008; 26:4124–4130.

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Staging and response assessment in lymphoma patients

Clinical and biological evaluation Diagnosis (histology), extension of the disease (staging), prognostic factors, and patient’s comorbidities need to be known to plan the management. The patient evaluation includes history, clinical examination, blood tests, imaging techniques, BM examination, and other histologyspecific tests. Detailed history must question for B-symptoms: fever (> 38° C), night sweats, and weight loss (>10% body weight). These occur in ~25% of patients.

Other non-specific symptoms include poor performance status (PS), pruritus, fatigue. Rarely, alcohol intake causes pain in involved LN in patients with HL. Physical examination must pay special attention to all superficial LN, Waldeyer ring, size of the liver and spleen, testes, and skin. Laboratory tests must include blood count, chemistry, electrophoresis, erythrocyte sedimentation rate (ESR), uric acid, LDH, b2-microglobulin, and albumin.

Infections to be searched by serology: HIV, HBV, HCV. In fertile age, women must be tested for pregnancy and men must be offered semen cryopreservation. Blood film and immunophenotyping may suggest the diagnosis (e.g. eosinophilia in HL, lymphocytosis in MCL, cleaved cells in FL, and blasts in DLBCL).

This is a cleaved cell

BM biopsy and immunophenotyping is mandatory to detect BM invasion. A diagnostic lumbar puncture should be done in BL, LL, and in high-risk DLBCL.

REVISION QUESTIONS 1. Which are the systemic symptoms defined as “B”? 2. Why is a BM trephine biopsy performed for staging purposes? 3. In which lymphomas is a diagnostic lumbar puncture recommended?

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Imaging and stage CT scan of the neck, chest, and abdomen is done to detect occult nodal and extranodal disease. Cranial MRI is required for patients with CNS lymphoma.

Maximum diameter of mediastinum

On CT, LN with ∅ >1 cm and filling defects in spleen/ liver are considered lymphoma involvement. Bulk is a nodal mass with ∅ ≥10 cm or >1/3 of chest ∅. Maximum diameter of chest

PET/CT is the most important recent advance in non-invasive staging, with high sensitivity and specificity in detecting nodal and extranodal sites not seen by CT.

PET should be part of the routine staging for HL and DLBCL, while its role in staging other lymphoma entities must still be established. Endoscopy and endoscopic ultrasound are suggested for MALT or other GI-involving lymphomas (such as MCL or PTCL), as GI tract is poorly visualized by radiology. The Ann Arbor classification was originally developed for HL, but is still used for staging NHL, although it is not very helpful for primary extranodal lymphomas.

It is based on the number of LN stations involved, their position in respect to the diaphragm, involvement of extralymphatic tissues, and presence of B-symptoms. The more recent Cotswolds modification integrates the use of CT in staging, improves the definition of bulk, extranodal disease, and treatment response. Suffixes: absence/presence of B-symptoms (A/B), involvement of spleen (S), extranodal site by continuity/lymphatic spread (E), bulky disease (X).

One lymph node station

Extranodal tissue involved

stage I More than one station on one side of diaphragm

stage II

stage III

stage IV

Lymph nodes on both sides of diaphragm

REVISION QUESTIONS 1. What is the definition of “bulk”? 2. Is the Ann Arbor classification useful for all types of lymphoma? 3. What is the meaning of the suffix “E” in the Ann Arbor classification?

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PET and its role in staging & treatment response assessment FDG-PET is a new and very helpful imaging technique capable of distinguishing persistent fibronecrotic scar tissue from potentially viable tumor. The best evaluation is obtained when PET images are acquired with an incorporated CT (PET/CT). PET/CT is used for staging and restaging at the end of treatment. The limit of resolution of current PET systems to detect tumors generally ranges between 0.5 and 1 cm, which translates into an estimated 108 to 109 cells.

PET images are usually interpreted by visual assessment, defining as positive a focal or diffuse FDG uptake which is higher than the surrounding background. SUV (standardized uptake volume) is a quantitative measurement of the relative FDG concentration by the tumor that may complement visual criteria. As PET detects more nodal and extranodal areas than CT, 10-25% of patients are upstaged by PET, sometimes resulting in a change in management. Image fusion readily localized tumor in the spleen (yellow arrow) in this patient with NHL (green arrowheads indicate normal physiological activity in the bowel and kidney).

Quantitative PET could also have a prognostic role: in studies on FL and MCL, SUVMAX at baseline is an independent prognostic factor for PFS. The International Harmonization Project (IHP 2007) added PET to the imaging techniques required for response assessment in HL and DLBCL. In other NHL the role of PET is still debated due to the variable FDG uptake: HL and aggressive lymphomas are most avid, indolent lymphomas are less FDG-avid.

REVISION QUESTIONS 1. Why is PET/CT so efficient in tumor staging as compared to CT? 2. What kind of quantitative measurement is used to interpret PET? 3. Which are the more FDG-avid NHL subtypes?

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End of treatment (EOT) response assessment The International Workshop Consensus (IWC, 1999) recommended to assess response to treatment by repeating CT and all abnormal investigations at baseline.

PET 0

CR is defined by the disappearance of all known sites involved at baseline. LN Ă&#x2DC; must be decreased to <1.5 cm.

PET 2

Enlarged spleen and liver should return to normal size and lymphoma-related nodules should disappear. BM must show no infiltration if involved at baseline.

PET end therapy

CRu (CR unconfirmed) referred to residual tissue (>75% size reduction) of undetermined significance. This category disappeared with the advent of PET (IHP 2007).

Residual mass de Wilt et al. Filmont et al. Foo et al. Jerusalem et al. Keresztes et al. Mikhaeel et al. Rigacci et al. Spaepen et al. Weihrauch et al.

0.0

0.2

0.4 0.6 Sensitivity

0.8

1.0

EOT PET has a high negative predictive value and lower positive predictive value, possibly due to inflammatory reactions causing false-positive images.

In HL, a high proportion of patients with a PET-neg residual mass after chemotherapy remain free of disease (high negative predictive value).

0.0

0.2

0.4 0.6 Specificity

0.8

1.0

A positive EOT PET in a single residual mass has a sensitivity of 43-100% in HL and 37-87% in DLBCL, while the specificity is 67-100% and 75-100%, respectively.

PFS according to PET and CT

Sensitivity and specificity of EOT PET in predicting disease relapse in DLBCL were 33-77% and 82-100%, respectively. A recent trial suggests that EOT PET in FL is the most potent predictor of remission duration after standard R-CHOP treatment. This result needs to be confirmed.

REVISION QUESTIONS 1. What is the definition of complete response according to IWC criteria? 2. What is the difference between IWC and IHP criteria for response assessment? 3. What is the role of end of treatment PET in follicular lymphoma?

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Interim PET and follow-up examinations Interim PET during treatment (after 2-3 cycles) is considered a surrogate test for chemosensitivity in lymphoma to predict final treatment outcome. In a study of advanced-stage HL, interim PET after 2 courses of ABVD was the most important independent prognostic factor for PFS. The 5-point scale (Deauville’s criteria) is a standardized method for interim PET reporting, comparing residual FDG uptake to the mediastinum or liver background.

Five-point scale 1. No uptake 2. Uptake ≤ mediastinum 3. Uptake > mediastinum but ≤ liver 4. Uptake moderately increased above liver at any site 5. Markedly increased uptake at any site including new sites of disease

In aggressive B-cell lymphoma, interim PET after 2 cycles has a lower specificity, although this can be improved by quantitative evaluation by ΔSUVMAX. A positive PET following salvage therapy prior to ASCT is associated with a poor outcome in HL and NHL. The possibility of tailoring the intensity of treatment based on interim PET response is being evaluated in several prospective trials in HL and DLBCL.

After achieving remission, patients should undergo followup with regular history, physical examination, blood counts, and biochemistry analysis. There is no evidence to support regular surveillance by CT or other imaging techniques, as relapses are identified by patients or physicians in >80% of cases. Follow-up with surveillance PET can detect relapses a few months earlier, but this does not impact on the clinical management or on patients’ survival.

REVISION QUESTIONS 1. Is there a prognostic role for interim PET in lymphoma? 2. Is the value of an interim PET the same for all lymphomas? 3. Is there any role for surveillance PET during follow-up in asymptomatic HL or DLBCL patients in CR?

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Summary: Staging and response assessment in lymphoma patients • Ann Arbor is the staging system currently used in HL and NHL • B-symptoms in lymphoma are: fever (>38°C), night sweats, and weight loss (>10%) • Imaging techniques required for staging: standard is CT, the role of PET is controversial • If interim or end of treatment PET is to be performed, a baseline PET is essential to facilitate interpretation • SUV is a quantitative measurement of the relative FDG concentration by tumor • Additional investigations are required for specific cases, e.g. lumbar puncture in BL, LL, and high-risk DLBCL • The IWC is the current criterion to evaluate response after treatment • CR is defined as the disappearance of all disease sites involved at baseline. LN Ø should decrease to <1.5 cm • In advanced-stage HL, interim PET scan after 2 courses of ABVD is the most important prognostic factor in predicting treatment outcome • Follow-up with surveillance imaging does not result in a better outcome

Further Reading Armitage JO, Loberiza FR. Is there a place for routine imaging for patients in complete remission from aggressive lymphoma? Ann Oncol 2006; 17: 883–884. Casasnovas RO, Meignan M, Berriolo-Riedinger A, et al. SUVmax reduction improves early prognosis value of interim positron emission tomography scans in diffuse large B-cell lymphoma. Blood 2011; 118:37–43. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999; 17:1244. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007; 25:579–586. Connors JM. Positron emission tomography in the management of Hodgkin lymphoma. Hematology: American Society of Hematology Education Program 2011; 2011:317–322. Gallamini A, Hutchings M. Hodgkin Lymphoma: A Comprehensive Update on Diagnostic and Clinics. Part II: Functional Imaging. Engert A & Horning SJ (Eds). Berlin, Heidelberg: Springer Verlag, 2011. Gallamini A, Hutchings M, Rigacci L, et al. Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin’s lymphoma: a report from a Joint Italian-Danish study. J Clin Oncol 2007; 25:3746–3752. Hoffman R, Benz EJ, Shattil SS, et al. Hematology: Basic Principles and Practice. Fifth edition. Philadelphia: Churchill Livingstone, 2009. Kwee TC, Kwee RM, Nievelstein RA. Imaging in staging of malignant lymphoma: a systematic review. Blood 2008; 111:504–516. Seam P, Juweid ME, Cheson BD. The role of FDG-PET scans in patients with lymphoma. Blood 2007; 110:3507–3516. Terasawa T, Nihashi T, Hotta T, Nagai H. 18F-FDG PET for posttherapy assessment of Hodgkin’s disease and aggressive non-Hodgkin’s lymphoma: a systematic review. J Nucl Med 2008; 49:13–21.

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Common treatments for lymphoma

Cytotoxic agents Lymphomas are treated with corticosteroids, chemotherapy, monoclonal antibodies, and radiotherapy, used either as single agents or in combination. Corticosteroids are very frequently used to treat lymphoma: they are lympholytic and also have an antiemetic effect. Alkylating agents were the first agents to show activity against lymphomas. As monotherapy they are very well tolerated but cumulative doses are leukemogenic.

Major chronic or late toxicities of chemotherapeutic agents Drug or drug class

Specific toxicity

Corticosteroids Alkylating agents

Anthracyclines

Osteonecrosis, osteoporosis Bone marrow failure Male oligospermic infertility Female anovulatory infertility Acute leukemia, myelodysplasia Cardiomyopathy

Bleomycin

Pulmonary fibrosis

Vinca alkaloids Platin derivatives

Peripheral neuropathy Renal failure Peripheral neuropathy Bone marrow failure Acute leukemia, myelodysplasia Acute leukemia, myelodysplasia

Purine analogs Etoposide

Alkylating drugs can be given as single agents (frequently orally) or in combination Alkylating agents used in patients with lymphoma Bendamustine

Carmustine (BCNU)

Chlorambucil

Lomustine (CCNU)

Cyclophosphamide

Dacarbazine (DTIC)

Melphalan

Temozolomide

Busulfan

Procarbazine

Ifosfamide

Thiotepa

Doxorubicin revolutionized lymphoma treatment: DLBCL became curable with CHOP and HL with ABVD, with lower risk of secondary leukemia compared to previous regimens. Other drugs are added to the alkylatinganthracycline backbone, the choice of agents depending on single-agent antilymphoma activity and non-cross-toxicities. Purine analogs (fludarabine, cladribine, and pentostatin) are very active in indolent but not in aggressive lymphomas. They can impair stem cell collection.

Some lymphomas tend to relapse in the CNS (brain parenchyma or CSF), but the majority of cytotoxic drugs do not pass the blood-brain barrier (BBB). To circumvent this problem cytotoxic drugs such as steroids, MTX, or Ara-C can be administered by direct intrathecal injection (i.t.) through a lumbar puncture. The other possibility is to administer systemically at high doses (HD) drugs which partly pass the BBB, such as steroids, MTX, Ara-C, etoposide, or thiotepa.

REVISION QUESTIONS 1. Which is the drug that made aggressive lymphomas curable? 2. What is the most specific toxicity for bleomycin? 3. How can chemotherapy drugs reach therapeutic concentrations in the CNS?

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Monoclonal antibodies (MoAb) Chimeric MoAb present a variable Fab segment of murine origin, recognizing specific targets on the surface of lymphocytes, such as CD20, CD22, CD19, or CD52.

Chimeric: rituXImab

Murine: tositumOmab (B1) ibritumOmab tiuxetan

The Fc segment in contrast is human and therefore not immunogenic. It is recognized by the patientsâ&#x20AC;&#x2122; effector cells, eliciting an immune response against the tumor. MoAb can be exploited for their direct effect on the tumor cells (unconjugated = cold = naked Ab), or as a vector for toxins (immunotoxins) or radioisotopes (radioimmunotherapy - RIT).

Humanized: veltuZUmab (2nd generation) obinutuZUmab: GA101 (3rd generation)

Human: ofatumUmab (2nd generation)

The most frequently used MoAb for the treatment of lymphoma is rituximab, binding to CD20 on B cells. It works through several mechanisms of action. The activity of rituximab varies in different B-cell lymphomas. It can be given as a single agent, in combination with chemotherapy, or as maintenance. As it effectively eliminates tumor but also normal B cells, its major side effect is the increased risk of infections, such as reactivation of HBV or JCV.

Brentuximab vedotin (SGN-35) Other anti-CD20 antibodies can be effective, such as ofatumumab and obinutuzumab. MoAb against other Ag such as CD80 (galiximab) also show antilymphoma activity. Alemtuzumab is an anti-CD52 MoAb that eliminates both normal and malignant tumor B and T cells. It is used mostly in CLL, but it is very immunosuppressive. Brentuximab vedotin and inotuzumab ozogamicin are immunotoxins binding to CD30 and CD22 and therefore active on HL or ALCL and NHL, respectively.

REVISION QUESTIONS 1. In addition to their use as unconjugated MoAb, how can MoAb be exploited for treatment? 2. Why should patients receiving rituximab be screened for HBV infection? 3. What is an immunotoxin?

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Radiotherapy (RT) and radioimmunotherapy (RIT) The dramatic effect of ionizing radiation on lymphoma was described shortly after the discovery of X-rays. All types of lymphomas are extremely radiosensitive. At present RT is used mainly to consolidate remissions obtained by chemotherapy (CT), but in special situations it is still used as a single treatment modality. The much feared long-term toxicities of the RT-CT combination, such as secondary cancer or heart and lung toxicity, can be reduced by lowering dose and fields.

1980

1990

2000

2010

Main indications for RT in lymphoma As the only treatment Early stage FL Early stage MZL, particularly when extranodal Skin lymphomas In combination with chemotherapy Hodgkin lymphoma DLBCL, particularly primary mediastinal Primary CNS lymphoma NK/T-cell lymphoma, particularly the nasal type

The combination with CT allowed reduction of both the RT fields and the doses from 45 Gy to 30-20 Gy. Irradiation fields have gradually reduced from the curative, exclusive, total node field to the minimal, consolidative, involved node field.

Total nodal

Regional nodal

Involved field

Involved node

An interesting technique to selectively irradiate multiple tumor sites is the use of radiolabeled antibodies directed to antigens present only on lymphoid cells.

The dose depends on histology (24 Gy for indolent, 30 Gy for aggressive NHL), on risk (20 Gy for low-risk, 30 Gy for high-risk HL), and on strategy (4 Gy for palliation in FL).

Anti-CD20 antibodies Only cells to which an Ab is bound undergo apoptosis

When the Ab binds to the Ag on the cell surface, not only this cell but also the adjacent tumor and some normal adjacent cells are irradiated (cross-fire effect). Radioimmunotherapy (RIT) based on anti-CD20 Ab is commercially available with the radionuclides 90-Yttrium (90Y-labeled ibritumomab tiuxetan, Zevalin®) and 131-Iodine (131I-labeled tositumomab, Bexxar®).

Also cells to which an Ab is not bound undergo apoptosis

Unlabeled “cold” antibody

Radiolabeled “hot” antibody

REVISION QUESTIONS 1. For which lymphomas and at which stage can radiotherapy alone be a treatment option? 2. What is an involved node field? 3. Does radioimmunotherapy completely spare normal tissues?

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Combination (immuno)chemotherapy A combination of several cytotoxic drugs is used mainly for treatments with curative intent or to treat patients in whom a rapid and sustained response is desired.

To cure aggressive NHL, appropriate dose intensity is essential, so that doses and planned schedules should be maintained, if necessary with the use of G-CSF.

How to improve on CHOP Increase the doses Substitute drugs with more potent ones Add further cytotoxic drugs Add antibodies Reduce the intervals between cycles Give drugs in continuous infusion

Finally, the activity of CHOP could be improved by administering some of the drugs as continuous infusion (as in the EPOCH or hyper-CVAD regimens). Some of the more active regimens increase the response rate and the duration of responses but they result in a higher toxicity so they do not improve OS. Fludarabine combinations with cyclophosphamide (FC), mitoxantrone (FCM), dexamethasone (FDM), and rituximab (FCR) are mainly used for indolent NHL.

Dose-dense therapy

Higher-dose therapy

Lower-dose therapy 1012 1010 Cell number

When administering the first cycle to rapidly growing or bulky lymphomas, tumor lysis syndrome should be prevented with hydration and allopurinol or rasburicase.

Effect of chemotherapy dose intensity and density on tumor cell kill and regrowth between cycles

10 8 10 6 10 4 10 2 0

Time (weeks)

CHOP given i.v. every 3 weeks is the most classical regimen for aggressive NHL. By adding rituximab, the regimen (R-CHOP) becomes more active for B-cell NHL. R-MACOP-B, R-CHEOP, or R-ACBVD are examples of more active but also more toxic regimens which were developed by adding further drugs. The intensity can also be enhanced with the aid of G-CSF by administering cycles every 2 weeks (CHOP-14) or increasing the dose of some drugs (Mega-CHOP).

Response rate of 1st line treatment in indolent lymphomas Response

FMR

CHOP-R

Overall

70%

90%

100%

96%

Complete

39%

45%

90%

76%

Partial

31%

45%

10%

20%

REVISION QUESTIONS 1. How can the efficacy of CHOP be increased? 2. Does a more active and more toxic regimen always improve survival? 3. Which are the indications for fludarabine-containing regimens?

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High-dose therapy (HDT) and stem cell transplantation Some lymphoma clones respond to chemotherapy in a dose-dependent way. In these cases the administration of very HD of drugs can be curative.

The autologous transplant process

1. Collection Stem cells are collected from the patient’s bone marrow or blood

5. Reinfusion Thawed stem cells are reinfused into the patient

As some cytotoxic drugs and RT have myelosuppression as the main limiting toxicity, they can be given at very high doses (HDT) provided BM toxicity is rescued. Reinfusion of the patients’ hematopoietic stem cells (autologous stem cell transplantation, ASCT) after the administration of the HDT results in BM rescue.

EFS of patients with HL treated with HDT and ASCT

2. Processing Blood or bone marrow is processed in the laboratory to purify and concentrate the stem cells

3. Cryopreservation Blood or bone marrow is frozen to preserve it

4. Chemotherapy High dose chemotherapy and/or radiation therapy is given to the patient

Stem cells used to be collected directly from the BM. At present, they are usually collected from the PB following mobilization with G-CSF +/- chemotherapy. HDT with ASCT is rarely used as part of the initial treatment in lymphoma, but mostly to consolidate a second or subsequent remission. An essential condition for the success of HDT with ASCT is the chemosensitivity of the lymphoma, demonstrated by a response to salvage therapy.

Patients who are chemoresistant have a much worse prognosis

a Myeloablative allogeneic hematopoietic stem cell transplantation

The effect of allogeneic stem cell transplant is based on a combination of cytotoxic and immune therapy. It requires the availability of an HLA-compatible donor. Conditioning cytotoxic regimens can be myeloablative (↑ toxicity, only for younger patients) or reduced-intensity (RIC), allowing an expansion of the indications.

b Non-myeloablative allogeneic hematopoietic stem cell transplantation

RIC regimens rely on the immune effect of the donor graft mounting an antilymphoma response (graft-versuslymphoma effect) rather than on its cytotoxicity.

REVISION QUESTIONS 1. What are the necessary conditions to proceed to HDT with ASCT? 2. What is the therapeutic effect of HDT with ASCT based on? 3. What is the therapeutic effect of allogeneic stem cell transplant based on?

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Summary: Common treatments for lymphoma • Single-agent chemotherapy can result in palliation, but curative treatment needs the use of multiple agent chemo(immuno)therapy, sometimes with the addition of RT • RT is very active in lymphomas and, as the single modality of treatment, can cure patients • RT fields and doses have been reduced over time to cause less long-term toxicity • Chimeric MoAb can be used unconjugated, as immunotoxins, or as radioimmunotherapy • The anti-CD20 MoAb rituximab greatly improved the prognosis of patients with B-cell lymphomas • The most frequently used chemotherapy regimens are CHOP for NHL and ABVD for HL. Their efficacy can be increased by adding drugs, increasing doses, shortening intervals, or by administration as continuous infusion • Chemotherapy regimens should be given at their original dose and schedule, if necessary with the help of G-CSF • For rapidly growing tumors or bulky disease, prevention of tumor lysis syndrome is mandatory • In some situations, chemotherapy can be given at high, myeloablative doses, with the support of autologous stem cell rescue • Allogeneic transplant can be used in very selected cases to exploit the graft-versus-lymphoma effect

Further Reading Artz AS, Somerfield MR, Feld JJ, et al. American Society of Clinical Oncology Provisional Clinical Opinion: Chronic hepatitis B virus infection screening in patients receiving cytotoxic chemotherapy for treatment of malignant diseases. J Clin Oncol 2010; 28:3199–3202. Brody J, Kohrt H, Marabelle A, Levy R. Active and passive immunotherapy for lymphoma: proving principles and improving results. J Clin Oncol 2011; 29:1864–1875. Goldsmith SJ. Radioimmunotherapy of lymphomas: Bexxar and Zevalin. Sem Nucl Med 2010; 40:122–135. Hodgson DC. Late effects in the era of modern therapy for Hodgkin´s lymphoma. Hematology 2011; 2011:323–329. Pouget JP, Navarro-Teulon I, Bardiès M, et al. Clinical radioimmunotherapy - the role of radiobiology. Nat Rev Clin Oncol 2011; 8:720–734. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 Update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 24:3187–3205. Weiner GJ. Rituximab: mechanism of action. Sem Hematol 2010; 47:115–123. Wilson WH. Principles of treatment. In: Canellos GP, Lister TA, Young BD (Eds). The Lymphomas. Philadelphia: Elsevier Saunders, 2006; 225–238. Yahalom J, Hoppe R, Mauch PT. Principles and techniques of radiation therapy for Hodgkin lymphoma. In Hoppe RT, Mauch PT, Armitage JO, Diehl V, Weiss LM (Eds). Hodgkin Lymphoma. Philadelphia: Lippincott Williams & Wilkins, 2007; 177–188. Younes A. Beyond chemotherapy: new agents for targeted treatment of lymphoma. Nat Rev Clin Oncol 2011; 8:85–96.

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Diffuse large b-cell lymphoma

Pathology and epidemiology DLBCL is characterized by a diffuse proliferation of atypical irregular large cells, with vesicular nuclei, prominent nucleoli, and basophilic cytoplasm. On immunohistochemistry, cells typically express pan–B-cell markers: CD19, CD20, CD22, CD79a. bcl-6 is expressed in 60% of cases. Gene expression profiling can distinguish two groups of DLBCL based on the cell of origin: germinal center B-cell (GCB) and non-GCB, activated B-cell subtype (ABC).

“Hans algorithm” allows GCB and non-GCB subtypes to be distinguished by immunohistochemistry

Germinal center like B-cell lymphoma - GCB (CD10+ or CD10-, bcl-6+, MUM1-) appear to have a better prognosis. Non-germinal center activated peripheral B-cell lymphomas – ABC or non-GCB (CD10-, bcl-6+, MUM1+) have a worse prognosis. Not all studies have confirmed the prognostic significance of the GCB and non-GCB subtypes of DLBCL when identified by IHC. T-cell rich, cutaneous, CNS, and EBV+ of the elderly, are 4 subtypes of DLBCL with peculiar characteristics.

DLBCL represents 1/3 of NHL in western countries, but it is more common in developing countries. The incidence increased during the last 3 decades. The etiology is unknown; the majority of DLBCL have a “de novo” origin, but some derive from the transformation of a pre-existing indolent lymphoma. HIV infection is a risk factor for DLBCL development; in this group of patients, it can be associated with EBV positivity.

REVISION QUESTIONS 1. Why are diffuse large B-cell lymphomas called this way? 2. What are the main DLBCL subtypes as distinguished by cell of origin? 3. Name some risk factors for DLBCL development

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Clinical presentation, staging, and prognosis The presentation is a rapidly growing, non-painful mass in a LN or extranodal organ. B-symptoms may be present. The median age at diagnosis is 60-70 years. A standard lymphoma staging with CT scan should be performed, with addition of PET/CT if possible. BM involvement is present in 11-27% of cases. In 60% of patients the disease presents in advanced stage (III-IV). Extranodal organs are involved in 40% of cases.

Prophylaxis of CNS relapse should be performed in patients with: Involvement of specific extranodal sites

Testis Paranasal sinuses Hard palate

F-18-FDG avidity in DLBCL

Commonly involved extranodal sites are the GI tract (mainly stomach), less frequently bone, breast, testis, CNS, thyroid, liver, and kidney. Additional examinations: endoscopy if GI symptoms are present, testicular ultrasound if testicular node or enlargement, brain MRI if neurological signs.

Orbit Paravertebral masses Bone marrow High-intermediate / High IPI score

CSF examination with cytology and flow cytometry is recommended in patients considered “at risk” for CNS infiltration.

High level of LDH and involvement of more than one extranodal site

International Prognostic Index

The International Prognostic Index (IPI) identifies 4 risk groups based on the presence of: age >60, stage III-IV, PS >1, elevated LDH, extranodal sites >2. The age-adjusted IPI (aaIPI) based on LDH, stage, and PS is used for patients <60 years. A revised IPI (R-IPI) was created for patients treated with rituximab.

Low Low intermediate High intermediate High

No. of risk factors 0, 1 2 3 4, 5

% of pts. 35% 27% 22% 16%

Complete response rate 87% 67% 55% 44%

5-yr survival rate 73% 51% 43% 26%

Other clinical (such as β2-microglobulin) or biological (such as bcl2 and myc rearrangement) prognostic factors have been described, but none is more discriminative than the IPI.

REVISION QUESTIONS 1. Which baseline assessments should be performed as part of the staging in patients with DLBCL? 2. Which are the risk factors for CNS involvement? 3. Which are the risk factors defining the International Prognostic Index?

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Over decades, the backbone for treating DLBCL was chemotherapy using the CHOP regimen. With some modifications, this is basically still true today. The addition of rituximab to CHOP (R-CHOP) resulted in a major improvement in the outcome of DLBCL patients, both in terms of PFS and OS. Further modifications of the CHOP regimen might improve outcome, either as the addition of other cytotoxic drugs or the intensification of the schedule.

R-ACVBP R-CHOP

Progression-free survival (%)

100

Survival Distribution Function

First-line treatment 10-year PFS: R-CHOP-21 37% vs. CHOP-21 20%

1.00 0.75 0.50 0.25 0.00 0

10-year OS: R-CHOP-21 44% vs. CHOP-21 28%

In younger low-risk patients, the addition of etoposide (R-CHOEP) or ifosfamide, MTX, and Ara-C (R-ACVBP) improved PFS and OS in comparison with CHOP. DA-R-EPOCH is an intensified version of R-CHOP, adding etoposide and infusing some drugs over 3 days, with dose increments at each cycle.

HR for progression 0·48 (95% CI 0·30–0·76) p=0·0015

Number at risk R-ACVBP R-CHOP

24 36 48 Months since randomisation

196 183

175 147

153 114

24 13

1 0

107 85

60 55

CHOP given every 14 days (CHOP-14) is superior to every 21 days, but the same does not hold true if rituximab is added (R-CHOP-14 = R-CHOP-21).

The number of cycles to be given (6 or 8) in advanced disease is not clearly defined but, based on observational data, many doctors give 6 cycles. Patients with early-stage DLBCL have the same outcome if treated with 3 cycles of R-CHOP followed by IF-RT or with 6 R-CHOP cycles. The best regimen for early stage depends on the site of disease. Chemotherapy alone is preferred to avoid RT on radiosensitive tissues, such as the ENT area.

REVISION QUESTIONS 1. Is the addition of rituximab to CHOP mandatory in the treatment of DLBCL? 2. Are there any differences in outcome between R-CHOP-14 and R-CHOP-21? 3. What are the treatment options for early stage DLBCL?

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R-CHOP is considered to be the standard treatment for patients who are young (<60) with low-risk IPI (0-2) or elderly, regardless of the IPI. Regimens which are more intensive than R-CHOP obtain better results but are more toxic; they are thus reserved for younger high-risk patients (IPI: 3-5). None of the more intensive rituximab-containing regimens can be recommended over the others, as there are no randomized studies comparing them.

Progression-free survival (%)

First-line treatment 100 90 80 70 60 50 40 30 20 10 0

Chemotherapy and rituximab

Chemotherapy alone

log-rank p<0·0001

413 410

24 36 Time (months) 266 151 205 104

313 253

37 27

0 1

Treatment issues in DLBCL: first line

There is no consensus on if and when further treatment modalities should be added after chemotherapy: CNS prophylaxis, RT, and HDT. Some studies suggest that CNS prophylaxis significantly reduces the incidence of CNS relapse in high-risk patients but other studies do not confirm this. If CNS prophylaxis is to be given, the choices are systemic HD-MTX and/or Ara-C or intrathecal chemotherapy with MTX or liposomal Ara-C.

Many authors consider these options experimental

Consolidation RT to the site of previous bulky disease or on PET+ residual masses remains a subject of debate. Consolidation of high-risk patients with HDT and ASCT improves PFS, but its effect on OS is less clear, even in the rituximab era. The acute toxicity and the potential risk of long-term complications should be taken into account when considering HDT with ASCT as part of 1st line therapy.

Follow-up

PFS HDT

PFS Chemo standard

OS HDT

OS Chemo standard

Vitolo et al. FIL-DLCL04

2 years

.009

n.s.

Stiff et al. SWOG/US

2 years

.005

n.s.

Schmitz et al. DSHNHL

4 years

n.s.

Le Gouill et al. GOELAMS

3 years

n.s.

REVISION QUESTIONS 1. Which is the best first-line treatment for elderly patients and young low-risk patients with DLBCL? 2. Is the standard treatment – R-CHOP-21 – adequate for young patients with poor risk? 3. Should the age at diagnosis influence the choice of treatment?

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Salvage treatment at relapse/progression Relapsed or progressing disease can still be cured with HDT with ASCT, but this option is only appropriate for patients who are young and fit.

HDT with ASCT is the best treatment for relapsed DLBCL in selected patients

HDT with ASCT is curative only in patients with chemosensitive disease, i.e. responding to salvage treatment. These are approximately 50% of cases. There are many possible salvage regimens (such as DHAP, ICE, ESHAP, GPD, IGEV). In general, none has proven to be better than the rest.

There are some suggestions that for the GCB type of DLBCL a salvage regimen containing platinum and Ara-C (DHAP) should be preferred.

Overall Survival (years) Survival Distribution Function

1.00

Prior rituximab: No (n = 41) Censored prior rituximab: No Prior rituximab: Yes (n = 187) Censored prior rituximab: Yes

0.75

Patients who received rituximab in 1st line and relapsing within 1 year have a bad prognosis

0.50

0.25 P = .0010

Adverse prognostic factors for outcome after HDT with ASCT are refractory disease, early relapse, highrisk IPI, PET+ after salvage, and previous rituximab. Patients relapsing after a rituximab-containing 1st line treatment have less chance of being cured with HDT and ASCT, as they respond poorly to salvage therapy.

Event-Free Survival (years)

Patients relapsing after HDT with ASCT or refractory to salvage chemotherapy may be considered for allogeneic transplantation. Patients at relapse not eligible for HDT with ASCT may be treated with combination chemotherapy with palliative intent or on clinical trials with novel drugs. Possible palliative options depend on clinical needs, and include monotherapy such as bendamustine or lenalidomide or different chemotherapy combinations.

Drugs interfering with the BCR pathway have shown efficacy in early clinical trials

REVISION QUESTIONS 1. What is the best treatment for DLBCL at relapse? 2. What are the prognostic factors at relapse? 3. How would you treat a patient at relapse if not eligible for HDT with ASCT?

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Summary: Diffuse large b-cell lymphoma • Histology: diffuse proliferation of large atypical cells • Immunohistochemistry: pan–B-cell markers (CD19, CD20, CD22, CD79a) • DLBCL is subdivided into two types based on the cell of origin: germinal center or activated B cells • International Prognostic Index: age, LDH, stage, performance status, number of extranodal sites • The standard 1st line therapy for most patients is R-CHOP-21 x 6-8 courses • In patients with localized disease, a shorter course of chemotherapy followed by RT might be considered • In younger patients with high-risk disease, more intensive options such as a more intensive chemotherapy or consolidation with HDT with ASCT might be considered • Adverse risk factors at relapse: refractoriness, PET+ before HDT with ASCT, high-risk IPI at relapse, 1st line containing rituximab • At relapse, young and fit patients with chemosensitive disease can be cured with HDT with ASCT • Consider experimental trials with novel drugs for patients not eligible for intensive therapy

Further Reading Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma. N Engl J Med 2002; 346:235–242. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28:4184–4190. Greb A, Bohlius J, Trelle S, et al. High-dose chemotherapy with autologous stem cell support in first-line treatment of aggressive non-Hodgkin lymphoma – results of a comprehensive meta-analysis. Cancer Treat Rev 2007; 33:338–346. Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med 2010; 362:1417–1429. Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 2008; 9:105–116. Pfreundschuh M, Trümper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006; 7:379–391. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 1995; 333:1540–1545. The non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s Lymphoma. Blood 1997; 89:3909–3918. Vitolo U, Chiappella A, Angelucci E, et al. Dose-dense and high-dose chemotherapy plus rituximab with autologous stem cell transplantation for primary treatment of diffuse large B-cell lymphoma with a poor prognosis: a phase II multicenter study. Haematologica 2009; 94:1250–1258. Witzig TE, Vose JM, Zinzani PL, et al. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma. Ann Oncol 2011; 22:1622–1627.

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Follicular lymphoma

Pathology and biology Follicular lymphoma (FL) is composed of germinal center B cells and shows a follicular (nodular) growth pattern recalling the normal follicles. Sometimes, large parts of the involved LN are invaded by cells with a diffuse pattern: in this case the designation is FL follicular and diffuse. On immunohistochemistry, cells typically express B-cell surface antigens such as CD20, follicle center B-cell markers CD10 and bcl-6, while in contrast to normal germinal center cells they express the cytoplasmic bcl-2 protein.

Nodule

FL is composed of variable proportions of small to medium-sized cells with cleaved nucleus (centrocytes) and large cells with round to oval nucleus and several nuclear membrane-bound nucleoli (centroblasts). Centroblast

Centrocyte

The grade is defined by the proportion of centroblasts: grade 1: 0-5 centroblasts per high power field (hpf), grade 2: 6-15 centroblasts per hpf, grade 3: >15 centroblasts per hpf. A grade 3 in which centrocytes are still recognizable is called grade 3a. If there are only sheets of centroblasts, it is called grade 3b.

FL is caused by the translocation t(14;18), bringing the BCL2 gene on Chr18 near to Ig heavy chain gene on Chr14, which acts as promoter: bcl-2 protein overexpression.

Translocation between Chr14 and 18

As the bcl-2 protein has antiapoptotic functions, these cells lose their programmed cell death capacities and become long-lived, accumulating in the organism. The accumulation of lymphocytes enlarges the LN, invades the BM and other organs, while the t(14;18) predisposes to further oncogenic mutations.

18qâ&#x20AC;&#x201C;

bcl-2

H chain enhancer

# 18 The H chain gene

stimulates the overexpression of the bcl-2 protein

antibody H chains

bcl-2 14q+

# 14

REVISION QUESTIONS 1. Why are follicular lymphomas so-called? 2. What is a grade 3a follicular lymphoma? 3. Why have follicular lymphoma cells lost their apoptotic capacity?

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Clinical presentation, prognosis The majority of cases have widespread disease (stage III-IV), with involved LN above and under the diaphragm, and more than 50% have BM involvement. Usually FL evolves slowly, patients can notice their LN growing and spontaneously regressing and they seldom have symptoms or cytopenias.

Risk of Transformation

Standard staging examinations include CT scan and BM examination. The role of PET in FL is still controversial, but can be important in early stages.

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

The median survival was ~10 years in the last decades but recently, thanks to better supportive care and new treatments, it has increased to 12-16 years.

Radiation (n = 90) Chemotherapy (n = 407) Watch and wait (n = 103)

All treatment modalities show the same transformation rate

Most of the patients will eventually die of their disease; thus, the cause-specific survival curve never reaches a plateau. FL is therefore considered incurable. P = 0.3

For the first time an increase in survival could be seen in a population study

Time to Transformation (years)

A frequent cause of death is transformation into a more aggressive lymphoma, mostly DLBCL, an event which occurs initially at a rate of 3%/year (~30% at 10 years).

The prognosis of FL patients can be estimated with the help of a clinical prognostic score, called FLIPI (Follicular Lymphoma International Prognostic Index). FLIPI-2 is a similar prognostic index designed prospectively in the rituximab era for patients in need of treatment. Grade 3, and more particularly 3b, has a worse prognosis than grade 1-2. Specifically, patients with grade 3b FL should be treated as DLBCL.

FLIPI risk factors: Age â&#x2030;Ľ 60 Hemoglobin < 12 g/dL Serum LDH > ULN Ann Arbor stage > II Nodal sites involved > 4

REVISION QUESTIONS 1. Is FL a curable disease? 2. How often do FL transform into high-grade disease? 3. How is it possible to predict the outcome of an FL patient?

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First-line treatment â&#x20AC;&#x201C; single agents

Randomized trials demonstrate that W+W allows chemotherapy to be delayed for years without any survival disadvantage when compared to immediate treatment.

100

Cumulative survival (%)

In the small proportion of patients with localized disease (stage I-II) at diagnosis, involved field RT (24-36 Gy) is considered the standard due to its curative potential.

More intensive treatment obtains a higher response rate, but causes more side effects and does not improve PFS or survival

Overall survival proportion

CHOP-B 0.2 p=0.2 0

Oral Cyclophosphamide 2

8 10 12 Years from entry

Observation (n=151) Chlorambucil (n=158)

12 16 Time (years)

Many single agents are active against FL: lowdose RT, radioimmunotherapy (RIT), chlorambucil, rituximab, fludarabine, and many others.

0.4

0.0

When patients become symptomatic, the choice of treatment varies from single agent to intensive combination chemoimmunotherapy.

1.0

0.6

In asymptomatic patients for whom W+W is not acceptable, monotherapy with rituximab results in a high response rate and does not impair quality of life.

0.8

Delaying treatment until the appearance of symptoms (W+W) does not compromise patient survival

Single agents are less active than combinations but cause less side effects. Survival is not affected by the lower activity, as salvage treatments are very effective.

Single-agent chlorambucil, oral cyclophosphamide, bendamustine, fludarabine, and also rituximab all have a similar clinical efficacy, although toxicity is different.

The response rates to single agents are in the range 60-80%, with 20-40% CR and a response duration of 1.5-2.5 years, depending mainly on baseline prognostic factors.

Responders with maintenance Stable disease with maintenance Responders without maintenance Stable disease without maintenance

1.0

Patients responding to single agent rituximab and receiving maintenance have a 35% chance to be in remission at 8 years

0.8

Probability

Bendamustine, a recently rediscovered drug, is increasingly being used due to its favorable therapeutic index (high RR with little toxicity).

Event-free survival in randomized follicular lymphoma patients

0.6 0.4 0.2 0.0 1

Years since treatment

REVISION QUESTIONS 1. What are the advantages of a watch and wait strategy? 2. Is mono- or combination chemotherapy better? 3. Which is the single-agent treatment with the best therapeutic index?

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First-line treatment â&#x20AC;&#x201C; combination therapy The addition of rituximab to several chemotherapy regimens was shown to improve PFS and, in a meta-analysis, also OS, becoming therefore the standard. CVP was for decades one of the standard treatments for FL; its more recent rituximab-including version (R-CVP) has substituted it in many countries. R-CHOP is a very active regimen, resulting in a long PFS but, because it is more toxic without improving OS, it is not universally preferred.

Probability of PFS

1.0 0.9

A recent randomized study in grade 1-2 FL showed that the R-bendamustine regimen is as active as R-CHOP but induces significantly less side effects.

p=0.0281

0.8 0.7

R-benda

Nevertheless, for patients with grade 3 FL, R-CHOP is still believed by many to be preferable, being suggested in retrospective studies to improve OS.

0.6 0.5 Chop-R

0.4 0.3 0.2 0.1 0.0 0

Fludarabine alone or in combination is more active but also more toxic than CVP. However, it should be used with caution as it can hamper PBSC collection and result in an increased rate of secondary malignancies.

Maintenance treatment with single-agent rituximab after 1st remission was shown in a meta-analysis to significantly improve EFS but not OS. Consolidating remission with RIT was also shown to improve PFS by a median of 2 years, but without significant effect on OS. ASCT has been used to consolidate 1st remission in randomized trials but, due to its toxicity without OS advantage, it should not been used outside trials.

Progression-Free Survival (%)

Months

The favorable effect of RIT consolidation was shown in patients receiving chemo without Two-sided log-rank P < .0001 rituximab, so it is not certain Hazard ratio, 0.304 that the advantage exists also in 95% CI, 0.213 to 0.434 rituximab-treated patients

100 80

Y-ibritumomab tiuxetan (n = 101): Median, 29.3 months

60 40 Control (n = 97): Median, 6.2 months

Time After Random Assignment (months)

REVISION QUESTIONS 1. Which treatment has improved the survival of FL patients in the last decade? 2. Is R-CHOP the standard chemotherapy for all FL? 3. How can a remission obtained with chemotherapy be prolonged?

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Options at relapse/progression A biopsy should be performed at each relapse to exclude transformation, particularly if there are indirect signs such as elevated LDH or rapidly growing tumors.

In this observation, patients responded to chlorambucil in 1st, 2nd, 3rd and 4th line, but the response duration shortened at every subsequent relapse

As with many other indolent cancers, FL can relapse slowly after longer intervals and can respond to a rechallenge with the previous regimen. If patients relapse with a few sites of disease and an indolent course, low-dose RT (2 x 2 Gy) to the involved sites can obtain sufficient palliation.

Response rate

1st line

Relapse

R-CHOP

96%

85%

R-Bendamustine

94%

90%

FCM

94%

58%

Radioimmunotherapy

91%

50%

Rituximab

73%

52%

Chlorambucil/PDN

70%

47%

Fludarabine

65%

37%

Alternatively a single agent (chemotherapy, rituximab, 90Y-ibritumomab tiuxetan) can be sufficient, the choice depending on response duration and prior treatments. For early and/or aggressive relapses, combination chemotherapy is preferred, with the addition of rituximab if not given in the previous 6-12 months. Consolidation of second or subsequent remission with ASCT can further prolong remission and possibly survival.

New anti-CD20 monoclonal antibodies could be used, including ofatumumab and obinutuzumab, but there is no evidence yet that they are more active than rituximab. Lenalidomide is an immunomodulatory agent with modest activity in FL, but it significantly increases the activity of rituximab when used in combination. Allogeneic SCT can be curative, but should only be proposed to relapsed fit and motivated patients, due to the high incidence of severe side effects and mortality.

Patients still alive 4 years after allotransplant are cured (plateau)

Half of patients die early from the consequences of allotransplant

REVISION QUESTIONS 1. Is there a standard 2nd line treatment for FL? 2. Are all patients with relapsed FL candidates for ASCT or allogeneic transplant? 3. Should rituximab be added to each line of chemotherapy?

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Summary: Follicular lymphoma • Histology: nodules resembling follicles, contain both centrocytes and centroblasts • Biology: translocation t(14;18) causes bcl-2 overexpression, inhibiting apoptosis • The risk of transformation to aggressive lymphoma is around 30% at 10 years • Usually indolent behavior, but incurable except for the (rare) stage I-II • Prognostic factors (FLIPI): age, Hb, LDH, stage, number of nodal sites • If asymptomatic, observe without treatment; alternative is single-agent rituximab • If symptomatic, choice between single agent or more aggressive treatment (such as R-CHOP) • Remission can be consolidated with radioimmunotherapy or maintained with rituximab • For indolent relapse, rechallenge with rituximab, chemotherapy, low-dose RT, radioimmunotherapy • For aggressive relapse, consider autologous (or later allogeneic) transplantation

Further Reading Al-Tourah AJ, Gill KK, Chhanabhai M, et al. Population-based analysis of incidence and outcome of transformed non-Hodgkin’s lymphoma. J Clin Oncol 2008; 26:5165–5169. Federico M, Bellei M, Marcheselli L, et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol 2009; 27:4555–4562. Feuerlein K, Zucca E, Ghielmini M. First-line treatment of follicular lymphoma: a patient-oriented algorithm. Leuk Lymphoma 2009; 50:325–334. Gribben JG. How I treat indolent lymphoma. Blood 2007; 109:4617–4626. Gyan E, Foussard C, Bertrand P, et al; Groupe Ouest-Est des Leucémies et des Autres Maladies du Sang (GOELAMS). High-dose therapy followed by autologous purged stem cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS with final results after a median follow-up of 9 years. Blood. 2009; 113:995–1001. Montoto S, Canals C, Rohatiner AZ, et al; EBMT Lymphoma Working Party. Long-term follow-up of high-dose treatment with autologous haematopoietic progenitor cell support in 693 patients with follicular lymphoma: an EBMT registry study. Leukemia 2007; 21:2324–2331. Relander T, Johnson NA, Farinha P, Connors JM, Sehn LH, Gascoyne RD. Prognostic factors in follicular lymphoma. J Clin Oncol 2010; 28:2902–2913. Schulz H, Bohlius JF, Trelle S, et al. Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma: a systematic review and meta-analysis. J Natl Cancer Inst 2007; 99:706–714. Swenson WT, Wooldridge JE, Lynch CF, Forman-Hoffman VL, Chrischilles E, Link BK. Improved survival of follicular lymphoma patients in the United States. J Clin Oncol 2005; 23:5019–5026. Vidal L, Gafter-Gvili A, Leibovici L, et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst 2009; 101:248–255.

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Chronic lymphocytic leukemia / small lymphocytic lymphoma

Epidemiology and classification Chronic lymphocytic leukemia (CLL) is the most common chronic leukemia in the world but it is uncommon in East Asia and Sub-Saharan Africa. In the western hemisphere, the incidence is 4/100 000/year, but after the age of 70 the incidence increases up to 50/100 000/year. CLL is nearly twice as common in men compared to women and is mainly a disease of the elderly: the median age at diagnosis is 72 years.

In the proliferation center, CLL cells are mixed with larger cells (prolymphocytes and paraimmunoblasts)

Japan has the lowest incidence of CLL

CLL cells resemble normal small B lymphocytes morphologically, but have a distinct immunophenotype with CD5 expression, otherwise a marker of T cells. In contrast to normal B cells, CLL cells have a weak surface immunoglobulin expression with clonal light chains (魏 or 位).

CLL in a lymph node with a proliferation center

Most CLL cells are in a resting state, but pseudofollicles called proliferation centers can be seen in BM, LN, and spleen.

CLL diagnosis requires >5x109/L B lymphocytes in blood with a typical phenotype (CD5+, CD19+, CD20dim, CD23+, 魏 or 位 restriction). Cases with infiltration of LN, spleen, or BM but without lymphocytosis are classified as small lymphocytic lymphoma (SLL). In a large proportion of healthy elderly, a small number of clonal lymphocytes can be found in the blood. This condition is called monoclonal B lymphocytosis (MBL).

Typical flow cytometry findings in CLL and SLL

REVISION QUESTIONS 1. Is there a gender difference in CLL incidence? 2. What distinguishes CLL cells from normal B cells? 3. What is MBL?

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Prognostic markers The majority of patients (80%) are asymptomatic at diagnosis. Many cases are diagnosed after the incidental finding of a lymphocytosis. The clinical course of CLL is extremely variable. Most cases have a slowly progressing disease, and 1/3 of the patients will never require any therapy. Staging is based on findings of lymphadenopathy or splenomegaly, anemia, or thrombocytopenia. The use of CT as a prognostic tool is still controversial.

Rai:

Binet:

0: Lymphocytosis only 1: Lymphadenopathy 2: Splenomegaly 3: Anemia (<11 g/L) 4: Thrombocytopenia (<100x109/L)

A: Palpable disease in â&#x2030;¤ 2 locations (neck, axillar and inguinal lymph nodes, spleen, and liver) B: â&#x2030;Ľ 3 involved areas C: Anemia (<10 g/L) and/or thrombocytopenia (< 100x109/L)

Rai and Binet are the main clinical staging systems in CLL

Cytogenetic aberrations have a strong impact on prognosis in CLL/ SLL. However, due to the low mitotic activity of CLL cells, conventional karyotyping is difficult. By FISH, chromosomal abnormalities can be found in 80% of the cases. The most common aberrations are 13q-, 11q-, 17p-, and trisomy 12. Cases with 13q- as the only abnormality have an excellent prognosis, whereas 17p- is associated with resistance to chemotherapy and poor OS.

Trisomy 12 by karyotyping and FISH

Several other prognostic markers have also been proposed: CD38 expression, thymidine kinase, LDH, b2-microglobulin, and lymphocyte doubling time. The mutational status of the immunoglobulin heavy chain variable (IGHV) region gene is a strong independent prognostic marker in CLL. ZAP70 expression by IHC is considered a surrogate marker for unmutated IGHV genes, although the correlation between the two tests is only 75-90%. 11q- has been regarded as a marker for poor prognosis. This may not be the case after R-FC therapy

REVISION QUESTIONS 1. What proportion of CLL patients are asymptomatic at diagnosis? 2. Why is conventional karyotyping difficult to perform in CLL? 3. Which chromosomal abnormality is associated with the worst prognosis?

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First-line treatment A wait and watch strategy is generally applied for asymptomatic CLL/SLL patients, since no OS advantage was demonstrated with early therapy. In recent years there have been advances in CLL therapy with approval of new chemotherapeutic agents, MoAb, and combinations. Most CLL patients are elderly and have comorbidities, so that the benefit of more intensive therapy has to be weighed against the adverse effects of the treatment.

Chlorambucil was for many years the preferred 1st line therapy in CLL, but nowadays it is mainly reserved for patients who cannot tolerate more intensive therapy.

100 90

Proportion surviving (%)

Complete remissions are rarely obtained with chlorambucil, in contrast to purine analog-based combination therapy.

70 60 50

Improved overall survival for R-FC compared to FC in the German CLL8 trial

40 30

Fludarabine-cyclophosphamide-rituximab (R-FC) was the first therapy associated with an improved OS in CLL in a randomized trial.

20 10 0

Chemoimmunotherapy Chemotherapy 0

Number at risk Chemoimmunotherapy 408 Chemotherapy 409

12 383 357

24 359 320

36 247 207

88 66

Treatment with bendamustine results in an improved PFS compared to chlorambucil, even in elderly patients. Patients with 17p- respond poorly to chemotherapy but better to alemtuzumab. These patients, if fit, are candidates for allogeneic transplant. There are no clinical trials specific for SLL. The management of these patients is the same as for CLL, since the diseases are considered biologically similar.

REVISION QUESTIONS 1. Should asymptomatic CLL/SLL patients be treated? 2. Which therapeutic regimen has shown improved overall survival in CLL? 3. Why is alemtuzumab indicated as first-line therapy in patients with 17p deletion?

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Therapeutic options at relapse With standard chemotherapy long-lasting remissions are achievable. However, eventually all patients will relapse.

At relapse, R-FC had better PFS than FC, but OS was not improved in the REACH trial

R-FC, bendamustine, and alemtuzumab are therapeutic options at relapse. Ofatumumab is approved in CLL refractory to both fludarabine and alemtuzumab. 17p- is more common in relapsed/refractory patients; therefore cytogenetic analysis by FISH should be repeated before therapeutic decisions are made.

Patients refractory to purine analog-based regimens or with an early relapse have a very poor prognosis despite the introduction of new therapeutic agents.

Probability of overall survival

1.0 CR

0.8

0.6

Allogeneic transplant, the only potentially curative treatment in CLL/SLL, should be considered in fit patients with poor risk factors.

Contrasting with most other lymphoid malignancies, ASCT has little or no role in CLL outside clinical trials.

0.4 < PR 0.2 p<0.001 0.0 0

40 60 80 Time after HSCT (months)

100

120

Long-term survival is achievable after allogeneic transplant, but pretransplant remission status is important

Several new compounds have shown activity in CLL and are currently being tested in clinical trials. Maintenance studies are also ongoing. New agents target the CLL microenvironment (such as lenalidomide) or inhibit the B-cell receptor signaling pathway (such as fostamatinib, CAL-101, and ibrutinib).

Ibrutinib

Chimeric antigen receptor-modified T cells (CARs) have shown to be remarkably effective in refractory patients in small experimental studies.

REVISION QUESTIONS 1. Is standard chemotherapy curative in CLL? 2. When and for which patients should allogeneic transplant be considered? 3. Is there a role for autologous stem cell transplantation in CLL?

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Complications The immune system is disturbed in CLL, leading to an increased risk of infectious complications, especially in patients relapsing after multiple courses of therapy. Hypogammaglobulinemia is present in virtually all patients with advanced disease. Substitution can be used to prevent infectious episodes.

Opportunistic infections such as CMV (right) and Aspergillus (below) do occur in CLL. However, bacterial infection (especially pneumonia, below right) is most common and the main cause of morbidity

The T-cell response is impaired in CLL and affected by therapy with purine analogs and alemtuzumab. Opportunistic infections are therefore not uncommon.

AIHA in CLL is in most cases caused by polyclonal IgG antibodies

Autoimmune hemolytic anemia (AIHA) is common, occurring in 5-10% of cases. It can be present at diagnosis but is more common in advanced stages. AIHA can be sporadic or therapy-related. Therapyrelated AIHA can occur during and after all types of therapy, but tends to be more severe after fludarabine. 1st line therapy for AIHA is high-dose steroids. In refractory cases, rituximab or splenectomy are good therapeutic alternatives.

CLL/SLL may transform to an aggressive lymphoma, mainly DLBCL, an event known as Richterâ&#x20AC;&#x2122;s syndrome (RS). RS occurs in 2-15% of CLL cases. Rapid discordant growth of lymph nodes, the emergence of Bsymptoms, or an unexpected rise in LDH is suggestive of RS.

MiB-1 staining shows high number of proliferating cells in the transformed area

The outcome for RS is worse than for primary DLBCL, but long-term survival is achievable. ASCT may be considered in this particular situation.

REVISION QUESTIONS 1. Why are CLL patients prone to infections? 2. How should autoimmune hemolytic anemia be treated in patients with CLL? 3. What is Richterâ&#x20AC;&#x2122;s syndrome?

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Summary: Chronic lymphocytic leukemia / small lymphocytic lymphoma • The CLL/SLL cell is a small B lymphocyte with a unique phenotype (CD5+, CD19+, CD23+) • CLL diagnosis requires lymphocytosis, otherwise the disease is classified as SLL • Rai/Binet stage and cytogenetics are the most used prognostic elements • Asymptomatic cases should not be treated • Comorbidity and performance status should be considered before therapy decisions • CLL/SLL is incurable with chemotherapy, but long remissions are common following current therapies • R-FC or R-bendamustine are therapeutic options for fit patients • Chlorambucil is a good palliative option for elderly or unfit patients • Alemtuzumab is indicated in patients with refractory disease or with 17p• Allogeneic transplant should be considered in fit patients with 17p- or patients relapsing early after immunochemotherapy

Further Reading Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343:1910–1916. Dreger P, Corradini P, Kimby E, et al. Indications for allogeneic stem cell transplantion in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia 2007; 21:12–17. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic lymphoma: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008; 111:5446–5456. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia: a randomised, open-label, phase 3 trial. Lancet 2010; 376:1164–1174. Hodgson K, Ferrer G, Montserrat E, Moreno C. Chronic lymphocytic leukemia and autoimmunity: a systematic review. Haematologica 2011; 96:752–761. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 2009; 27:4378–4384. Lozanski G, Heerema NA, Flinn IW, et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood 2004; 103:3278–3281. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46:219–234. Rossi D, Cerri M, Capello D, et al. Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter Syndrome. Br J Haematol 2008; 142:202–215. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: International Agency for Research on Cancer, 2008; 180–182.

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Mantle cell lymphoma

Pathology and biology The disease is named after its histological appearance. The image is of cells resembling those of the mantle zone surrounding normal germinal center follicles. MCL cells can proliferate in a nodular or diffuse pattern accumulating in the lymphoid tissue. Cytologically two cell types are distinguished: typical and blastoid.

Cells are distributed around the atrophic germinal center, resulting in a mantle zone pattern

Typical cells have intermediate size and irregular nuclei, while in the more aggressive blastoid variant cells are large, with finely dispersed chromatin.

Immunohistochemical staining of cyclin D1: the positive nuclear reaction indicates cyclin D1 overexpression

The typical immunophenotype expression resembles that of mature B lymphocytes (CD19+, CD20+, CD79a+) but with co-expression of the T-cell antigen CD5. In contrast to the other CD5+ lymphoma (CLL), MCL is negative for CD23 and lacks the expression of the germinal center-associated antigens bcl-6 and CD10. The genetic hallmark of MCL is the translocation t(11;14)(q13;q32), found in >95% of cases, which brings the IgH promoter near to the cyclin-D1 gene.

This genetic alteration triggers the overexpression of cyclin D1, a protein that promotes cell proliferation and inhibits apoptosis.

Possible evolution of MCL over time

MCL represents the lymphoma with the highest rate of secondary cytogenetic alterations, as ATM or p53 inactivation by mutation and deletion, both associated with shorter OS. On the other hand, a minority of MCL have an indolent clinical course. These cases carry only the t(11;14) translocation and only few other genomic alterations.

REVISION QUESTIONS 1. Why are MCL so named? 2. What is the typical immunophenotype in MCL? 3. What is the genetic key event in MCL, and what are the secondary genetic alterations?

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Clinical presentation, prognosis The incidence of MCL is 2-3/100 000/year, comprising about 5-10% of all NHL.

Survival of B-cell lymphoma subtypes in the series of the Oncology Institute of Southern Switzerland,1980-2006

The median age at diagnosis is 63-70 years, men being diagnosed with MCL more frequently than women (male:female ratio = 3-4:1).

The OS curve initially drops as in DLBCL, but, in contrast, there is not a plateau

The median survival is 4-5 years, without longterm survival plateau. MCL has one of the worst prognoses of B-cell lymphoma and is considered incurable.

Most patients present with stage IV. Extranodal involvement is common (>90%), especially in BM (90% of cases), GI tract (60%), and liver (20%). Staging examinations include CT and BM examination. Endoscopy should be performed in patients with localized stages or GI symptoms. In contrast to indolent lymphomas, patients should receive treatment at diagnosis, except for the few cases (10%) with clinically slow progression.

The MIPI score is based on age, LDH level, PS, and absolute leukocyte count and it is a strong predictor of outcome. The most important biological predictor of the clinical course is cell proliferation, determined by Ki-67 expression on immunohistochemistry staining.

Survival (%)

The prognosis of MCL patients can be estimated by a clinical prognostic score, called MIPI (Mantle Cell Lymphoma International Prognostic Index).

100

Ki-67 Index

P<0.0001 <10%

10â&#x20AC;&#x201C;40% >40%

25 0 0

All patients with a high Ki-67 MCL die within 2 years

120

144

168

192

Time (months)

REVISION QUESTIONS 1. What is the overall prognosis of MCL compared to other B-cell lymphomas? 2. In which stage do most patients present? Which extranodal sites are common? 3. Which patient characteristics and biological markers affect overall survival?

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Intensive first-line treatment Most patients will require treatment at diagnosis, but the nature and intensity of the therapy will depend on their age and PS. For patients who are young and fit, an intensive induction treatment followed by consolidation with ASCT is the first choice. Anthracyclin-containing regimens such as CHOP are the backbone of induction, although their superiority over other regimens has not been formally proven.

probability of EFS

HD Ara-C containing regimens provide a higher chance of long-term remission

The addition of rituximab to the induction therapy increases the quality and duration of responses, so that it is now part of all remission-induction treatments. There is controversy on the potential risk of CNS involvement, both at diagnosis and at relapse, and the consequent need for staging LP and CNS prophylaxis. Some regimens, as hyper-CVAD, include HD-MTX, which has the potential to decrease the risk of CNS relapse.

Retrospective comparisons and one randomized study showed promising results for ASCT in terms of an increased PFS and OS.

probability

HD Ara-C also has an important role in obtaining a higher RR and a longer response duration, so it is frequently incorporated in the induction regimen.

The incorporation of new drugs active in MCL such as lenalidomide and bortezomib in 1st line protocols could be the next step towards improving patientsâ&#x20AC;&#x2122; OS.

REVISION QUESTIONS 1. How do patient characteristics influence the treatment approach? 2. What is the preferred treatment modality in younger patients? 3. Which are the four mandatory components of an intensive 1st line regimen for MCL?

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Conventional first-line treatment In patients who are elderly or have compromised organ function and poor PS, conventional immunochemotherapy is the first choice, with a RR of ~90%. R-CVP and R-CHOP are the most commonly used regimens. A randomized trial showed a lower OS for a fludarabine-containing regimen compared to R-CHOP. Bendamustine in combination with rituximab can be administered with comparable RR and OS to those with R-CHOP, but with less side effects.

probability of EFS

In MCL, rituximab has a lower activity as compared to other B-NHL. The RR in both untreated and pre-treated patients is ~30%. Adding rituximab to CHOP improves the RR (RR 94% vs 75%, CR 34% vs 7%) and PFS. The results of a meta-analysis also show an improvement in OS. In addition, maintenance therapy with rituximab every two months following R-CHOP chemotherapy significantly prolongs OS.

Radioimmunotherapy consolidation after chemotherapy results in a longer PFS compared with historical controls. Frail patients unable to tolerate aggressive treatment are treated with palliative chemotherapy of reduced intensity, usually with single agents. Favorable toxicity profiles with marked activity are seen with rituximab monotherapy, bendamustine (+/- rituximab), or chlorambucil (+/- rituximab).

WHO Grade 0

3/4 (%)

Leukocytes (n = 216)

Thrombocytes (n = 214)

173

Anemia (n = 199)

169

—

Nausea/vomiting

136

102

—

Allergic reaction

230

—

Cardiotoxicity

239

—

Neurotoxicity

239

—

Alopecia

235

—

NOTE. All data are No. of cycles except where indicated.

REVISION QUESTIONS 1. Which chemotherapeutic approach is mostly chosen in unfit patients? 2. What is the impact of adding rituximab to chemotherapy? 3. Is there any established post-induction therapy in elderly patients?

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Treatment at relapse The management at relapse depends on age and PS, but in most cases the goal of treatment needs a shift to a more palliative approach.

young patient â&#x2030;¤65 years

older patient >65 years

compromised patient

In 1st relapse, immunochemotherapy such as R-DHAP (young + fit) or R-bendamustine is an adequate option depending on prior therapy and response duration. For patients who have not received ASCT as part of the 1st line treatment, this option can be used to consolidate second remission.

Young and motivated patients may have their response consolidated with allogeneic transplant, given its curative potential. Due to the high treatmentrelated mortality, allogeneic transplant is generally only proposed to fit patients, who have relapsed after ASCT. Many oncogenic signaling pathways are altered in MCL, rendering this entity highly attractive for testing molecular targeted substances.

Temsirolimus is registered in EU and has shown superiority over other agents in heavily pretreated patients, with a RR of 23% and a PFS of 5 months. Bortezomib, a proteasome inhibitor registered in US, achieves a RR of 29-47%, with a median PFS of 7 months. Lenalidomide, an immunomodulatory agent, is also effective in relapsed MCL with a RR of 42% and may be an option in heavily pretreated patients.

REVISION QUESTIONS 1. When would you use an allogeneic transplant in patients with MCL? 2. What variables determine the choice of secondary treatment in MCL? 3. Which molecular targeted substances are efficient in relapsed MCL?

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Summary: Mantle cell lymphoma • Histology: the image is of mantle zone cells surrounding normal germinal center follicles • Biology: the translocation t(11;14)(q13;q32) leading to cyclin D1 overexpression is typical • The prognosis can be estimated based on the MIPI • Usually aggressive behavior, so the majority of patients are treated at diagnosis • Initial treatment is always a chemotherapeutic approach, depending on patient characteristics • Young patients should be treated with aggressive regimens followed by ASCT as 1st line • Elderly patients should be initially treated with conventional chemotherapy combinations • Rituximab maintenance therapy should be discussed after PR and CR • Frail patients are treated with single agents or dose-reduced combinations • At relapse, young patients should be evaluated for allogeneic transplant • Molecular targeted substances have widened the options for treatment in subsequent relapses

Further Reading Chang J, Kahl BS. Current status of targeted therapies for mantle cell lymphoma. Drugs 2011; 71: 2307–2326. Dreyling M, Lenz G, Hoster E, et al. Early consolidation followed by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood 2005; 105:2677–2684. Update ASH 2009, #880. Dreyling M, Hiddemann W; European MCL Network. Current treatment standards and emerging strategies in mantle cell lymphoma. Hematology: American Society of Hematology Education Program 2009: 542–551. Fernàndez V, Hartmann E, Ott G, Campo E, Rosenwald A. Pathogenesis of mantle-cell lymphoma: all oncogenic roads lead to dysregulation of cell cycle and DNA damage response pathways. J Clin Oncol 2005; 23:6364–6369. Ghielmini M, Zucca E. How I treat mantle cell lymphoma. Blood 2009; 114:1469–1476. Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma; German Low Grade Lymphoma Study Group (GLSG); European Mantle Cell Lymphoma Network. Blood 2008; 111:558–565. Update ASH 2009, #138. Jares P, Colomer D, Campo E. Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics. Nat Rev Cancer 2007; 7:750–762. Lenz G, Dreyling M, Hoster E, et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 2005; 23:1984–1992. Update ASH 2008, #3049. Martin P, Chadburn A, Christos P, et al. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol 2009; 27:1209–1213. Pérez-Galán P, Dreyling M, Wiestner A. Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood 2011; 117:26–38. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). ASH Annual Meeting Abstracts 2009; 114:405.

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Extranodal marginal zone lymphoma of MALT type

Pathology MALT lymphomas are a subtype of marginal zone lymphomas (MZL), deriving from the marginal zone of lymphoid follicles. They develop in extranodal sites (i.e. outside the LN). The MALT acronym represents the “MucosaAssociated Lymphoid Tissue”. Lung alveoli invaded by lymphoma cells

It is composed of morphologically heterogeneous small B cells, and scattered, large cells (blasts) as in the marginal zone of reactive follicles.

Lymphoma cells can infiltrate and disrupt the mucosal crypts and glands, forming lymphoepithelial lesions, typical but not pathognomonic of MALT lymphoma. Usually there is some degree of plasma cell differentiation

Lymphoma cells invading the gland

There are no specific immunohistochemical markers for MALT lymphoma. Cells express CD20, sIg, and lack CD5 and CD10. There is immunoglobulin light chain restriction, but this may be often difficult to demonstrate in small biopsy specimens.

Monoclonality can be detected by PCR in most cases, but, by itself, cannot be diagnostic for MALT lymphoma. If large cells form solid or sheet-like proliferations this must be reported as an associated diffuse large B-cell lymphoma, indicating histological transformation.

Large cells

The disease can occur at any anatomical site: stomach (most common site), thyroid, salivary glands, lung, orbits/conjunctiva, breast, skin, and others.

REVISION QUESTIONS 1. What does “MALT” mean? 2. What is a lymphoepithelial lesion? 3. How is the histological transformation into diffuse large B-cell lymphoma defined?

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Epidemiology and biology Many MALT lymphomas originate from lymphoid tissue acquired in the background of a chronic inflammation, caused by an autoimmune disorder or by infections.

THE MALT CONCEPT Mucosa-Associated Lymphoid Tissue

Somatic hypermutation and intraclonal variation of the IgHV genes are consistently found, suggesting a continuous antigen-driven process.

• Native MALT normally present in certain extranodal sites (e.g. Peyer’s patches)

Hashimoto’s thyroiditis or Sjögren’s syndrome have been linked to MALT lymphomas of the thyroid and of the lachrymal and salivary glands, respectively.

• Acquired MALT where lymphoid tissue is not a natural component (e.g. Sjögren, Hashimoto, H. pylori-gastritis)

In gastric MALT lymphoma there is evidence that a chronic infection with Helicobacter pylori has a pathogenetic role. A history of chronic H. pylori infection is present in most patients with gastric MALT lymphoma and the bacterium can usually be detected in the stomach. Immunohistochemical staining of H. pylori from a gastric biopsy

Other infectious agents are linked to non-gastric MALT lymphomas. Chlamydophila psittaci has been associated with ocular adnexa lymphoma. Other examples are Borrelia burgdorferi in cutaneous lymphomas and Campylobacter jejuni in immunoproliferative small intestinal disease (IPSID).

Eradication of H. pylori infection with antibiotics and proton pomp inhibitors results in histological regression in ~75% of gastric MALT lymphomas.

Immunohistochemical staining of Chlamydophila from an orbital biopsy

Eradication of these agents is also reported to induce MALT lymphoma regression in some cases, but the evidence is less solid than for H. pylori.

REVISION QUESTIONS 1. Which conditions are associated with the development of MALT? 2. Which are the lines of evidence implicating H. pylori infection in the pathogenesis of gastric MALT lymphoma? 3. In which other anatomical sites of MALT lymphoma have bacterial infections been implicated?

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Molecular biology Unbalanced genomic aberrations (trisomy 3, trisomy 18, 6q23 deletion) and chromosomal translocations are recurrently observed in MALT lymphomas. The most common translocation is the t(11;18)(q21;q21), fusing BIRC3 on 11q21 with MALT1 on 18q21.

t(11;18)(q21;q21) in MALT lymphoma 5＇

3＇ BIRC3 Chromosome 11q21

MALT1 Chromosome18q21

• detected in 30-35% of cases, usually as the sole abnormality

The t(14;18)(q32;q21) brings MALT1 under the control of the promoter region of the immunoglobulin heavy chain variable (IgHV) genes with MALT1 deregulation.

• found at many different sites (most commonly the GI tract and the lung) • results in BIRC3/MALT1 fusion transcripts with antiapoptotic properties • under normal circumstances, BCL10 and MALT1 bind to activate NF-kappaB • BIRC3/MALT1 transcripts can activate NF-kappaB independently of BCL10

Less common is the t(1;14)(p22;q32) translocation, which determines high level of BCL10 expression due to its juxtaposition to the IgHV promoter region. A pathogenetic model has been proposed for gastric MALT lymphoma incorporating the chronic antigenic stimulation and the genetic lesions. At least four genetic lesions determine the activation of the NF-kappaB signaling pathway, making this an interesting therapeutic target.

The NF-kappaB pathway has a physiological central role in regulating immunity, inflammation, cell survival, and apoptosis. The chromosomal translocations are mutually exclusive and show different frequencies at different anatomical sites. Gastric MALT lymphomas with t(11;18) are often H. pylori-negative and do not respond to antibiotics, but may have a lower risk of histological transformation.

Chromosomal Aberrations

Involved Genes

NF-kappaB Pathway Frequency Activation

Preferential Anatomical Site Stomach, lung

t(11;18)(q21;q21) BIRC3-MALT1

Yes

15%-40%

t(14;18)(q32;q21)

IgHV-MALT1

Yes

20%

Lung, salivary gland, skin, ocular adnexa

t(1;14)(p22;q32)

IgHV-BCL10

Yes

<5%

Stomach, lung

t(3;14)(p13;q32)

IgHV-FOXP 1

<5%

Unclear

6q23 loss

TNFAIP3

Yes

15%-30% Equal distribution

Trisomy 3 / 3q gain

Unclear

20%-40% Equal distribution

Trisomy 18 / 18q gain

Unclear

20%-40% Equal distribution

REVISION QUESTIONS 1. Which is the most common chromosomal translocation in MALT lymphomas? 2. Which is the important signaling pathway affected in the majority of cases? 3. Has the presence of the t(11;18) any clinical relevance?

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Clinical presentation and treatment Presenting symptoms are related to the primary site. High LDH or b2-microglobulin levels as well as B-symptoms are extremely rare. MALT lymphoma is usually localized. The clinical course is indolent with long-term OS rates exceeding 80% irrespective of the site of disease and treatment. Dissemination to regional lymph nodes or to multiple mucosal sites may occur in up to 1/4 of cases. BM is involved in ~20% of cases.

MALT lymphoma overall survival 1.00 0.75 0.50

Similar outcome of gastric (––) and nongastric (––) lymphomas in the IELSG series

0.25 0.00 0

Years from diagnosis

Initial work-up should include basic blood counts and biochemical studies, CT of the chest, abdomen and pelvis, and BM biopsy. Gastroduodenal endoscopy with multiple biopsies is recommended in all MALT lymphomas. In gastric MALT, endoscopic ultrasound provides prognostic information. H. pylori status should be determined either by IHC, breath test, or serology in patients with gastric MALT.

Anti-H. pylori treatment is the initial choice for localized gastric MALT lymphoma. After 4-6 weeks a breath test should be performed to confirm H. pylori eradication.

Reference

No. of Patients

Complete Remission (CR) Rate

Triple therapy (a proton pump inhibitor, clarithromycin, amoxicillin or metronidazole) is the most frequently used regimen to eradicate the microorganism.

Savio, 1996

84%

2-4

Pinotti, 1997

67%

3-18

Neubauer, 1997

80%

1-9

Nobre Leitao, 1998

100%

1-12

Steinbach, 1999

56%

3-45

Montalban, 2001

95%

2-19

Ruskone-Formestraux, 2001

79%

2-18

Hancock, 2009

231

46%

3-24

Criteria for histological response evaluation are controversial. Differences in response rate in different studies can be due to the non-standardized criteria.

Response to antibiotics in localized gastric MALT lymphoma Time to CR No. of (Months) Reported Relapses

REVISION QUESTIONS 1. How often do patients with MALT lymphoma present with advanced disease? 2. What is the front-line treatment for localized H. pylori-positive gastric MALT lymphoma? 3. What proportion of patients with MALT lymphoma are expected to be long-term survivors?

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Treatment Gastric MALT lymphoma usually regresses within 6 months after H. pylori eradication but delayed (>12 months) responses have been reported. Endoscopic follow-up is recommended with multiple biopsies at 3-6 months after antibiotics, and then twice a year for 2 years. Minimal residual disease is sometimes seen, but can be safely followed with watchful waiting in patients without symptoms or clinical/endoscopic progression.

Radiotherapy results in MALT lymphoma Author

No. of Site Patients

Schechter, 1998 17

RT Dose (Gy)

Progression-Free Survival

Gastric

28-43

100% at 2 years 100% at 5 years

Tsang, 2001

Gastric

20-30

Yahalom, 2002

Gastric

22.5-43.59 89% at 4 years

Goda, 2010

192

Gastric and 17.5-35 non-gastric

95% at 10 years for thyroid 92% for stomach 68% for salivary glands 67% for orbit

Endoscopy, blood counts, and clinical, radiological or ultrasound examinations are recommended yearly, as these patients are at higher risk of gastric carcinoma. For gastric H. pylori-negative or antibiotic-resistant gastric MALT lymphomas or for non-gastric localizations no specific treatment can be considered the standard. Radiotherapy (30-40 Gy) is widely used for localized non-gastric or antibiotic-resistant gastric cases, resulting in an excellent long-term local control.

Toxicity can be reduced using modern techniques and minimizing the RT dose to non-target organs

In patients with disseminated disease, a watch and wait policy in asymptomatic patients is acceptable, as in most indolent lymphomas.

IELSG-19 trial: event-free survival

When treatment is required, immunochemotherapy (with a non-intensive regimen) is an appropriate treatment option. Histological presence of sheets of large cells should be treated according to the recommendations for diffuse large B-cell lymphoma.

Addition of rituximab to chlorambucil improves EFS but not OS

REVISION QUESTIONS 1. Is systemic treatment always needed for patients with disseminated MALT lymphoma? 2. What is the standard therapy for disseminated MALT lymphoma? 3. Are aggressive chemotherapy regimens the first-line therapeutic approach for patients with non-gastric MALT lymphoma?

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Summary: Extranodal marginal zone lymphoma of malt type • Histology: heterogeneous small cells, scattered large cells, and plasma cell differentiation • Epidemiology: association with chronic inflammation and pathogenetic role of H. pylori infection in gastric lymphoma • Biology: translocation t(11;18) and other genetic alterations causing NF-kappaB deregulation • Usually indolent behavior, with prolonged survival irrespective of treatment • H. pylori eradication may result in lymphoma regression in most H. pylori-positive gastric MALT lymphoma • Endoscopic evaluations should be performed regularly during the follow-up of patients with gastric MALT due to the increased risk of gastric carcinoma • Radiotherapy can be used in H. pylori-negative and localized non-gastric cases • Rituximab plus chemotherapy is effective in disseminated disease, but aggressive regimens are not usually needed

Further Reading Bertoni F, Coiffier B, Salles G, et al. MALT lymphomas: pathogenesis can drive treatment. Oncology (Williston Park) 2011; 25:1134–1142, 1147. Ferreri AJ, Dolcetti R, Du MQ, et al. Ocular adnexal MALT lymphoma: an intriguing model for antigen-driven lymphomagenesis and microbial-targeted therapy. Ann Oncol 2008; 19:835–846. Isaacson PG. Update on MALT lymphomas. Best Pract Res Clin Haematol 2005; 18:57–68. Stathis A, Bertoni F, Zucca E. Treatment of gastric marginal zone lymphoma of MALT type. Expert Opin Pharmacother 2010; 11:2141–2152. Thieblemont C. Clinical presentation and management of marginal zone lymphomas. Hematology: American Society of Hematology Education Program 2005; 307–313. Wotherspoon AC, Doglioni C, Diss TC, et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 1993; 342:575–577. Zucca E, Dreyling M; ESMO Guidelines Working Group. Gastric marginal zone lymphoma of MALT type: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21(Suppl 5):175–176. Zucca E, Bertoni F, Roggero E, et al. Molecular analysis of the progression from Helicobacter pylori-associated chronic gastritis to mucosa-associated lymphoid-tissue lymphoma of the stomach. N Engl J Med 1998; 338:804–810. Zucca E, Conconi A, Martinelli G, et al. Chlorambucil plus rituximab produces better event-free survival in comparison with chlorambucil alone in the treatment of MALT lymphoma: 5-year analysis of the 2-arms part of the IELSG-19 randomized study. Blood (ASH Annual Meeting Abstracts) 2010; 116: Abstract #432.

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11 Peripheral t-cell lymphomas Demographics and epidemiology T-cell derived lymphomas (TCL) account for 10-15% of all NHL, a frequency similar to that of HL and MCL. The first attempt to classify TCL was the updated Kiel classification (1988), followed by the REAL (1994) and the WHO (2001, 2008) classifications. The 2008 WHO classification subdivides TCL in 2 groups: (i) precursor TCL and (ii) peripheral (post-thymic, mature) T/NK-cell lymphoma (PTCL).

WHO Classification 2008 PTCL: Primary nodal and primary extranodal entities* Peripheral T-cell lymphoma, not otherwise specified Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma (ALCL), alk+

Nodal

Anaplastic large cell lymphoma (ALCL), alkExtranodal NK/T-cell lymphoma, nasal type Enteropathy-associated T-cell lymphoma Hepatosplenic T-cell lymphoma

PTCL comprises 21 subtypes. They are grouped according to their main clinical presentation into nodal, extranodal, cutaneous, leukemic, and virusassociated.

Extranodal

Subcutaneous panniculitis-like T-cell lymphoma *Primary leukemia, cutaneous and virus-associated subtypes omitted

PTCL-NOS is the most common subtype, representing approximately 25-30% of all PTCL cases, followed by AITL (15-20%) and systemic ALCL (10-15%). Some subtypes are more common in certain geographical areas: T/NK-NT in Asia, EATL in Northern Europe, and ATLL in Japan and the Caribbean area. PTCL presents in elderly patients (median age at diagnosis ~65 years), with the exception of alk+ ALCL, which is more common in young adults and children.

The most common ones are the nodal subtypes: PTCL-not otherwise specified (NOS), angioimmunoblastic (AITL), and systemic anaplastic large cell (sALCL). The extranodal PTCL subtypes are: T/NK nasal type (T/NK-NT), enteropathy-associated (EATL), subcutaneous panniculitis-like (SPL) and hepatosplenic (HS).

2.5% 0.9% 1.4% 1.7%

Peripheral T-cell Lymphoma

12.2%

Angioimmunoblastic 25.9%

Natural killer/T-cell lymphoma Adult T-cell leukemia/lymphoma Anaplastic large cell lymphoma, alk+

4.7%

Anaplastic large cell lymphoma, alk5.5%

Enteropathy-type T-cell Primary cutaneous ALCL

6.6%

18.5% 9.6%

Hepatosplenic T-cell Subcutaneous panniculitis-like

10.4%

Unclassifiable PTCL Other disorders

REVISION QUESTIONS 1. Why is a subset of T-cell lymphomas called “peripheral”? 2. How can PTCL be grouped according to their clinical presentation? 3. Which PTCL subtypes occur endemically and in which geographical areas?

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Pathology, biology, and clinical features PTCL-NOS is a heterogeneous category, which does not correspond to any of the entities defined in the current classification (exclusion diagnosis).

Broad cytological spectrum of medium-sized/ large cells with irregular, pleomorphic nuclei

Morphological variants (lymphoepithelioid, follicular, T-zone) do not have clinical correlations

Tumor cells have clonally rearranged T-cell receptor (TCR) genes, are often CD3+, but do not display specific immunophenotypic or genetic abnormalities. PTCL-NOS often presents with B-symptoms, generalized disease, and some degree of BM infiltration, which is histopathologically difficult to assess.

High endothelial venules

Regressed germinal center

Clear cytoplasm

PTCL-NOS (HE)

Lymphoepithelioid (4x)

CD3 positive tumor cells

Lymphoepithelioid (40x)

AITL originates from follicular T-helper cells. Tumor cells are clonally TCR rearranged, express CD4 or CD8, and overexpress the chemokine CXCL13. The histology shows peculiar features including the infiltration with EBV+ B cells that can evolve into B-cell lymphoma. Autoimmune features and polyclonal hypergammaglobulinemia are common. Immune dysfunction leads to frequent infectious complications (e.g. EBV viremia).

sALCL consists of large blastoid CD30+, EMA+ cells with irregular, often horseshoe-shaped, nuclei. The cells infiltrate nodal sinuses and show cohesive growth. 70% of young adults and 95% of pediatric sALCL have a t(2;5) (or a variant), leading to expression of the ALK-fusion protein, which correlates with a good prognosis. sALCL ALK- has a peak incidence in adults (40-65 years). It usually presents with disseminated nodal disease often associated with B-symptoms.

Tumor cell with horse-shoe shaped nucleus

ALK-negative ALCL

CD30-positive tumor cells

ALK-positive ALCL

REVISION QUESTIONS 1. Which are the characteristic clinical features in PTCL-NOS? 2. What are the characteristic histomorphological findings in AITL? 3. In which PTCL entity is the expression of ALK of relevance?

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Prognosis A poorer outcome for PTCL compared to aggressive B-cell lymphoma was demonstrated in the late 1990s, with the notable exception of cases of ALCL histology. EBV status (positivity of tumor cells for EBER or LMP-1) has repeatedly been reported as a negative prognosticator in PTCL. Cytotoxic phenotype has also been proposed as an adverse prognostic factor for PTCL in general and AITL in particular.

Recently, a large retrospective study (Int T-cell Project) showed marked differences in the outcome of the different PTCL subtypes. Examples of subtype-specific features with favorable influence on prognosis are ALK-positivity (sALCL) and αβ TCR gene rearrangement in SPL. Of note, ALK-related prognosis only applies to sALCL. Although all primary cutaneous cases (cALCL) are ALK-negative, they usually have a good prognosis.

The IPI, primarily applied to aggressive B-cell lymphomas, was shown to be a useful prognostic tool also in PTCL.

A prognostic role for PET imaging pre-, per-, and post-therapeutically has been suggested. However, its role is still investigational and confirmatory data are needed.

Overall survival (%)

The PIT score was originally developed for PTCLNOS and later applied to other subtypes. However, it does not seem unequivocally superior to the IPI.

PIT in PTCL-NOS (prognostic index for PTCL=NOS)

1.0 0.8

0.6

PIT parameters Age

0.4

0.2

0.0 0

3-4 12

Performance score S-LDH level BM involvement

Time (months)

REVISION QUESTIONS 1. Which prognostic index would you regard as broadly useful in PTCL? 2. What are the prognostic factors included in the PIT score? 3. Does alk-negativity imply an adverse prognosis in cutaneous ALCL?

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Treatment CHOP chemotherapy has been used in PTCL with, in general, unsatisfactory results, contrasting with those in aggressive B-cell lymphomas.

31 clinical trials with a total of 2815 patients (period: 1990-2010) Pooled overall 5 yr OS (without ALCL): 36.6% PTCL Subtype*

A meta-analysis of phase II studies on CHOP/ CHOP-like regimens in PTCL showed a pooled 5-year OS ranging from 20% (EATL) to 57% (ALCL). Retrospective outcome analyses of more intensive polychemotherapy regimens (e.g. hyper-CVAD) did not reveal any significant survival improvement.

Histology

5 yr OS (5 yrs med follow-up)

Whole cohort

51%

ALCL

70%

AILT

52%

PTCL-NOS

47%

Histology

5 yr OS (5 yrs med follow-up)

Whole cohort

44%

ALCL

61%

AILT

49%

PTCL-NOS

38%

5 yr OS

95%CI

ALCL

56.5%

42.8-69.2

AITL

32.1%

27.2-37.5

EATL

20.3%

12.5-31.2

Recent reports have suggested a possible beneficial effect of etoposide in some subsets of patients with PTCL (e.g. ALK-negative ALCL, low-risk IPI). HDT with ASCT to consolidate 1st line remission is still debated, as the only evidence is based on phase II trials including heterogeneous patients. Recently, a large 1st line PTCL trial on dose-dense CHOEP + upfront ASCT showed 5-year OS and PFS of 51% and 44%, respectively (best for alkALCL).

Gemcitabine has shown efficacy as monotherapy or in combination regimens either as 1st or 2nd line treatment. Long-term responses are uncommon. In relapsed PTCL, ASCT can be considered in chemosensitive disease. Allo-SCT has some promising results. Toxicity is still an issue. Trials are ongoing. PTCL trials run so far show that most therapy failures occur early due to refractory disease. New drugs improving on induction treatment are therefore needed.

REVISION QUESTIONS 1. What is the expected pooled 5-year OS of PTCL after standard CHOP chemotherapy? 2. Which PTCL subtype seems to benefit most from a 1st line dose-dense induction consolidated by ASCT? 3. According to the relapse pattern observed in recent upfront ASCT trials in PTCL, in which part of the treatment course is the highest frequency of treatment failures seen?

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New drugs A substantial number of new drugs are currently being tested at phase I, II, and III levels, either alone or in combination with chemotherapy.

Compound

ORR (monotherapy)

Alemtuzumab (CD52)

36%

Siplizumab (CD2)

31%

Belinostat

32%

Zanolimumab (CD4)

26%

Pralatexate

29%/39%

Romidepsin

26%/38%

Brentuximab vedotin (CD30)

87%/86%

New drugs are e.g.: monoclonal antibodies, antibody–drug conjugates, antifolates, histone deacetylase inhibitors (HDACi), antiangiogenic molecules etc.

Antifolate

HDACi

Alemtuzumab

Pralatrexate

Romidepsin

Structure

Unconjugated mAb

Alemtuzumab, monotherapy or combined with chemotherapy (CT), has a long phase II feasibility curriculum. Main toxicity: infectious complications. The antifolate, pralatrexate, was tested in rel/ref PTCL patients. The ORR was 29% and the median duration of response (mDR) was 10 months. Main toxicity: mucositis.

Systematic PTCL

Group

As monotherapy in relapsed/refractory PTCL, these new drugs have overall response rates (ORR) of 25-40%, except brentuximab vedotin with an ORR of 86%.

HDACi, such as romidepsin (RD), have shown ORR of 25-35%, with mDR of 12 months. Main toxicity: bone marrow suppression and infections.

Monotherapy rel/ref ORR: 36%

Monotherapy rel/ref ORR: 29%

Monotherapy rel/ref ORR: 25%

A conjugate of anti-CD30 (brentuximab vedotin) linked to the antitubulin agent, monomethyl auristatin E, has been developed to target CD30+ neoplasms such as ALCL. A trial in rel/ref ALCL showed an ORR of 86% (CR 57%) and mDR of 9 months. Main toxicity: sensory neuropathy. An upfront phase III trial is planned. Other drug types such as proteasome, mTor, aurora kinase inhibitors, lenalidomide, antiangiogenic drugs are currently being tested in PTCL.

REVISION QUESTIONS 1. What is the range of ORR following the majority of new drugs in PTCL? 2. What are the main toxicities of (i) alemtuzumab, (ii) pralatrexate, and (iii) romidepsin? 3. What is the overall response rate and the fraction of complete remissions in relapsed/refractory ALCL treated with brentuximab vedotin? And what is the conjugate’s main side effect?

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Summary: Peripheral t-cell lymphomas • 10–15% of all lymphomas, very heterogeneous group • Can be primary nodal, primary extranodal, primary cutaneous, or primary leukemic • The International Prognostic Index is a useful prognostic tool in the majority of PTCL • Heterogeneous outcome, ALCL has one of the best outcomes, HS PTCL one of the worst • In systemic ALCL, lack of expression of the alk-fusion protein is correlated with a worse prognosis • The same feature is irrelevant in primary cutaneous ALC • Overall the 5-year OS for PTCL (all subtypes) when treated with standard CHOP is approximately 35% • The role of upfront stem cell therapies is still debated • The largest fraction of treatment failures (25-35%) is upfront, during induction • A number of new drugs are currently being tested in phase III trials (e.g. alemtuzumab, pralatrexate, romidepsin) • The anti-CD30 antibody–drug conjugate, brentuximab vedotin, achieved an ORR of 86% with 57% CRs

Further Reading Coiffier B, Pro B, Prince HM, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol 2012; 30:631–636. D’Amore F, Relander T, Lauritzsen GF, et al. Upfront autologuos stem cell transplantation in peripheral T-cell lymphoma (NLG-T-01). J Clin Oncol 2012 Jul 30 [Epub ahead of print]. De Leval L, Gaulard P. Pathology and biology of peripheral T-cell lymphomas. Histopathology 2011; 58:49–68. Delabie J, Holte H, Vose JM, et al. Enteropathy-associated T-cell lymphoma: clinical and histological findings from the international peripheral T-cell lymphoma project. Blood 2011; 118:148–155. Foss FM, Zinzani PL, Vose JM, Gascoyne RD, Rosen ST, Tobinai K. Peripheral T-cell lymphoma. Blood 2011; 117:6756–6767. Gutiérrez-García G, García-Herrera A, Cardesa T, et al. Comparison of four prognostic scores in peripheral T-cell lymphoma. Ann Oncol 2011; 22:397–404. O’Connor OA, Pro B, Pinter-Brown L, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol 2011; 29:1182–1189. Savage KJ. Prognosis and Primary Therapy in Peripheral T-Cell Lymphomas. Hematology: American Society of Hematology Education Program 2008; 280-288. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: International Agency for Research on Cancer, 2008. Vose J, Armitage J, Weisenburger D; International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2008; 26:4124–4130.

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12 Hodgkin lymphoma Epidemiology, pathology, biology Hodgkin lymphoma (HL) is a B-cell derived malignancy with an incidence of 2-3/100 000/year in developed countries. Young adults are most often affected.

Hodgkin lymphoma incidence by sex and age in the US population in 2007 Hodgkin lymphoma has a bimodal age distribution

Classical HL (cHL) accounts for about 95% of cases; 5% of patients are diagnosed with nodular lymphocyte-predominant HL (NLPHL). There are 4 histological cHL subtypes: nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted. NLPHL is a distinct entity.

The detection of Hodgkin and Reed-Sternberg (H-RS) cells is necessary to diagnose cHL. Lymphocyte-predominant (LP) cells are diseasedefining in NLPHL.

Reed-Sternberg cells in a characteristic reactive background infiltrate

Reed-Sternberg cell

In HL, less than 1% of cells in the affected LN tissue are malignant. They are embedded in an inflammatory background composed of reactive cells. In cHL, malignant cells stain positive for CD30 and CD15. In contrast, LP cells typically express CD20, CD45, and epithelial membrane antigen (EMA).

Activation of the NF-kappaB pathway in Hodgkin and Reed-Sternberg cells.

Some signaling pathways appear to play a crucial role in cHL.

RANKL

EBV infection (40%)

CD30L

CD40L

CD30

CD40

CD40L APRIL BAFF CD40

LMP1

BCMA TACI

RANK

Those include the nuclear factorkappaB (NF-kappaB), the janus kinase (JAK), and the signal transducer and activator of transcription (STAT) pathway. Signaling pathways are activated either constitutively or in an autocrine/paracrine manner via soluble and membrane-bound molecules.

TNFAIP3 mutations (60% EBV–) TNFAIP3

NIK

NEMO

IKKα IKKα

IKKα IKK β

Classical NF-κB pathway

Alternative NF-κB pathway

NFKBIA and NFKBIE mutations IκBα and (10–20%) IκBε

REL amplification (30%)

p50

RIP TRAF

p65

p50

p100

p65

RELB Proteasomal degradation

BCL3 gains or translocations (rare)

Nuclear membrane

BCL-3 p50

p50

p52 RELB

REVISION QUESTIONS 1. What HL subtypes are being distinguished? 2. What cells are disease-defining in cHL? 3. Which are the typical surface antigens distinguishing cHL from NLPHL?

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Clinical presentation and prognosis HL commonly presents with indolent lymphadenopathy. Liver, spleen, lung, and BM are other localizations that can be affected.

Lymph node regions (left) and areas (right) are not the same and must be distinguished

B-symptoms are frequently reported. Some patients present with severe pruritus, while pain in the involved LN after ingestion of alcohol is rare but characteristic. HL typically spreads following a contiguous pattern from one LN region to the next one.

Treatment groups according to the EORTC/GELA and the GHSG Treatment group EORTC/GELA

GHSG

Limited stage patients CS I-II without risk factors (supradiaphragmatic)

CS I-II without risk factors

Intermediate stage patients

CS I-II with ≥ 1 risk factor (supradiaphragmatic)

CS I, CS IIA with ≥ 1 risk factor; CS IIB with risk factors C/D, but not A/B

Advanced stage patients

CS III-IV

CS IIB with risk factors A/B, CS III/IV

Risk factors

(A) large mediastinal mass (B) age ≥ 50 years (C) elevated ESR (D) ≥ 4 nodal areas

(A) large mediastinal mass (B) extranodal disease (C) elevated ESR (D) ≥ 3 nodal areas

Overall, more than 80% of HL patients are cured with current standard first-line protocols.

The number of involved LN areas (≠ number of LN regions) is one of the features that determines risk groups. Depending on the Ann Arbor stage and the presence/ absence of risk factors, patients are allocated to different treatment groups. According to the classification mostly used in Europe, HL patients are divided into those with early favorable HL, early unfavorable HL, and advanced HL.

Age-standardized 5-year relative survival by sex for Hodgkin lymphoma patients in England and Wales

Even at relapse, about 60% of patients achieve a second durable remission when treated with an adequate salvage therapy. In contrast, after second relapse, cure is rather uncommon. However, the OS of these patients has improved in recent years.

Prognosis of Hodgkin lymphoma has steadily improved in recent decades

REVISION QUESTIONS 1. Besides classical B-symptoms, which symptoms are frequently reported by HL patients? 2. Which criteria influence the allocation of patients to a certain treatment group? 3. What proportion of HL patients is cured with first-line treatment?

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First-line treatment As treatment for HL has evolved so successfully, the current goal of treatment development is focused on maintaining efficacy while reducing toxicity.

Progression-free survival for patients with early favorable Hodgkin lymphoma treated within the GHSG HD10 trial

Treatment for early favorable cHL consists of a brief chemotherapy (as 2xABVD) followed by involved-field radiotherapy (IF-RT) at 20 Gy. At present, the omission of RT in patients with a negative PET after chemotherapy is being evaluated in clinical trials to further decrease toxicity. Clinical outcome with 2xABVD followed by 20 Gy IF-RT is equivalent to that observed with more aggressive approaches

The standard treatment for patients with early-stage NLPHL is RT alone. There is controversy about the addition of chemotherapy.

Progression-free survival for patients with early unfavorable Hodgkin lymphoma treated within the GHSG HD14 trial Progression-Free Survival (probability)

1.0 0.9 0.8

Relapse rate after 4xABVD is significantly higher than after 2xBEACOPPescalated followed by 2xABVD

0.7 0.6 0.5 0.4 0.3 0.1

95% CI (%)

89.1 95.4

86.3 to 91.9 93.7 to 97.1

P < .001

0 No. at risk Arm A Arm B

5-year PFS (%) Arm A Arm B

0.2

Patients with early unfavorable HL are usually treated with 4 cycles of chemotherapy (usually ABVD) followed by IF-RT. In younger patients this standard is being challenged by more intensive regimens such as BEACOPP. Of note, BEACOPP should not be given to patients >60 years.

Time (months) 765 752 722 675 603 511 445 366 292 227 145 97 763 753 720 688 616 538 473 375 302 239 173 113

45 61

For years, 6 to 8 cycles of ABVD were standard in advanced HL, but more intensive approaches such as 6 cycles of BEACOPPescalated result in a longer PFS. In advanced HL, RT is applied in cases of initial bulk or residual masses. RT is not necessary if the PET is negative after intensive BEACOPP chemotherapy. Trials using interim PET to either escalate or deescalate the intensity of treatment according to early tumor responsiveness are currently ongoing.

Treatment concepts for advanced Hodgkin lymphoma currently evaluated in clinical trials Option 1

Option 2

Less intensive 1st line

More intensive 1st line

↓

Interim PET+

Interim PET-

↓

Escalate

De-escalate

Risk: undertreatment

Risk: overtreatment

REVISION QUESTIONS 1. How should early favorable HL be treated? 2. What chemotherapy regimens are commonly used in advanced HL? 3. Which diagnostic tool is increasingly used for early treatment stratification?

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Treatment of relapsed disease In general, the treatment of choice for young and fit patients with relapsed HL is HDT with ASCT, provided they respond to salvage chemotherapy. Patients usually receive 2 to 4 cycles of a salvage protocol to reduce the tumor burden and to mobilize stem cells.

Standard procedure in case of relapsed Hodgkin lymphoma Histologically proven Hodgkin lymphoma relapse

↓

2 – 4 cycles of salvage chemotherapy (e.g. DHAP, ICE, IGEV)

↓

Stem cell harvest (after one of the cycles)

↓

The choice of salvage regimens depends on the drugs used in the initial therapy. Poor-risk patients may profit from tandem ASCT.

High-dose chemotherapy (BEAM)

↓

Autologous stem cell transplantation (ASCT)

Progression-free survival and overall survival of relapsed NLPHL patients treated with rituximab

In selected patients (minimally treated) with relapsed HL, a different conventional chemotherapy regimen and/or RT may be sufficient. In patients not eligible for ASCT, a prolonged survival and a satisfactory quality of life can be achieved with palliative approaches (i.e. gemcitabine, vinblastine). In relapsed NLPHL, anti-CD20 antibody treatment results in excellent response rates and long-term remissions in a significant proportion of patients.

Curative treatment options for patients who relapse after HDT with ASCT are very limited.

Overall survival after allogeneic stem cell transplantation (alloSCT) for Hodgkin lymphoma according to the type of conditioning regimen

Allogeneic transplantation is a potentially curative approach. However, the results in HL patients reported to date are rather disappointing. Patients with multiple relapses should be managed palliatively and are candidates for treatment with novel drugs such as brentuximab vedotin (SGN-35).

REVISION QUESTIONS 1. What is the standard treatment for most patients with relapsed HL? 2. What is the treatment of choice for most patients with relapsed NLPHL? 3. What treatment options exist for patients with multiple HL relapses?

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Follow-up and long-term sequelae Follow-up examinations should be conducted regularly to detect treatment-related late effects and recurrence of disease as early as possible. Follow-up visits should include physical examination and laboratory analyses (e.g. thyroid function tests for patients who have received mediastinal RT). Imaging investigations (i.e. CT scans) are not mandatory in the absence of signs or symptoms suggestive of progression.

Examinations may vary according to the individual patient

Recommended follow-up examinations in Hodgkin lymphoma patients

Examination of the body Case history Laboratory examinations: Differential blood count ESR, CRP TSH Echocardiography ECG Computed tomography1) (if PR) Chest X-ray (if no CT) Pulmonary function Abdominal ultrasound 1) 2)

Overall survival and freedom from treatment failure after diagnosis of secondary acute myeloid leukemia or myelodysplastic syndrome in Hodgkin lymphoma patients

2nd to From 4th year 5th year Every 6 Month 1 Month 3 Month 6 Month 12 Every year months 1st year

Examination times

X X

X X X

X X X X X

X X X X 2) X 2)

X X X X X

X 2)

X X X

further CTs are recommended depending on suspicious findings imaging examinations once a year

Common long-term sequelae after HL treatment include secondary malignancies, infertility, heart and lung failure, hypothyroidism, and chronic fatigue. Secondary malignancies are divided into therapyrelated hematological malignancies and secondary solid tumors. Among therapy-related hematological malignancies, acute myeloid leukemia (AML) is associated with a particularly poor prognosis.

Especially young women receiving mediastinal RT are at risk of developing breast cancer. Therefore cancer screening is particularly important in these patients.

The actuarial risks of death from major disease categories in Hodgkin lymphoma survivors

Depending on the drugs given and the number of chemotherapy cycles applied, a relevant proportion of patients may become permanently infertile. Thus, reproductive counseling should be offered to younger patients before treatment.

REVISION QUESTIONS 1. What are the most common long-term sequelae after HL treatment? 2. What is the most severe therapy-related hematological malignancy? 3. Which secondary solid tumor often occurs in young women receiving mediastinal RT?

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Summary: Hodgkin lymphoma • HL is a malignancy of the lymphatic system most often affecting young adults • Nodular lymphocyte-predominant HL is an entity clearly distinct from classical HL • Several signaling pathways including the NF-kappaB pathway are involved in the pathogenesis of HL • HL patients present frequently with indolent lymphadenopathy often accompanied by B-symptoms • The type of treatment is chosen depending on the clinical stage and the presence/absence of risk factors • Patients are divided into those with early favorable, early unfavorable, and advanced stages • Patients with early-stage disease are commonly treated with combined-modality approaches; most patients with advanced HL receive chemotherapy alone • High-dose chemotherapy followed by ASCT is considered the standard of care for most patients with relapsed HL • Overall, 80-90% of HL patients achieve long-term remission and can be considered cured • Regular follow-up visits are necessary to detect relapses and long-term sequelae as early as possible

Further Reading Canellos GP, Niedzwiecki D, Johnson JL. Long-term follow-up of survival in Hodgkin’s lymphoma. N Engl J Med 2009; 361:2390–2391. Engert A, Haverkamp H, Kobe C, et al; German Hodgkin Study Group; Swiss Group for Clinical Cancer Research; Arbeitsgemeinschaft Medikamentöse Tumortherapie. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet 2012; 379:1791–1799. Engert A, Plütschow A, Eich HT, et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med 2010; 363:640–652. Fermé C, Eghbali H, Meerwaldt JH, et al. Chemotherapy plus involved-field radiation in early-stage Hodgkin’s disease. N Engl J Med 2007; 357:1916–1927. Josting A, Müller H, Borchmann P, et al. Dose intensity of chemotherapy in patients with relapsed Hodgkin’s lymphoma. J Clin Oncol 2010; 28:5074–5080. Josting A, Wiedenmann S, Franklin J, et al. Secondary myeloid leukemia and myelodysplastic syndromes in patients treated for Hodgkin’s disease: a report from the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 2003; 21:3440–3446. Morschhauser F, Brice P, Fermé C, et al. Risk-adapted salvage treatment with single or tandem autologous stem-cell transplantation for first relapse/refractory Hodgkin’s lymphoma: results of the prospective multicenter H96 trial by the GELA/SFGM study group. J Clin Oncol 2008; 26:5980–5987. Steidl C, Connors JM, Gascoyne RD. Molecular pathogenesis of Hodgkin’s lymphoma: increasing evidence of the importance of the microenvironment. J Clin Oncol 2011; 29:1812–1826. van der Kaaij MA, Heutte N, Meijnders P, et al. Premature ovarian failure and fertility in long-term survivors of Hodgkin’s lymphoma: a European Organisation for Research and Treatment of Cancer Lymphoma Group and Groupe d’Etude des Lymphomes de l’Adulte Cohort Study. J Clin Oncol 2012; 30:291–299. von Tresckow B, Plütschow A, Fuchs M, et al. Dose-intensification in early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin study group HD14 trial. J Clin Oncol 2012; 30:907–913.

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More advanced knowledge

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13 Etiology and epidemiology Burden of lymphomas – incidence and mortality Epidemiology data on lymphoma derive from population registries (covering 15% of the world population), which collect information on incidence, mortality, and clinical data. The global incidence of the “lymphoid neoplasms” category (NHL, MM, HL, and leukemias) is 12.5 x 105, making this group the 7th most common in incidence of cancer. Higher incidence rates of NHL, MM, HL, and CLL are observed in industrialized-rich countries. Lowest rates are observed in eastern Asia.

Age-adjusted SEER incidence rates by cancer site all ages, all races, male 1975-2008 (SEER 9)

Rate per 100,000

Increasing incidence has been observed in many countries: the incidence of NHL ↑ 11% and the incidence of MM ↑ 70% among ♂ during 1997-2008.

NHL incidence has increased over the last decades in the US (annual increase = 4.2% in ♂ and 2.8% in ♀ during 1975-2001)

Non-Hodgkin Lymphoma

NHL is the 8th most common cause of cancer death in the world. Around 191 599 died in 2008 of NHL, 29 902 of HL, 72 453 of MM, and 257 161 of leukemia.

High rates of NHL are observed in specific countries like Egypt, where NHL has been linked to a high prevalence of hepatitis C. The incidence of certain cancers is increased in specific ethnic groups, e.g. MM incidence is higher in AfricanAmericans and CLL is lower in Asians.

Estimated age-standardized mortality rate per 100 000 Non-Hodgkin lymphoma: both sexes, all ages

Three quarters of all deaths from NHL occur in people >65 years. Mortality rates of NHL, HL, MM, and leukemias are higher for ♂ worldwide. Lymphoma deaths (including CML) are expected to increase from 551 115 cases in 2008 to 636 888 in 2015, due only to natural demographic variation. <1.9

<2.6

<3.0

<3.9

<7.3

REVISION QUESTIONS 1. How frequent are “lymphoid neoplasms” in comparison with other types of cancer? 2. How can you explain the differential incidence and mortality across the world? 3. Do you think all lymphoma subtypes have the same geographical distribution?

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Etiology - Genetic and environmental factors The likelihood of being diagnosed with a hematological malignancy markedly ↑ with age and it is more frequent in ♂ than in ♀.

Incidence rates per 100 000 and number of cases (World - Non-Hodgkin Lymphoma) 45000

35000

Number of cases

Familial aggregation of lymphoma has been consistently reported, thus implicating either genetic susceptibility or shared environmental exposures.

30000 25000

U2AF2 interaction SF3B14 interaction HEAT domain

Y623C K700E V701F R625H H662D K741N G742D D894G N626Y T663I K666E

40 30

20000 15000

10000

5000 0

0 0-14

15-39

40-44

45-49

50-54

55-59

60-64

65-69

70-74

75+

Age Male cases

Rate per 100 000

Primary and acquired states of severe immunosuppression (HIV/AIDS and organ transplantation) constitute well-established risk factors for NHL and HL.

The diagnosis of hematological malignancies increases with age and it is more frequent in men

40000

Female cases

Male rates

Female rates

Recurrent mutations in the SF3B1 gene have recently been identified in CLL

The risk of NHL is ↑ about 2- to 3-fold in firstdegree relatives of patients with hematopoietic cancer, being about 7-fold or more for CLL. Genotype variations in HLA are linked to HL. Whole genome association studies (GWAS) and sequencing case studies are active research areas.

The global ↑ in NHL incidence suggests a key role of environmental factors in their etiology, interacting in a complex network with genetic and infectious factors.

Thr663 Arg625 Val701 Asn626 Lys666 His662 Lys700 Tyr623

Asp894 Gly742 Lys741

The exposure to environmental factors related with occupation, such as pesticides, benzene, or organochlorines, may ↑ lymphoma risk.

Risk associated with organochlorine exposure interacts with the genotype

Chemical exposures such as use of hair dyes have been occasionally linked to an ↑ risk of CLL. Risk was strong and consistent for exposures before 1980s. Medical conditions such as diabetes may ↑ lymphoma risk while use of statins may ↓ it. Inconsistent data have been reported on a protective effect for UV and Vit D.

REVISION QUESTIONS 1. Do you think that all NHL subtypes share the same risk factors? 2. What are the most well-known risk factors for NHL? 3. Why are environmental factors considered in the etiology of NHL?

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Etiology - Environmental and infectious factors Reproductive factors could explain the ↑ incidence of lymphoma in ♂ than in ♀. Some studies report a ↓ risk associated with ↑ parity. The effect of alcohol consumption, tobacco, and dietary factors on the risk of NHL is uncertain and subject to continuous research. An ↑ body mass index (BMI) has been associated with NHL, and particularly with DLBCL (13% ↑ risk of DLBCL associated with a 5 kg/m2 increment in BMI).

Parity may decrease lymphoma risk

Viruses consistently associated with malignant lymphomas include EBV, HHV-8, HCV, and HTLV-1. H. pylori is a bacterium causally related to lymphoma. HIV does not cause lymphoma by a direct mechanism, but through immunosuppression. The role of HHV-8 in the etiology of NHL is not clear in the absence of HIV.

A higher BMI could increase the risk of DLBCL

EBV infection, and consequently the history of infectious mononucleosis, has been consistently associated mainly with HL, endemic BL, and DLBCL.

Aberrant serological anti-EBV immune response patterns are associated with lymphoma, indicating an underlying loss of immune control of EBV infection. The association of HCV infection with some NHL (DLBCL, MZL, and LPL) has been found in large populations with both ↓ and ↑ HCV seroprevalence.

Several studies have shown that the prevalence of antibodies against HCV is higher in patients with NHL than in controls

HTLV-1 is the cause of adult T-cell leukemia/ lymphoma. HLTV-1 transmission occurs with sexual relations, breastfeeding, and blood transfusions.

REVISION QUESTIONS 1. Explain potential reasons for the increase in incidence of lymphoma observed in some countries 2. Do you think that genetic predisposition to lymphoma can be modulated by environmental factors? 3. What infectious agents are the most consistently associated with lymphoma?

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Summary: Etiology and epidemiology • “Lymphoid malignancies” are the 7th commonest type of cancer • The incidence of lymphoma varies widely across different regions of the world • Lymphomas represent globally a large burden in industrialized countries, but precise knowledge on the burden in developing countries is limited • Men have a higher incidence and mortality, for reasons not well understood • The incidence of lymphoma increases with age • Family history of hematological malignancies increases the risk of lymphoma • Immune suppression is a major risk factor for lymphoma, largely including HIV and organ transplant recipients • Some specific lymphomas have been linked to specific infections, such HTLV-1 to ATLL or H. pylori to MALT • Endemic Burkitt has been linked to EBV and probably to concomitant environmental factors • There are other less well known risk factors such as high BMI, parity, and environmental factors such as exposure to pesticides

Further Reading Blinder V, Fisher SG. The role of environmental factors in the etiology of lymphoma. Cancer Invest 2008; 26:306–316. de Sanjose S, Benavente Y, Vajdic CM, et al. Hepatitis C and non-Hodgkin lymphoma among 4784 cases and 6269 controls from the International Lymphoma Epidemiology Consortium. Clin Gastroenterol Hepatol 2008; 6:451–458. Ekström-Smedby K. Epidemiology and etiology of non-Hodgkin lymphoma - a review. Acta Oncol 2006; 45:258–271. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007; 370:59–67. Hartge P, Devesa SS. Quantification of the impact of known risk factors on time trends in non-Hodgkin’s lymphoma incidence. Cancer Res 1992; 52(19 Suppl):5566s–5569s. Obrams GI, O’Conor G. The emerging epidemic of non-Hodgkin’s lymphoma: current knowledge regarding etiological factors. Time trends and pathological classification: a summary. Cancer Res 1992; 52(19 Suppl):5570s. Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer 2006; 118:3030–3044. Rogena EA, De Falco G, Schurfeld K, Leoncini L. A review of the trends of lymphomas in the equatorial belt of Africa. Hematol Oncol 2011; 29:111–115. Serraino D, Salamina G, Franceschi S, et al. The epidemiology of AIDS-associated non-Hodgkin’s lymphoma in the World Health Organization European Region. Br J Cancer 1992; 66:912–916. Sillé FC, Thomas R, Smith MT, Conde L, Skibola CF. Post-GWAS functional characterization of susceptibility variants for chronic lymphocytic leukemia. PLoS One 2012; 7:e29632. Wang, R, Zhang Y, Lan Q, et al. Occupational exposure to solvents and risk of non-Hodgkin lymphoma in Connecticut women. Am J Epidemiol 2009: 169:176–185.

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14 History of lymphoma classification The 1960s and 1970s “To classify” is a multistep process, which starts by describing and naming diseases, followed by grouping them in categories according to similar traits.

Classification steps in lymphomas description

A good classification results in the clear description of the characteristics that define a specific entity, thus allowing an unambiguous diagnosis. Pathologists play a critical role in developing classifications of lymphomas. Classification is always a compromise.

Requisites for a successful classification • Sharp distinction of single entities • Clinically useful • Updated in view of recently described entities • Periodically updated

definition

diagnosis

treatment

study of pathogenesis

The history of lymphoma classification reflects the evolution of advances in the knowledge of the biology of lymphomas. Classification is an ongoing phenomenon. Accordingly, there is not an ultimate, gold standard classification for any disease and in particular for lymphomas. A successful classification requires that single entities must be clearly kept separate, must be clinically distinctive, and include recently defined entities.

Lymphoma classification in the 1970s recognized basically four different proposals: two from the USA, one from the UK, and one from Europe. Rappaport’s and BNLI classification included only morphological details, while Kiel and Lukes & Collins schemes introduced the concept of B- and T-lineages. The main limitations of a purely morphological classification are poor reproducibility among pathologists and reduced reliability among clinicians.

Classification in the 1970s • Rappaport (USA): lymphocytic, well and poorly differentiated; mixed lymphocytic and histiocytic; histiocytic. Nodular and diffuse patterns • Lukes & Collins (USA): cleaved, non-cleaved, convoluted cells; B, T and ‘undefined’ phenotype • BNLI (UK): prognostic categories grade I and II NS-HL • Kiel (Europe): introduction of B and T immunophenotype and histological low- and high-grade subsets

REVISION QUESTIONS 1. What does it mean that a classification is a compromise? 2. Which are the requirements of an ideal classification system? 3. Which are the limits of a lymphoma classification based on morphological grounds alone?

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The 1980s and 1990s During the 1980s, two main classifications were used: the International Working Formulation (IWF) (USA, 1982) and the updated Kiel classification (Europe, 1988). For the first time, IWF was adopted by both pathologists and clinicians. IWF considered only morphological features such as cytology and growth pattern.

Classification in the 1980s • Working Formulation tried to find a common language between pathologists and clinicians • Different entities were grouped, according to their degree of malignancy, in low-, intermediate-, and high-grade

IWF stratified lymphomas in low-, intermediate-, and high-grade aggressive categories. This characterization was not always clinically useful.

Updated Kiel classification B lymphomas

T lymphomas

• B-lymphoblastic

• T-lymphoblastic

• B-lymphocytic, CLL

• T-lymphocytic

• Centrocytic

• Small cell cerebriform

• Centroblastic-centrocytic

• T-zone

• Monocytoid

• Pleomorphic, medium, and large cell T-NHL

• Centroblastic

• Angioimmunoblastic

• B-immunoblastic

• T-large cell anaplastic

The updated Kiel classification better defined immunophenotypic properties of single entities and introduced new entities. The basic characteristics of the initial morphologybased Kiel classification were retained, but lymphomas were divided according to B- or Tphenotype. The correlation between pathological subtypes and clinical characteristics and outcome was still not complete.

• Burkitt

Discordantly evaluated entities among different classifications: the paradigm of mantle cell lymphoma

In the 1990s, the difficulties arising from using different classifications in Europe and US highlighted the need for a common tool to diagnose lymphomas. The lack of a common language hampered the comparison of pathological and clinical series among different institutions. It was recognized that histologically identical lymphomas were biologically distinct (e.g. systemic DLBCL vs CNS DLBCL).

The same entity was called ‘centrocytic’ by Kiel classification and ‘small lymphocytic’ or ‘diffuse, small cleaved cell’ by IWF before being defined as ‘mantle cell’ by REAL classification

REVISION QUESTIONS 1. What were the advantages and disadvantages of the International Working Formulation? 2. What did the updated Kiel classification introduce? 3. Which were the main limitations of available classification schemes in the early 1990s?

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The development of a modern classification The REAL (Revised European-American Lymphoma) classification was the first approach to integrate clinical, pathological, cytogenetic, and molecular data. The 2001 WHO classification adopted the principles of the REAL classification, with the aim of defining unique clinicopathological entities.

An example of a clinicopathological entity: mantle cell lymphoma

• Morphology: centrocytic-like cells • Immunophenotype: CD20+, CD5+, CD23-, cyclin D1+, CD3• Cytogenetic features: t(11;14) • Clinical course: usually aggressive and refractory to therapy

This comprehensive approach allowed withdrawing previous entities not fulfilling the above-mentioned criteria and new diseases were described.

The 2001 WHO classification introduced the concept of a “provisional” entity, when there is a suggestion but no demonstration that it can be differentiated from others.

Critical parameters in 2008 WHO classification

Provisional entities are ultimately accepted as definitive categories only after validation of their distinctive properties by prospective evaluation. The WHO classification was updated in 2008 and is currently regarded as the reference lymphoma classification in clinical practice.

Genetic techniques already integrated in the classification of lymphomas: the example of FISH

The 2008 WHO classification’s outstanding characteristic is the integration of new entities and a more stringent interaction with clinical data.

New classifications will include newer, more sophisticated genetic techniques

Forthcoming classifications should include genetic data derived from array CGH, gene expression profiling, and whole genome sequencing data. In the forthcoming years, an increasing role will also be played by proteomic- and metabolomic-generated data. t(11;14)

REVISION QUESTIONS 1. What is the major advance reached by the 2001 WHO classification? 2. How should “provisional entities” be regarded? 3. Which is the currently used lymphoma classification in clinical practice?

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Summary: History of lymphoma classification • Morphology represents the backbone of all lymphoma classifications • In the 1970s, Kiel and Rappaport classifications were used in Europe and USA, respectively • In the 1980s, the updated Kiel classification introduced the distinction between B- and T-cell derived entities • The IWF was an attempt to make the lymphoma classification useful for clinicians • In the 1990s, the necessity for a common worldwide classification resulted in the REAL classification • The WHO 2001 classification, inspired by the REAL, integrated clinical, pathological, cytogenetic, and genetic information • A modern classification requires the integration of histological, immunophenotypic, cytogenetic, molecular, and clinical information to define unique clinicopathological entities

Further Reading Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: International Agency for Research on Cancer; 2008.

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15 Molecular biology of lymphomas Basis and methods of study The study of the molecular genetics of lymphoma contributes to the diagnosis, prognosis, and management. Several techniques can be used. B- and T-cell precursors rearrange their Ig or TCR genes to become mature B or T cells, and this rearranged gene is unique to each B or T cell. As a result, all lymphomas have a clonal marker that can be sensitively detected by the polymerase chain reaction (PCR) technique.

The defining features of some specific lymphoma types are specific chromosomal translocations, although they may also occasionally occur in other lymphomas. These specific translocations may be detected by chromosome banding, FISH (use of fluorescent chromosome probes), and PCR techniques. PCR detection of IgH/BCL2 rearrangement

Many of the translocations involve the Ag receptor genes as a partner due to errors at the time of their rearrangement (i.e. IgH/BCL2 rearrangement in FL).

FISH can be performed on metaphase and interphase (non-dividing) cells as well as in fresh or paraffin-embedded tissues, so it is a very versatile technique. The main disadvantage of PCR/FISH is that, depending on the primers/probes used, they can tell if there is or is not a specific translocation but will not detect other abnormalities.

Cytogenetics allows the study of the whole karyotype

Microarrays analyze many genes at the same time, creating a gene expression profile (GEP). Abnormally activated pathways result in specific patterns of expression (signatures). FISH studies detect only a specific abnormality

REVISION QUESTIONS 1. What feature defines clonality in lymphomas? 2. Mention three techniques used in the study of the molecular biology of lymphomas 3. What is the common factor in many of the chromosomal translocations defining lymphomas?

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Applicability of molecular genetics studies The WHO classification includes specific chromosomal alterations to diagnose some types of NHL. FISH probes are available to detect most translocations. Molecular abnormalities can be critical to define new lymphoma entities such as the so-called â&#x20AC;&#x153;double-hitâ&#x20AC;? lymphomas. Some lymphoma subtypes are defined by specific GEP signatures, e.g. 2 signatures for DLBCL: the activated B cell-like (ABC) and the germinal B celllike (GCB).

Germinal center B-like diffuse large B-cell lymphoma

Lymphoma

Chromosome abnormality

Genes

B-cell NHL

t(V;14)(V;q32)

IGH

t(14;18)(q32;q21)

IGH, BCL2

MCL

t(11;14)(q13;q32)

CCND1, IGH

DLBCL

t(3;14)(q27;q32) t(2;3)(p12;q27) t(3;22)(q27;q11.2)

BCL6, IGH IGK, BCL6 BCL6, IGL

MALT

t(11;18)(q21;q21) t(14;18)(q32;q21)

AP12, MALT IGH, MALT

t(8;14)(q24;q32) t(2;8)(p12;q24) t(8;22)(q24;q11.2)

MYC, IGH MYC, IGK MYC, IGL

ALCL

t(2;5)(p23;q35) t(V;5)(V;q35)

ALK, NPM

T-NHL

7q35 7p14-15 14q11.2 rearrangements

TCR beta TCR gamma TCR alpha/delta

The signatures of DLBCL define two subtypes with different prognosis (GCB, better OS than ABC). The molecular signature might guide therapy in the future.

Activated B-like diffuse large B-cell lymphoma

The persistence of minimal residual disease (MRD) after treatment (disease not detected macroscopically) can help guiding management decisions.

Genes

PCR is more sensitive than FISH and is better for MRD detection. MRD positivity correlates with prognosis in some types of lymphomas.

REVISION QUESTIONS 1. How can molecular biology studies help in the diagnosis of lymphoma? 2. What information is provided by GEP studies in DLBCL? 3. What is the best technique to study minimal residual disease?

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The future The discovery of biomarkers and their incorporation into clinical trials will help to better define the patients benefiting from pathway-directed therapy. The future will require molecular diagnostics for treatment stratification with biological therapies and for combination therapy with these compounds.

A number of molecular biology techniques are under research, but many are still experimental, expensive, and not applicable to the routine practice.

Technique

Advantages

Disadvantages

Flow cytometry

Good for diagnostics

Needs fresh tissue

Well developed Banded cytogenetics

Looks at all chromosomes

Needs fresh viable cells Technically difficult

FISH

Interphase and any tissue

Low sensitivity Specific to area of analysis. Lengthy and expensive to perform

PCR

Quick, very sensitive, good for MRD

Not applicable to many alterations

Relatively cheap

Usually needs fresh tissue

Expression arrays SNPs MicroRNA profiling Epigenetic profiling

Help to define disease Applicable to DLBCL

Currently remains largely experimental but commercial cheap analyses are rapidly developing

Large scale mutational analysis Next generation sequencing (NGS)

400 gene profiling possible at low cost from paraffin

Experimental

Whole genome sequencing

The ultimate answer

Needs fresh tissue. Costs too much at the moment

REVISION QUESTIONS 1. How can molecular genetics studies help in the future? 2. What are the advantages and disadvantages of PCR in the management of lymphoma? 3. What advantages does NGS have, making it a very promising tool for the future?

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Summary: Molecular biology of lymphoma • All lymphomas have clonal antigen receptor rearrangements detectable by PCR • WHO includes distinctive chromosomal alterations in the classification to define specific subtypes of lymphoma • FISH remains the most versatile although less sensitive technique • Non-translocation alterations are less well defined • DLBCL is molecularly defined as ABC or GCB by gene expression. The molecular subtype is associated with prognosis • PCR is the best technique to measure minimal levels of disease • Novel molecular biology techniques might help in the future to stratify patients to receive targeted biologicals according to the abnormal pathways involved

Further Reading de Kerviler E, Benet C, Brière J, de Bazelaire C. Image-guided needle biopsy for diagnosis and molecular biology in lymphomas. Best Pract Res Clin Haematol 2012; 25:29–39. Frick M, Dörken B, Lenz G. New insights into the biology of molecular subtypes of diffuse large B-cell lymphoma and Burkitt lymphoma. Best Pract Res Clin Haematol 2012; 25:3–12. Fruman DA, Rommel C. PI3Kδ Inhibitors in cancer: rationale and serendipity merge in the clinic. Cancer Discov 2011; 1:562–572. Hill BT, Sweetenham J. Clinical implications of the molecular subtypes of diffuse large B-cell lymphoma. Leuk Lymphoma 2012; 53:763–769. Linton K, Howarth C, Wappett M, et al. Microarray gene expression analysis of fixed archival tissue permits molecular classification and identification of potential therapeutic targets in diffuse large B-cell lymphoma. J Mol Diagn 2012; 14:223–232. Pasqualucci L. Relevant pathogenic pathways in diffuse large B cell lymphoma. Haematology Education 2011; 5:191–198. Schneider C, Pasqualucci L, Dalla-Favera R. Molecular pathogenesis of diffuse large B-cell lymphoma. Semin Diagn Pathol 2011; 28:167–177. Tousseyn T, De Wolf-Peeters C. T Cell/histiocyte-rich large B-cell lymphoma: an update on its biology and classification. Virchows Arch 2011; 459:557–563. Yeung DT, Parker WT, Branford S. Molecular methods in diagnosis and monitoring of haematological malignancies. Pathology 2011; 43:566–579. Yohe SL, Bahler DW, Kinney MC. Molecular Pathology of Mature B-Cell and T-Cell Lymphomas. In Crisan D (Ed). Hematopathology: Genomic Mechanisms of Neoplastic Diseases. New York: Humana Press, 2010; 157–214.

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16 New drugs and novel treatment strategies Introduction The mechanisms of action of conventional cytotoxic drugs are based on the inhibition of general functions of the cells (e.g. DNA replication or mitotic spindle formation).

Vinca alkaloids interfere with formation of mitotic spindle

Their efficacy is based on the fact that the growth and survival of tumor cells depends on these mechanisms more than normal cells. Side effects are caused by the interference with the same mechanisms in those normal tissues that have a physiological high replication rate (such as BM).

Inhibition of signaling pathways

Anthracyclines - intercalation with DNA

Tumor cells often have a shrunken signaling network. Novel targeted therapies aim to attack pathways that are of crucial importance for these cells.

Restoration of potential to undergo apoptosis

These pathways can be dominantly or exclusively present in tumor cells or have a causal relationship with tumor development. Some targeted therapies are involved in engaging host-specific responses against tumor, overriding resistance mechanisms or restoring capability to undergo apoptosis.

Inhibition of new fusion proteins resulting from genetic recombinations

The development of novel agents can be limited, as the more specific the target is, the smaller the group of patients that can benefit from it.

Current classifications include biologically different entities, thus increasingly small subgroups are defined

New models for clinical testing are needed (e.g. competitive testing of various drugs) as synergisms can depend on types of combination and sequence. Unexpected side effect profiles may occur, as not all functions of the targets may have been explored and can differ depending on combination partners.

Given the availability of a high number of novel options and the smaller number of patients, new trial strategies are required Drugs have to be developed separately for subgroups and combinations have to be developed carefully due to different side effect profiles

REVISION QUESTIONS 1. Why do conventional chemotherapies share a variety of common side effects? 2. Can novel and conventional agents be combined without being tested in early clinical trials? 3. Is the side effect profile of targeted therapies predictable?

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Immunotherapies The most important group of immunotherapies are monoclonal antibodies (MoAb) against various antigens present on the surface of lymphoid cells. Ideal tumor antigens are stably expressed on the cell or internalized upon binding, lack a soluble form, are specific for the target, and not present on normal cells.

Complementmediated cytolysis

Vaccination effect

Unconjugated (â&#x20AC;&#x153;nakedâ&#x20AC;?) MoAb act through antibody-dependent cytotoxicity (ADC), complement-dependent cytotoxicity (CDC), or induction of apoptosis.

Delivery of toxins which are released with internalization (e.g. inotuzumab, ozogamicin, brentuximab vedotin)

Direct cell killing

Targeted radiotherapy: radioisotopes deliver irradiation direct to tumor (e.g. ibritumomab tiuxetan)

Antibodydependent cellular toxicity

Conjugated MoAb do not act directly, but use their high specificity to redirect attached effectors directly to the tumor cells. Radioisotopes have been linked to MoAb, resulting in direct irradiation of lymphoma cells. Toxins can also be bound to MoAb and released upon internalization. Finally, bispecific antibodies are able to attract immune effectors directly to the lymphoma cells and cause specific lysis.

Bispecific antibodies redirect immune effectors to the tumor cell (e.g. blinatumomab)

A specific immune response can be promoted by the administration of an idiotypic vaccine developed against a specific idiotype of the individual lymphoma. Immunomodulators (IMIDs) such as lenalidomide result in activation of NK/T cells, upregulation of costimulatory molecules, and abrogation of proinflammatory cytokines.

Allogeneic stem cell transplant induces graftversus-lymphoma effect

Idiotypes can be used to develop specific vaccines

DONOR

Further immunological approaches include reduced-intensity conditioning regimen allogeneic transplants to exploit the graftversus-lymphoma effect.

IMIDs activate immune effectors, modulating the interactions with stroma

REVISION QUESTIONS 1. Which are the mechanisms of action of monoclonal antibodies? 2. Which active immunotherapies can be used for the treatment of lymphoma? 3. Which drugs influence the environment of lymphoma cells?

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Targeting signaling, epigenetics, and apoptosis Some signaling pathways are of special importance in lymphoma. The B-cell receptor pathway, transducing a growth stimulus, can be attacked at different levels.

PI3K inhibitors: CAL-101

PKCĂ&#x; inhibitors: enzastaurin

Drugs interacting with key elements of the B-cell receptor pathway (Syk, BTK, or PKCĂ&#x; inhibitors) are already undergoing clinical trials.

Syk inhibitors: fostamatinib

The PI3K/AKT/mTOR is another key pathway for transduction of growth stimuli and cell proliferation. Various drugs (e.g. mTOR inhibitors) interfere with this pathway. HDAC inhibitors can restore normal gene expression

BTK inhibitors: ibrutinib

AKT inhibitors mTOR inhibitors: temsirolimus, everolimus, ridaforolimus

Blocking DNA repair makes tumor cells more susceptible to cytotoxic agents

ALK inhibitor: crizotinib

Epigenetic therapies such as histone deacetylase inhibitors can stop proliferation by modulating gene expression through modification of DNA-related molecules. Some lymphomas depend for their survival on interactions with stroma or bystander cells. Research on blocking these interactions is under way.

Inhibition of interaction between microenvironment and tumor: interruption of feedback loops

Tumor cells need effective DNA-repair machinery, the inhibition of which (e.g. with PARP inhibitors) is an interesting option, especially if combined with cytotoxics. Elimination of anti-apoptotic proteins restores apoptosis

Interference with protein homeostasis can be of therapeutic value: proteasome inhibitors are in clinical use; heat shock protein inhibitors are under evaluation. Inhibition of the replication machinery of the cell is another interesting approach. Examples are cyclin, aurora kinase, or hedgehog pathway inhibitors. Lymphoma cells overexpress proapoptotic elements of the bcl-2 family. Drugs like ABT-263, obatoclax, or survivin inhibitors can restore programmed cell death.

Inhibition of proteasome can inversely influence transcription signals

Inhibition of cell cyle progression results in stopping proliferation

REVISION QUESTIONS 1. Which pathways are especially important in lymphomas? 2. Do all therapeutic approaches directly address the tumor cells? 3. How do lymphoma cells become resistant to apoptosis?

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Summary: New drugs and novel treatment strategies • Historical approaches: drugs interfering with general functions of dividing cells • Novel strategies: aim to target tumor-specific features of following categories • Immunological approaches: • Antibodies for ADC- or CDC-dependent lysis • Antibodies for delivery of toxins or radioisotopes or redirection of tumor cells • Active or passive immunotherapies such as vaccination, allogeneic SCT, or immunomodulation • Inhibition of specific pathways • B-cell receptor pathway: Syk, BTK, or PKCß inhibitors • PI3K/AKT/mTOR pathway: PI3K, AKT, or mTOR inhibitors • Approaches aiming at stress responses, microenvironment, restoration of apoptosis, epigenetics, stromal interaction, and inhibition of mediators • Broadened understanding of effects and side effects as well as optimal combination approaches requires welldesigned and harmonized clinical testing

Further Reading Ai WZ, Tibshirani R, Taidi B, Czerwinski D, Levy R. Anti-idiotype antibody response after vaccination correlates with better overall survival in follicular lymphoma. Blood 2009; 113:5743–5746. Bargou R, Leo E, Zugmaier G, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 2008; 321:974–977. Brody JD, Ai WZ, Czerwinski DK, et al. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. J Clin Oncol 2010; 28:4324–4332. Fisher RI, Bernstein SH, Kahl BS, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 2006; 24:4867–4874. Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010; 115:2578–2585. Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med 2010; 362:1417–1429. Mahadevan D, Fisher RI. Novel therapeutics for aggressive non-Hodgkin’s lymphoma. J Clin Oncol 2011; 29:1876–1884. Pérez-Galán P, Dreyling M, Wiestner A. Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood 2011; 117:26–38. Wilson WH, O’Connor OA, Czuczman MS, et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol 2010; 11:1149–1159. Zeldis JB, Knight R, Hussein M, Chopra R, Muller G. A review of the history, properties, and use of the immunomodulatory compound lenalidomide. Ann N Y Acad Sci 2011; 1222:76–82.

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17 Cutaneous lymphoma Cutaneous T-cell lymphomas (CTCL): Mycosis fungoides Primary cutaneous lymphomas (PCL) are NHL that present in the skin without evidence of extracutaneous involvement. PCL differ in clinical behavior, prognosis, and treatment from nodal lymphomas involving the skin secondarily, and are therefore classified separately. The different types of cutaneous T-cell (CTCL) and cutaneous B-cell lymphoma (CBCL) have characteristic clinicopathological features.

Limited patches (stage IA)

Skin tumors (stage IIB)

Patches and plaques over >10% of skin surface (stage IB)

Mycosis fungoides (MF) is the most common type of CTCL with an annual incidence of 0.3/100 000. It mainly affects adults. The course is indolent (years to decades) with slow progression from patches and plaques to tumors. Less than 25% of patients develop nodal or visceral disease. Histologically, the early stages of MF show infiltration of atypical CD4+ T cells with convoluted and hyperchromatic nuclei into the epidermis (arrows).

Treatment and prognosis are dependent on stage, including type/extent of skin lesions (patch, plaque, or tumor) and the presence of extracutaneous disease.

Ann Arbor staging is not used in patients with MF/SS but there is a specific staging classification for MF/SS

Skin-limited disease is treated with skin-directed therapies, including topical steroids, topical nitrogen mustard, phototherapy (PUVA, UVB), or RT. In refractory disease these therapies are combined with Îą-IFN or retinoids. Systemic chemotherapy is given in case of nodal or visceral disease (stage IV).

REVISION QUESTIONS 1. Which type of skin lesions can be seen in MF? 2. What is the 10-year survival of patients with limited patches and plaques (stage IA)? 3. Which type of treatment is preferred in patients who present only with skin lesions?

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CTCL other than MF Sezary syndrome is a leukemic form of CTCL defined by a pruritic erythroderma, enlarged LN, and clonal CD4+ T cells in skin and blood (Sezary cells). In addition, alopecia, palmoplantar hyperkeratosis, and onychodystrophy may be present. Differentiation from benign forms of erythroderma may be difficult. The prognosis is generally poor (5-year OS: 25%). Treatment options are extracorporeal photopheresis (+/- Îą-IFN) or low-dose prednisone plus chlorambucil.

Sezary cells, cerebriform nucleus (electronic micrograph)

Erythroderma

Sezary cell (blood smear)

Cutaneous anaplastic large cell lymphoma (ALCL) is a tumor of large anaplastic or pleomorphic CD30+ cells. Most patients present with a solitary (ulcerating) tumor. A similar histology can be seen in lymphomatoid papulosis (recurrent, self-healing papules) and transformed MF. Thus, clinicopathological correlation is crucial. The prognosis of cutaneous ALCL is excellent (5-year OS â&#x2030;&#x2C6; 90%). Solitary lesions can be treated with RT or surgery, multifocal lesions with low-dose MTX. CD30 staining

Primary cutaneous peripheral T-cell lymphomas, unspecified (including some rare subtypes) often present with rapidly growing (ulcerating) tumors. Histology: diffuse infiltrates of medium to large cells, usually with pleomorphic nuclei. Phenotype: CD4+, CD8+ or CD4-, CD8-, often with expression of cytotoxic proteins. These lymphomas have an aggressive clinical course and should be treated with multiagent chemotherapy. The prognosis is poor (5-year OS: <20%).

REVISION QUESTIONS 1. What are the characteristic clinical features of Sezary syndrome? 2. What is the first-choice treatment of a primary cutaneous anaplastic large cell lymphoma presenting with a solitary skin tumor? 3. What is the prognosis of patients with a primary cutaneous peripheral T-cell lymphoma, unspecified?

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Cutaneous B-cell lymphomas (CBCL) Primary cutaneous marginal zone B-cell lymphoma may present with solitary, localized, or multifocal lesions, often located on the trunk and arms. Histologically, they are composed of small B cells, including marginal zone B cells, lymphoplasmacytoid cells, and monotypic plasma cells. This is an indolent type of lymphoma, which can be managed easily by (intralesional) steroids, excision, or RT. Extracutaneous dissemination is rare.

Primary cutaneous follicle center lymphoma generally presents with localized lesions on the trunk or scalp, and uncommonly with generalized skin lesions. Histologically, it consists mainly of medium-sized to large centrocytes and variable numbers of centroblasts. The growth pattern may be diffuse, follicular, or mixed.

Large cells with cleaved nuclei

Local RT is the first choice of treatment. The prognosis is excellent with a 5-year OS >90%. Extracutaneous dissemination is uncommon.

Primary cutaneous large B-cell lymphoma, leg type characteristically presents with tumors on the (lower) legs in elderly patients, particularly in women. Histology shows confluent sheets of large cells with round nuclei and prominent nucleoli (centroblasts and immunoblasts). Bcl-2 is strongly expressed. The prognosis is intermediate with a 5-year OS â&#x2030;&#x2C6;50%. R-CHOP is the first line of treatment. For small solitary lesions, RT may be considered. BCL2

REVISION QUESTIONS 1. What is the characteristic clinical presentation of the three main types of CBCL? 2. What is the prognosis of the three main types of CBCL? 3. What is the preferred therapy in patients with primary cutaneous follicle center lymphoma?

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Summary: Cutaneous lymphoma • The term “primary cutaneous lymphoma” refers to NHL presenting in the skin without evidence of extracutaneous disease • Different types of CTCL and CBCL have characteristic clinical features and course • Mycosis fungoides is the most common type of CTCL • Stage of disease in MF is important for first-choice treatment and for prognosis • MF patients with only patches and plaques should be treated with skin-directed therapies • Sezary syndrome is a leukemic form of CTCL with a poor prognosis • Primary cutaneous anaplastic large cell lymphoma generally presents with solitary or localized skin lesions, which can easily be managed with radiotherapy • Primary cutaneous marginal zone B-cell lymphoma and primary cutaneous follicle center lymphoma are indolent types of CBCL and should not be treated with multiagent chemotherapy • Primary cutaneous B-cell lymphoma, leg type should be treated with R-CHOP

Further Reading Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol 2010; 28:4730–4739. Bekkenk M, Geelen FAMJ, van Voorst Vader PC, et al. Primary and secondary cutaneous CD30-positive lymphoproliferative disorders: a report of the Dutch Cutaneous Lymphoma group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment. Blood 2000; 95:3653–3661. Kempf W, Pfaltz K, Vermeer MH, et al. EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Blood 2011; 118:4024–4035. Kim YH, Liu HL, Mraz-Gernhard S, Varghese A, Hoppe RT. Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol 2003; 139:857–866. Olsen EA, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007; 110:1713–1722. Prince HM, Whittaker S, Hoppe RT. How I treat mycosis fungoides and Sézary syndrome. Blood 2009; 114:4337–4353. Senff NJ, Hoefnagel JJ, Jansen PM, et al. Reclassification of 300 primary cutaneous B-cell lymphomas according to the new WHO-EORTC classification for cutaneous lymphomas: clinicopathologic correlations and prognostic factors. J Clin Oncol 2007; 25:1581–1587. Senff NJ, Noordijk EM, Kim YH, et al. European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas. Blood 2008; 112:1600–1609. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105:3768–3785.

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18 Peripheral T-cell lymphomas (extranodal) Enteropathy-associated T-cell lymphoma (EATL) EATL is a rare primary intestinal T-cell lymphoma that is often, but not always, associated with celiac disease (CD). Refractory CD often precedes EATL. Type-1 EATL shows a variable histology consisting of monomorphic large CD3+, CD4-, CD8-, CD56-, TCRβ+, CD30+ cells against an inflammatory background. Type-2 EATL is characterized by a monomorphic infiltrate of small-medium CD3+, CD4-, CD8+, CD56+, TCRβ+, CD30-/+ cells, less often associated with CD.

B CD30 staining

Villous atrophy characteristic of CD

In most patients the tumor is multifocal, forming ulcers, nodules, plaques, polyps, and strictures, predominantly in the jejunum. Splenic atrophy may be present. Abdominal pain, diarrhea, malnutrition, B-symptoms, complications like perforation, obstruction, bleeding, and infection are frequent presenting features. A large tumor mass (≥5 cm), PS >2, and elevated serum CRP and LDH are adverse predictors for failure-free survival (FFS) and OS. The median OS is ≈ 10 months.

CHOP is the most widely used chemotherapy regimen. ≈ 50% of patients with EATL cannot receive chemotherapy because of poor PS, infection, or advanced age. The role of surgery in EATL is the debulking and resection of masses in cases with a high risk of obstruction, bleeding, or perforation. The best current treatment choice in selected patients is the combination of surgical resection, CHOP chemotherapy, and consolidation with HDT with ASCT.

REVISION QUESTIONS 1. With which disease is EATL often associated? 2. What are the common presenting features of EATL? 3. Is there a role for surgery in the treatment of EATL?

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Extranodal NK/T-cell lymphoma, nasal type (NK/T-CL) Extranodal NK/T-cell lymphoma, an EBV-associated lymphoma, comprises 5-10% of all PTCL and is much more common in Asian and Hispanic populations. Most of the cases are localized in the nasal and upper airway region (nasal NK/T-CL). It can rarely occur in other sites like testis, skin, intestine, and soft tissue. NK/T-CL shows an angiocentric and angiodestructive pattern. Tumor cells are CD56+, cytoplasmic CD3+, surface CD3-, and express cytotoxic proteins.

Angioinvasion

Large cells, frequent mitosis

OS and DFS according to local tumor invasiveness

CD56+

NK/T-CL is more prevalent in ♂ in their 5th decade. Nasal NK/T-CL can cause local symptoms: nasal obstruction, epistaxis, and hard palate destruction. In nasal NK/T-CL, some features of the tumor, such as size and local invasiveness, are better predictors of outcome than the IPI. A new prognostic index based on the presence of B-symptoms, stage III-IV, ↑ LDH, and regional LN discriminates patients more accurately than the IPI.

For stage I/II nasal NK/T-CL, chemotherapy (i.e. SMILE, possibly better than CHOP) with IF-RT intercalated after 3 cycles is the standard of care.

≈50% of patients might be cured with SMILE

For stage III/IV nasal and extranasal NK/TCL, chemotherapy with SMILE (steroid, MTX, ifosfamide, L-asparaginase, etoposide) is an effective option. It has been suggested that autologous or allogeneic stem cell therapy may provide survival benefit for patients with extranasal or advanced nasal NK/T-CL.

REVISION QUESTIONS 1. What are the typical pathological features of NK/T-CL? 2. What are the most important prognostic factors in nasal NK/T-CL? 3. What is the role of radiotherapy in the treatment of nasal NK/T-CL?

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Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) SPTCL and HSTL are rare aggressive extranodal lymphomas derived from cytotoxic T-cells. SPTCL mimics a panniculitis and is often associated with hemophagocytic syndrome (HPS). SPTCL-AB (α/β T-cell phenotype) typically presents a CD3+, CD4-, CD8+, CD56- phenotype and expresses cytotoxic proteins (granzyme B, TIA-1, perforin). SPTCL-GD (γδ T-cell phenotype) represents a separate group of cutaneous γδ T-cell lymphomas with poor prognosis. It is CD4-, CD8-, often CD56+, and EBV-.

Multiple tender partially indurated patches

SPTCL-AB clinically presents with solitary or multiple, deep-seated nodules or plaques, often associated with B-symptoms, laboratory abnormalities, and effusions. SPTCL-GD presents more often with generalized plaque-like and ulcerating lesions, B-symptoms, cytopenias, liver abnormalities, and HPS. The 5-year OS of SPTCL-AB without HPS is 91% and with HPS is 46%. SPTCL-GD is associated with a poor prognosis regardless of HPS, with 5-year OS: 11%. Abdominal CT scan shows multiple nodules (arrows) in the subcutaneous fat.

Hepatosplenic T-cell lymphoma (HSTL) carries a similar phenotype to SPTCL-GD. About 70% of cases occur in younger males, 20% of HSTL arise in the setting of chronic immunosuppression. Patients present with marked hepatosplenomegaly, B-symptoms, cytopenias, and liver abnormalities. At presentation, diagnosis can be made on BM or liver. Patients with SPTCL-AB with HPS, SPTCL-GD, and HSTL are resistant to CHOP-like therapy, so early HDT-ASCT or allo-SCT might be considered.

REVISION QUESTIONS 1. What are the differences between SPTCL-AB and SPTCL-GD? 2. How should patients with SPTCL-AB be treated? 3. Is there a role for transplant in the treatment of patients with SPTCL and HSTL?

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Summary: Peripheral t-cell lymphomas (extranodal) • EATL is a rare intestinal T-cell lymphoma often associated with refractory celiac disease • The prognosis of EATL is poor due to sepsis, bowel perforation, or malnutrition secondary to CD at diagnosis and because of treatment resistance • Adverse prognostic factors in EATL are large tumor mass, poor PS, and elevated CRP and LDH • Treatment strategy in EATL should include initial surgical resection, CHOP, and autologous transplantation • Extranodal NK/T-CL is a rare aggressive EBV-associated lymphoma with a poor prognosis • Combination chemotherapy (i.e. SMILE) and early IF-RT is recommended for localized nasal NK/T-CL • Multiagent innovative therapy is promising for advanced nasal and extranasal NK/T-CL • SPTCL and HSTL are extremely rare extranodal cytotoxic T-cell lymphomas • If fulminant HPS is present, the prognosis of SPTCL is poor despite aggressive chemotherapy • SPTCL-AB without HPS has a favorable prognosis as it responds well to immunosuppressive agents. SPTCL-GD and HSTL exhibit a marked chemoresistance to currently used regimens

Further Reading Au W, Weisenburger DD, Intragumtornchai T, et al. Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project. Blood 2009; 113:3931–3937. Bagheri F, Cervellione KL, Delgado B, et al. An illustrative case of subcutaneous panniculitis-like T-cell lymphoma. J Skin Cancer 2011;2011:824528. Delabie J, Holte H, Vose JM, et al. Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International Peripheral T-Cell Lymphoma Project. Blood 2011; 118:148–155. Di Sabatino A, Biagi F, Gobbi PG, Corazza GR. How I treat enteropathy-associated T-cell lymphoma. Blood 2012; 119:2458–2468. Ferreri AJM, Govi S, Pileri SA. Hepatosplenic gamma-delta T-cell lymphoma. Crit Rev Oncol Hematol 2011; 83:283–292. Gill H, Liang RHS, Tse E. Extranodal natural-killer/T-cell lymphoma, nasal type. Advances in Hematology 2010, Article ID 627401. Available at: http://www.hindawi.com/journals/ah/2010/627401/ Jang MS, Baek JW, Kang DY, Kang JS, Suh KS, Kim ST. Subcutaneous panniculitis-like T-cell lymphoma: successful treatment with systemic steroid alone. J Dermatol 2012; 36:96–99. Jung HR, Yun SY, Choi JH, Bae SH, Ryoo HM, Kum YS. Cyclosporine in relapsed subcutaneous panniculitis-like T-cell lymphoma after autologous hematopoietic stem cell transplantation. Cancer Res Treat 2011; 43:255–259. Kim TM, Park HE, Lee SY, et al. Local tumor invasiveness is more predictive of survival than International Prognostic Index in stage IE/IIE extranodal NK/T-cell lymphoma, nasal type. Blood 2005; 106: 3785–3790. Willemze R, Jansen PM, Cerroni L, et al. Subcutaneous panniculitis-like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Study of 83 cases. Blood 2008; 111:838–845. Yamaguchi M, Kwong YL, Kim WS, et al. Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: the NK-Cell Tumor Study Group study. J Clin Oncol 2011; 29:4410–4416.

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19 Non-malt marginal zone lymphomas Marginal zone lymphomas (MZL) The name “marginal zone lymphoma” (MZL) alludes to the fact that the neoplastic lymphocytes derive from and infiltrate the marginal zone of lymphoid follicles.

Mantle zone

Marginal zone

The WHO 2008 classification includes 3 types: MZL of MALT, nodal MZL (NMZL), and splenic marginal zone lymphoma (SMZL). The main difference between MZL of MALT and NMZL is their primary origin: extranodal in MALT and nodal in MZL, while the histology is identical.

Spleen. Lymphoid follicle

In NMZL the neoplastic lymphocytes infiltrate the marginal zone of the follicles, but also colonize reactive follicles and expand to interfollicular areas. Follicle colonization

The infiltrate is composed of centrocyte-like lymphocytes (CD20+, CD5-, CD10-, CD23-, bcl-6, cyclin D1-) with variable plasma cell differentiation. Given the histological similarity with nodal infiltration by MALT lymphomas, primary extranodal involvement should be excluded.

NMZL presents with localized or generalized enlarged LN, with occasional BM (~20-40%) and PB involvement. Association with HCV is common in some geographical areas. Most patients are asymptomatic. NMZL has an indolent course so treatment is required only when symptoms develop.

TTP in NMZL according to the presence of PB involvement, which is seen in ≈10% of cases

Time to progression (TTP) for NMZL is shorter that in SMZL, but the median OS is similar for both types (~9 years). Treatment is similar to that of SMZL.

REVISION QUESTIONS 1. How can NMZL be distinguished from MALT lymphoma with lymph node involvement? 2. Which are the most important clinical features of NMZL? 3. What is the most usual course of NMZL?

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Splenic marginal zone lymphoma (SMZL) â&#x20AC;&#x201C; Diagnosis SMZL is a distinct clinicopathological entity, despite the similarity of names with the other MZL subtypes. SMZL is characterized by PB, BM, and splenic infiltration by small lymphocytes CD20+, CD5-, CD10-, CD23-, CD43-, cyclinD1-, CD103-. In some cases, villous lymphocytes can be found in the PB. Villous lymphocytes are not specific to SMZL and can be found in other lymphoproliferative disorders.

Intrasinusoidal infiltration (CD20+)

The most frequent cytogenetic abnormality is trisomy 3, but the most characteristic, that is unique to SMZL, is allelic loss of 7q. BM infiltration may show interstitial, nodular, diffuse, or mixed patterns. Intrasinusoidal infiltration of BM is very characteristic, although not exclusive to SMZL. The same immunophenotype is found in BM and spleen infiltration, thus both tissues are valid for diagnosis.

Spleen infiltration shows expansion of the white pulp with a macroscopic miliary aspect. In the white pulp, small lymphocytes surround or replace reactive germinal centers infiltrating the marginal zone. The red pulp is also involved. Spleen histology is not mandatory for diagnosis, which should be based on a combination of PB morphology, BM histology, immunophenotype, and cytogenetics.

REVISION QUESTIONS 1. Are villous lymphocytes diagnostic of SMZL? 2. Which is the most characteristic cytogenetic finding in SMZL? 3. Is the spleen, and therefore splenectomy, required for the diagnosis of SMZL?

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SMZL â&#x20AC;&#x201C; Clinical features and management SMZL is an indolent lymphoma, occurring mostly in elderly patients. At diagnosis, 25% are asymptomatic, but in most cases the disease tends to progress.

Massive splenomegaly in SMZL; in contrast, enlarged LN are rare (13-25%)

Cytopenias and splenomegaly (80%) are the leading symptoms. The presence of a monoclonal IgM band, AIHA, and other immune phenomena are common. Nodal and extranodal dissemination or transformation to DLBCL may occasionally occur (10-13%) at any moment and at any site during the evolution of SMZL.

Treatment is required only if painful splenomegaly, significant cytopenia (Hb <10 g/dl, platelet <80 000/ÂľL), progressive LN, or extranodal involvement occur. There is no standard treatment for SMZL. Splenectomy is the historical treatment, resulting in clinical but not molecular responses. Splenectomy is not curative. It is not clear whether different chemotherapy treatments, alone or combined with splenectomy, may achieve better results than splenectomy alone.

Rituximab is a good and relatively non-toxic alternative to splenectomy and it is replacing surgery as first-line treatment for SMZL. In certain areas SMZL is associated with HCV infection: in these patients antiviral therapy (INF + ribavirine) should be the first step of treatment.

Cumulative Proportion Surviving

Rituximab results in a rapid clinical and even molecular response but it is not known if the addition of chemotherapy can improve its effect.

Median FU: 24 m (range: 4-102) (after rituximab) Months from Rituximab Treatment

REVISION QUESTIONS 1. Should all patients with SMZL be treated at diagnosis? 2. What is the standard treatment for SMZL? 3. Is splenectomy still the first line of treatment for SMZL?

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Summary: Non-MALT marginal zone lymphomas • The exclusion of primary extranodal involvement is required for the diagnosis of NMZL • NMZL presents with lymphadenopathy and usually has an indolent course • In endemic areas, HCV infection is associated with both NMZL and SMZL • SMZL is a clinicopathologically different entity characterized by PB, BM, and spleen involvement and frequent autoimmune phenomena • Villous lymphocytes may occur in SMZL, but they are not specific for this type of lymphoma • 7q deletion is the most characteristic, whereas trisomy 3 is the most frequent cytogenetic finding in SMZL • The diagnosis of SMZL should be obtained from the study of PB, BM, and cytogenetics. Spleen histology is not essential for the diagnosis • Only symptomatic NMZL or SMZL patients should be treated. There is no standard therapy • Rituximab is a better and relatively non-toxic treatment alternative to splenectomy for SMZL • In SMZL, spleen should not be routinely removed, as it is not required for diagnosis and splenectomy is no longer the standard treatment

Further Reading Arcaini L, Lazzarino M, Colombo N, et al. Splenic marginal zone lymphoma: a prognostic model for clinical use. Blood 2006; 107:4643–4649. Arcaini L, Burcheri S, Rossi A, et al. Prevalence of HCV infection in nongastric marginal zone B-cell lymphoma of MALT. Ann Oncol 2007; 18:346–350. Bennett M, Sharma K, Yegena S , Gavish I, Dave HP, Schechter GP. Rituximab monotherapy for splenic marginal zone lymphoma. Haematologica 2005; 90:856–858. Berger F, Felman P, Thieblemont C, et al. Non-MALT marginal zone B-cell lymphomas: a description of clinical presentation and outcome in 124 patients. Blood 2000; 95:1950–1956. Chacón JI, Mollejo M, Muñoz E, et al. Splenic marginal zone lymphoma: clinical characteristics and prognostic factors in a series of 60 patients. Blood 2002; 100:1648–1654. Hermine O, Lefrère F, Bronowicki J, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 2002; 347:89–94. Iannitto E, Tripodo C. How I diagnose and treat splenic lymphomas. Blood 2011;117:2585–2595. Kalpadakis C, Pangalis GA, Dimopoulou MN, et al. Rituximab monotherapy is highly effective in splenic marginal zone lymphoma. Hematol Oncol 2007; 25:127–131. Matutes E, Oscier D, Montalban C, et al. Splenic marginal zone lymphoma proposals for a revision of diagnostic, staging and therapeutic criteria. Leukemia 2008; 22:487–495. Thieblemont C, Felman P, Berger F, et al. Treatment of splenic marginal zone B-cell lymphoma: an analysis of 81 patients. Clin Lymphoma 2002; 3:41–47.

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Lymphoplasmacytic lymphoma (LPL) / Waldenström’s macroglobulinemia (WM)

Clinicopathological features LPL is a neoplasm of lymphoplasmacytoid cells, usually involving the BM (sometimes LN/spleen). WM is an LPL with BM infiltration and an IgM monoclonal component.

Monoclonal paraprotein

Symptoms of WM are due to direct infiltration of the BM or other lymphoid organs and to the amount and the physicochemical and immunological properties of IgM.

Immunofixation electrophoresis showing an IgM(k)

The concentration of IgM varies widely. A diagnosis of WM can be made irrespective of the IgM concentration if there is BM infiltration by lymphoplasmacytic cells. Lymphoplasmacytic cells express pan–B-cell markers (CD19, CD20, CD22, CD24, CD79a and FMC7) and surface IgM

Plasma cells are MUM1+

Lymphoplasmacytic cells are small lymphocytes with plasmacytoid or plasma cell differentiation. An ↑ number of mast cells is frequent in the BM. WM is a rare disease (≈ 2% of all hematological malignancies) of elderly patients: the median age at diagnosis ranges from 63 to 70 years.

CS20

MUM1

CD79a, CD138

IgM

Plasma cells are CD138+

Cytopenias (anemia and less often thrombocytopenia) are the most common presenting features. Liver, spleen, or LN enlargement is not very common.

Lymphoplasmacytic cells and plasma cells are IgM+

↑ IgM causes the hyperviscosity syndrome, treated with plasmapheresis. This leads to resolution of the symptoms but the ↓ of IgM is transient. The IgM can have an auto-Ab activity, i.e. IgM against myelin-associated glycoprotein (MAG), causing a distal, symmetrical, chronic demyelinating peripheral neuropathy. Other clinical manifestations caused by the IgM are renal failure, cryoglobulinemia, and Raynaud’s syndrome.

Dilated retinal vessels, peripheral hemorrhages

Raynaud’s in a patient with cryoglobulinemia

“Venous sausaging”

Fundoscopic examination of a WM patient with hyperviscosity

REVISION QUESTIONS 1. What type of monoclonal immunoglobulin do the lymphoplasmacytic cells of WM produce? 2. What is the typical immunophenotype of WM lymphoplasmacytic cells? 3. What is the threshold of IgM above which the diagnosis of WM is established?

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Prognosis and treatment indications The most important risk factor for the development of WM is pre-existing IgM MGUS, which is associated with a 46-fold ↑ in the risk of WM.

100% All Patients

9-Year Events / N Estimate 12 / 59 21%

80%

The median OS for patients with symptomatic WM is 5-7 years. ≈30% of patients die from other cancers, cardiovascular disease, or other unrelated conditions.

At 9 years, only 21% have required therapy

60%

Median time to symptomatic progression: 7years

40%

20%

WM is an incurable disease; therefore patients with asymptomatic WM should not be treated as they can remain stable for years.

0% 0

Proportion surviving

Low risk

The International Prognostic Scoring System (ISSWM) for WM (age, anemia, thrombocytopenia, ↑ β2-microglobulin, and ↑ monoclonal IgM) discriminates 3 risk groups.

0.6

Intermediate risk

P < .001

0.2

Low Intermediate High

0.0 0.0

1.0

2.0

3.0

Indications for treatment include constitutional symptoms, IgM-related complications, bulky LN or splenomegaly, cytopenias, or evidence of transformation.

0.8

0.4

Years from Enrollment

Survival after first treatment initiation according to the ISSWM 1.0

High risk 4.0

5.0

6.0

7.0

8.0

Patients with an IgM-related disorder usually require treatment to ↓ the circulating and/or deposited IgM and to suppress the malignant clone producing the IgM.

9.0 10.0

Survival time in years

A number of agents have shown single-agent activity in WM: DXM, chlorambucil, cyclophosphamide, bendamustine, fludarabine, cladribine, and rituximab. Single-agent rituximab is effective but slow acting. Transient ↑ in serum IgM (”flare”) is common (≈50%) and may require plasmapheresis to ↓ hyperviscosity. Rituximab monotherapy can also be used for the management of IgM-related disorders such as neuropathy or coldagglutinin anemia.

100%

Median OS after fludarabine therapy: 6.8 years

80%

Overall Survival Event-Free Survival

Median Events / N in Years 115 / 183 6.8 147 / 183 3.0

60%

40%

Median PFS after fludarabine: 3 years

20%

Years from Registration 2 (Treatment)

REVISION QUESTIONS 1. What is the most significant risk factor for the development of WM? 2. Are nucleoside analogs active in WM? 3. What is “IgM flare”?

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Treatment 1st line therapy for fit patients is usually a combination of cytotoxic drugs and rituximab such as DRC (DXM, rituximab, and cyclophosphamide).

Without Progression (%)

1.0

R-CHOP is also active but is more toxic than DRC, especially for elderly patients. Other options include combinations of nucleoside analogs and rituximab. For elderly or unfit patients, monotherapy (i.e. rituximab if cytopenias) can be effective. Plasmapheresis is an adequate alternative option if the main symptoms are due to hyperviscosity but some patients will also require chemotherapy.

1.0

0.6 0.4

After frontline rituximab-based therapy without a nucleoside analog, R-FC (rituximab, fludarabine, and cyclophosphamide) may be very effective.

PFS after ASCT for patients in PR/VGPR Overall survival PFS

Any of the drugs active in WM can be used at relapse, the choice depending on the age and fitness of the patient, previous treatment(s), and response duration.

0.6

0.2

Time From Treatment Initiation (months)

Overall survival

0.4

2-year PFS for patients treated with DRC: 67%

0.2

PFS OS after ASCT for patients in PR/VGPR

0.8

Probability of Survival

0.8

Time Since ASCT (years)

HDT with ASCT may have a role in some patients with chemosensitive disease and less than 3 prior lines of therapy.

Other drugs used in patients with indolent lymphomas have also shown to be active in WM; among these are proteasome inhibitors, MoAb, and small molecules. 2

4 5 with/without 6 7 rituximab 8 Bortezomib is effective in previously treated patients. Other alternatives Time Since ASCT (years) are MoAb (ofatumumab, alemtuzumab) or radioimmunotherapy.

Drugs such as everolimus and perifosine targeting the PI3K/AKT/mTOR pathway have shown activity in relapsed WM.

% change of serum IgM levels at best response following treatment with bortezomib

REVISION QUESTIONS 1. Is R-CHOP the standard first-line treatment for WM? 2. What are the treatment options for patients who relapse after DRC or R-CHOP? 3. Should all relapsed WM be offered HDT with ASCT?

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Summary: Lymphoplasmacytic lymphoma (LPL) / Waldenström’s macroglobulinemia (WM) • Histology: lymphoplasmacytic cells which express pan–B-cell surface markers and surface IgM • Cytopenias (anemia and less often thrombocytopenia) are the most common presenting features • Prognostic factors (ISSWM): age, Hb, low platelets, β2-microglobulin, IgM ≥7000 mg/dl • The median OS for patients with symptomatic WM is 5-7 years • The hyperviscosity syndrome is managed with plasmapheresis • If asymptomatic, observe without treatment – median time to symptomatic WM is ~7-10 years • Rituximab may cause transient increases in serum IgM (“IgM flare”) in ~50% • 1st line: usually rituximab-based therapy (DRC or nucleoside analogs with rituximab or R-CHOP) • Options in relapsing patients: rituximab with nucleoside analogs or combination chemotherapy • Bortezomib with or without rituximab is active and induces rapid responses

Further Reading Dhodapkar MV, Hoering A, Gertz MA, et al. Long-term survival in Waldenstrom macroglobulinemia: 10-year follow-up of Southwest Oncology Group-directed intergroup trial S9003. Blood 2009; 113:793–796. Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, et al. Primary treatment of Waldenström macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. J Clin Oncol 2007; 25:3344–3349. Dimopoulos MA, Gertz MA, Kastritis E, et al. Update on treatment recommendations from the Fourth International Workshop on Waldenstrom’s Macroglobulinemia. J Clin Oncol 2009; 27:120–126. Dimopoulos MA, Kyle RA, Anagnostopoulos A, Treon SP. Diagnosis and management of Waldenstrom’s macroglobulinemia. J Clin Oncol 2005; 23:1564–1577. Kastritis E, Kyrtsonis MC, Hatjiharissi E, et al. No significant improvement in the outcome of patients with Waldenström’s macroglobulinemia treated over the last 25 years. Am J Hematol 2011; 86:479–483. Kyle RA, Greipp PR, Gertz MA, et al. Waldenström’s macroglobulinaemia: a prospective study comparing daily with intermittent oral chlorambucil. Br J Haematol 2000; 108:737–742. Kyriakou C, Canals C, Sibon D, et al. High-dose therapy and autologous stem-cell transplantation in Waldenstrom macroglobulinemia: the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 2010; 28:2227–2232. Morel P, Duhamel A, Gobbi P, et al. International prognostic scoring system for Waldenstrom macroglobulinemia. Blood 2009; 113:4163–4170. Stone MJ. Waldenström’s macroglobulinemia: hyperviscosity syndrome and cryoglobulinemia. Clin Lymphoma Myeloma 2009; 9:97–99. Treon SP, Branagan AR, Ioakimidis L, et al. Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia. Blood 2009; 113:3673–3678.

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21 Burkitt lymphoma and lymphoblastic lymphoma Burkitt lymphoma (BL): Pathology and biology BL is characterized histologically by a “starry sky” appearance at low-power magnification. The proliferation rate assessed by Ki-67 is >95%. Immunophenotype: the cells express CD19, CD20, CD22, CD10, bcl-6, and CD79a and are negative for CD5, CD23, bcl-2, and TdT. BL cells are medium-sized with round nuclei, multiple small nucleoli, moderate amount of basophilic plasma with vacuoles only at smears or touch preparations.

Chromosomal translocations involving MYC oncogene (located on 8q24) and one of three Ig loci (on chromosomes 14, 2, and 22) are characteristic of BL. The most common translocation is t(8;14) in 80% of BL. The other translocations are t(2;8) in ≈15% and t(8;22) in 5%. All result in MYC overexpression. MYC overexpression is not pathognomonic of BL: it is also overexpressed in 5-15% of DLBCL, the most frequent subtype of NHL.

Endemic BL is the most common form of BL. Geographical distribution = Plasmodium falciparum. It affects facial bones, typically the jaw. EBV+ in >90%. Sporadic BL occurs in 2-3/106/year. The terminal ileum, cecum, and intra-abdominal LN are the most common sites of disease. 15-30% of sporadic BL are EBV+. Immunodeficiency-associated BL is seen in HIV+ patients and to a lesser extent in transplant recipients. It accounts for 30-40% of HIV-lymphomas.

REVISION QUESTIONS 1. What is the appearance of BL at low-power magnification? 2. Is MYC overexpression diagnostic of BL? 3. Which are the commonest sites of disease in sporadic BL?

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BL: First-line treatment BL is much more common in children than in adults. Therefore, treatment protocols for adults often derive from the pediatric experience. The St. Jude/Murphy staging system, later modified by Magrath, is widely used for staging of childhood BL, but rarely used in adults. â&#x2030;&#x2C6;1/3 of the patients present BM and 15% CNS involvement. In stages I-II, >90% can be cured, contrasting with 60-80% in stage III-IV.

CSF involvement: BL cells on a cytospin preparation

LDH normal and WHO PS 0-1 and stage I-II and no bulk (<10 cm)

The differential diagnosis between BL and DLBCL is crucial because BL is not effectively treated with R-CHOP and needs shorter, more intensive regimens. Treatment should include cyclophosphamide at high doses and CNS prophylaxis to reduce the high risk of CNS relapse, and must be given in experienced centers.

All others

Tumor lysis syndrome prophylaxis with rasburicase should be started immediately at diagnosis to prevent spontaneous tumor lysis.

Different chemotherapy protocols can be used. Some of them adapt the intensity of the treatment according to the stage or other risk factors. As there are no trials comparing different regimens for adult BL, no specific regimen can be recommended. Relapses rarely occur after 2 years of initial therapy. HDT with ASCT or allogeneic transplant should be considered in patients achieving 2nd remission.

Author

Regimen

Mead GM, et al

CODOX-M / IVAC

Rizzieri DA, et al

CALGB 9251

van Imhoff GW, et al

HOVON

Thomas DA, et al

R-Hyper CVAD

Hoelzer D, et al

GMALL

Dunleavy K, et al

DA-EPOCH

REVISION QUESTIONS 1. Is R-CHOP an appropriate regimen for BL? 2. What are the cornerstones in the treatment of BL? 3. When should prophylaxis for tumor lysis syndrome be started?

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Lymphoblastic lymphoma (LBL) Lymphoblastic lymphoma (LBL) and acute lymphoblastic leukemia (ALL) are considered to be the same disease with different clinical presentation. LBL is arbitrarily defined by the presence of enlarged LN (frequently a mediastinal mass) and <20-25% lymphoblasts in the BM, contrasting with >25% in ALL. The histology is characterized by a diffuse or paracortical infiltration of small cells with indistinct nucleoli, finely dispersed chromatin, and scant cytoplasm.

B lymphoblastic leukemia/lymphoma NOS B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities

t(9;22)(q34;q11.2); BCR-ABL1 t(v;11q23); MLL rearranged t(12;21)(p13;q22); TEL-AML1 (ETV6-Runx1) with hyperdipoidy with hypodiploidy t(5;14)(q31;q32); IL-3-IGH t(1;19) (q23;p13.3); E2A-PBX1 (TCF3-PBX1)

LBL accounts for 2% of all NHL. It is predominantly seen in children and young adults. The median age at presentation in adults is 39 years. B-cell immunophenotype accounts for 10% and T-cell for 85-90% of LBL. In the WHO classification, B-LBL is further subdivided according to cytogenetics. As in ALL, there is a high risk of CNS infiltration at diagnosis, so CNS should be evaluated with CSF examination including flow cytometry.

Conventional regimens for NHL result in a short DFS. Intensive NHL protocols improve the results. ALL protocols are recommended. LBL should be exclusively treated in experienced centers with ALL-like regimens such as R-hyper-CVAD, GMALL07/2003, NIHG-ALL09/00. CNS prophylaxis with intrathecal chemotherapy, high-dose MTX or Ara-C, or irradiation reduces the high risk of CNS relapse.

Therapy

Age (range)

5a DFS (range)

Conventional NHL

28-45

58%

26%

Modified NHL

14-22

92%

49%

High-grade NHL

25-34

67%

51%

ALL

22-37

80%

56%

REVISION QUESTIONS 1. Are LBL and ALL different diseases? 2. What is the most common phenotype of LBL? 3. Which are the best therapy regimens?

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Summary: Burkitt lymphoma and lymphoblastic lymphoma • The characteristic histological features of BL are the “starry sky” picture and the very high proliferation rate • Biology: myc overexpression due to myc oncogene rearrangement is highly suggestive of BL. However, not all myc-positive lymphomas are BL • Because of its aggressive behavior, BL should be treated with intensive multiagent chemotherapy at experienced centers • CNS prophylaxis is mandatory in the treatment of BL due to the high risk of CNS relapse • Tumor lysis syndrome prophylaxis should be started immediately at diagnosis • Despite BL being a very aggressive disease, it can be cured in more than half the cases • At relapse, HDT with ASCT or allogeneic transplantation should be considered in patients achieving a second response • LBL and ALL are the same disease with different clinical presentation • LBL is more frequently of T-cell phenotype • LBL should be treated with ALL-like protocols, including CNS prophylaxis

Further Reading Aldoss IT, Weisenburger DD, Ku K, et al. Adult Burkitt lymphoma: advances in diagnosis and treatment. Oncology 2008; 22: 1508–1517. Blum KA, Lozanski G, Byrd JC. Adult Burkitt leukemia and lymphoma. Blood 2004; 104:3009–3020. Cortelazzo S, Ponzoni M, Ferreri AJM, Hoelzer D. Lymphoblastic lymphoma. Crit Rev Oncol Hematol 2011; 79:330–343. Diebold J, Jaffe ES, Raphael M, Warnke RA. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. In: Jaffe ES, Harris NL, Stein H, Vardiman JW (Eds). World Health Organization Classification of Tumours. Lyon: IARC Press, 2001; 181–184. Dunleavy K, Little RF, Pittaluga S, et al. A prospective study of dose-adjusted (DA) EPOCH with rituximab in adults with newly diagnosed Burkitt lymphoma: a regimen with high efficacy and low toxicity. Ann Oncol 2008; 19(Suppl-4):iv83–84 (abstract 009). Gökbuget N, Arnold R, Böhme A, et al. Treatment of adult ALL according to the protocols of the German Multicenter Study Group for adult ALL. In : Estey EH, Faderl SH, Kantarjian H (Eds): Acute Leukemais. Berlin, Heidelberg, New York: Springer, 2008; 167–176. Mead GM, Sydes MR, Walewski J, et al. An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt’s lymphoma: results of United Kingdom Lymphoma Group LY06 Study. Ann Oncol 2002; 13:1264–1274. Thomas DA, Faderl S, O’Brien S, et al. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer 2006; 106:1569–1580.

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22 Extranodal lymphomas Primary CNS lymphoma Extranodal lymphomas are usually of two different histotypes: marginal zone lymphoma (MZL) or diffuse large B-cell lymphoma (DLBCL). DLBCL primarily arising in the CNS (PCNSL) is a clinical entity characterized by aggressive behavior, poor prognosis, and therapeutic peculiarities. The median age of subjects affected by PCNSL is ≈60 years, with a slight prevalence among ♂. Presentation consists of rapid neurological impairment.

Neoplastic B lymphocytes are CD20+, CD10-, and MUM1+ and usually grow forming perivascular cuffings

The most common presenting symptoms include: motor/ sensory focal deficits, personality changes, headache, intracranial hypertension, uveitis, and seizures.

Lesions are single in 60% of patients

Meningeal and intraocular involvement is reported in ≥15% of cases (probably an underestimation)

The standard treatment is chemoradiotherapy with MTX (the most active drug) administered at high doses in combination with HD Ara-C, followed by WBRT. As consolidation WBRT is associated with an ↑ risk of severe neurotoxicity, its replacement with conventional or HD chemotherapy is being investigated.

Frontal lobe and periventricular areas are often involved. Staging work-up should include CSF and ophthalmological examinations. The prognosis is very poor. Age, PS, LDH serum level, CSF protein concentration, and involvement of the deep areas of the CNS are the main prognostic factors.

A significant improvement in outcome has been reported with the addition of HD Ara-C to HD-MTX in an international randomized trial

The plateau in the FFS curves suggests that 1/3 of the patients can be cured. However, late relapses have been also reported

Patients with relapsed PCNSL can respond to salvage chemotherapy including drugs crossing the BBB. HDT with ASCT has been used to consolidate 2nd remission.

REVISION QUESTIONS 1. Which is the most common lymphoma category arising in the CNS? 2. Which are the main prognostic factors in PCNSL patients? 3. How will you treat your next patients with PCNSL?

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Testicular lymphoma Testicular lymphoma in adults is almost always of DLBCL subtype. It affects elderly subjects; it is usually localized at presentation and is bilateral in 15% cases. Cause-specific survival (CSS) curve reflects deaths due to lymphoma (the main cause of death) whereas the poor OS reflects the advanced age at diagnosis

In spite of the limited stage at diagnosis, its prognosis is poorer in comparison to other stage I DLBCL. This is due to an ↑ relapse risk with a particular pattern. Surgery plays a diagnostic and a therapeutic role in testicular lymphoma. Orchidectomy avoids potential persistence of disease in a chemotherapy sanctuary.

Dissemination in advanced stage often involves retroperitoneal LN, lungs, bone, and CNS. Other extranodal organs can be involved at relapse. 1st line treatment for testicular lymphoma includes orchidectomy, R-CHOP chemoimmunotherapy, CNS prophylaxis, and contralateral testis RT. Prophylactic scrotal RT is administered as it dramatically reduces the high risk of failure in the contralateral testis.

Intrathecal/systemic chemotherapy prophylaxis is given to ↓ the risk of CNS relapse (10-year risk: 30%) but does not completely eliminate this complication. CNS infiltration (either at diagnosis or at relapse) requires the use of drugs with good CNS penetration such as HD MTX or HD Ara-C.

Only a few drugs have good CNS bioavailability but they should be given at high doses, not well tolerated by elderly patients

Salvage treatment at relapse is strongly conditioned by patients’ age and sites of disease. Most recurrences should be managed like relapsed nodal DLBCL.

REVISION QUESTIONS 1. Is testicular DLBCL a disease frequently seen in younger adults? 2. What is the cumulative risk of CNS dissemination in testicular lymphomas? 3. Which is the first-line treatment for testicular lymphoma?

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Other entities/localizations Primary mediastinal large B-cell lymphoma (PMLBCL) is a unique type of aggressive B-cell lymphoma probably arising from a putative thymic B cell. PMLBCL occurs mostly in young ♀. It presents with an invasive anterior mediastinal mass, often producing cough, dyspnea, and superior vein cava syndrome.

Most patients have stage I-II, bulky disease, with pleural or pericardial effusions in a third of cases. Systemic symptoms are present in <20% of patients, and increased LDH levels in 70-80%

Anthracycline-based chemotherapy in combination with rituximab is the therapeutic cornerstone. The role of consolidation RT remains to be defined.

The stomach is the most common extranodal site primarily involved by lymphomas, with DLBCL as the most frequent histological subtype. Gastric DLBCL usually presents with limited stage. It can be associated or not with Helicobacter pylori infection and MALT-type areas. Gastric wall thickening

It occurs more frequently in ♂ with a median age of 50-60 years. Its prognosis after R-CHOP ± IF-RT is good, with a 5-year OS ≈90%.

Pathological fracture occurs in 1/3 of patients

Primary bone lymphoma usually presents as localized disease, affecting patients with a median age of 5055 years, without gender prevalence. Presenting symptoms are pain, followed by impaired function of limb and swelling. Long bones are most commonly affected. Patients with disease limited to a single lesion have an excellent prognosis after chemo-RT, contrasting with the poor outcome in patients with multiple lesions.

Patients with osseous lymphomas usually have abnormal X-rays with a heterogeneous lytic pattern, with or without cortical erosion and calcification of soft tissues

REVISION QUESTIONS 1. Which are the most common presenting symptoms in patients with PMLBCL? 2. Which infectious agent is associated with gastric lymphomas? 3. Which is the most important determinant of prognosis in patients with primary bone lymphomas?

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Summary: Extranodal lymphomas • Most lymphomas of the CNS, testis, gastrointestinal tract, mediastinum, and skeleton are DLBCL • The staging work-up varies according to the involved organ; for instance, CNS assessment is needed in brain and testicular lymphomas • The prognosis varies according to the affected extranodal organ: it is poor in the CNS, testes, and bowel; it is good in the stomach, mediastinum, and bone • Localized stages (I-II) are curable with chemoimmunotherapy ± involved-field radiotherapy • In PCNSL, CHOP must be replaced with high-dose methotrexate and cytarabine and this should be followed by WBRT • Given the neurotoxicity associated with WBRT, alternative consolidation strategies such as HD chemotherapy with ASCT are being investigated • Testicular lymphoma should be treated with orchidectomy, R-CHOP, CNS prophylaxis, and contralateral testis irradiation • Anthracycline-based chemotherapy is the therapeutic cornerstone of PMLBCL. The role of consolidation radiotherapy remains to be defined • The prognosis of gastric DLBCL is excellent with R-CHOP ± involved-field radiotherapy • The prognosis of bone lymphoma depends on the number of lesions

Further Reading Bhagavathi S, Fu K. Primary bone lymphoma. Arch Pathol Lab Med 2009; 133:1868–18671. Ferreri AJ, Montalbán C. Primary diffuse large B-cell lymphoma of the stomach. Crit Rev Oncol Hematol 2007; 63:65–71. Ferreri AJ, Reni M, Foppoli M, et al. High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009; 374:1512–1520. Ferreri AJ. How I treat primary CNS lymphoma. Blood 2011; 118:510–522. Martelli M, Ferreri AJ, Johnson P. Primary mediastinal large B-cell lymphoma. Crit Rev Oncol Hematol 2008; 68:256–263. Martinelli G, Gigli F, Calabrese L, et al. Early stage gastric diffuse large B-cell lymphomas: results of a randomized trial comparing chemotherapy alone versus chemotherapy + involved field radiotherapy (IELSG 4). Leuk Lymphoma 2009; 50:925–931. Vitolo U, Chiappella A, Ferreri AJ, et al. First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximabCHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial. J Clin Oncol 2011; 29:2766–27672. Vitolo U, Ferreri AJ, Zucca E. Primary testicular lymphoma. Crit Rev Oncol Hematol 2008; 65:183–189. Zinzani PL, Stefoni V, Finolezzi E, et al. Rituximab combined with MACOP-B or VACOP-B and radiation therapy in primary mediastinal large B-cell lymphoma: a retrospective study. Clin Lymphoma Myeloma 2009; 9:381–385.

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Lymphomas in the immunocompromised patient

Lymphomas in HIV patients The incidence of lymphoma is significantly increased in HIV patients: NHL ≈100x and HL ≈10-20x higher than in the general population. The incidence of AIDS-related NHL is related to the low CD4 count in this population and hence has significantly decreased since the introduction of HAART.

Incidence of NHL in HIV-infected patients % of patients on HAART

Cancer is the cause of death in one third of patients with HIV infection in the HAART era, NHL being the commonest type.

Lymphoma also occurring in immunocompetent patients Burkitt and Burkitt-like lymphomas Diffuse large B-cell lymphomas • Centroblastic • Immunoblastic (including primary CNS lymphomas) Extranodal MALT lymphoma (rare) Peripheral T-cell cell lymphoma (rare) Classical Hodgkin lymphoma Lymphoma occurring more specifically in HIV-positive patients Primary effusion lymphoma

NHL is an AIDS-defining malignancy that includes several entities. The WHO 2008 groups them according to how specific they are to HIV infection. DLBCL and BL are the most frequent subtypes. The incidence of PCNSL has significantly decreased in the HAART era. HL is a non-AIDS defining malignancy. The most common subtype in HIV patients is mixed cellularity.

Plasmablastic lymphoma of the oral cavity Lymphoma also occurring in other immunodeficiency states Polymorphic B-cell lymphoma (PTLD-like) (rare)

Both NHL and HL present in HIV patients with aggressive clinical features, with high-risk IPI and high-risk IPS scores.

This graph shows a better outcome for NHL patients who receive HAART during chemotherapy. The same has been shown for HL

In the HAART era, the outcome of HIV patients with NHL/HL has significantly improved, and it is similar to the outcome of NHL/HL in HIV-negative patients. Patients with HIV and lymphoma should be managed in combination with the HIV team and receive HAART and prophylactic antibiotics during chemotherapy.

REVISION QUESTIONS 1. What are the specific features of HIV patients associated with a higher incidence of lymphoma? 2. What are the commonest subtypes of NHL in HIV patients? 3. How has the introduction of HAART impacted on the incidence and outcome of lymphoma in HIV patients?

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Lymphomas in HIV patients The most important prognostic factors for DLBCL in HIV patients are the IPI and the CD4 count. Rituximab â&#x2020;&#x2018; treatment toxicity in patients with CD4 <50/ÎźL.

0.8

The standard first-line therapy for DLBCL is R-CHOP, as in HIV-negative patients. Other protocols used are infusional regimens such as R-DA-EPOCH.

1.0

As in HIV-negative patients, the standard therapy for DLBCL at relapse or not in CR after first line is salvage chemotherapy followed by ASCT.

0.6

HIV-neg (N=15): 2-yr DFS 93%, 95%CI 82-99%

0.9 HIV-pos (N=16): 2-yr DFS 87%, 95%CI 72-99%

Proportion alive in CR1

0.8 0.7 0.6 0.5 0.4

The outcome of HIV+ patients with BL treated with an intensive chemotherapy (B-ALL NHL2002) is comparable to that of HIVpatients with BL treated with the same protocol

0.2

0.0

24 36 Months after ASCT

BL is diagnosed in patients with a relatively high CD4 count who frequently present with extranodal disease. The outcome of patients with HIV and BL is comparable to that of HIV-negative patients when treated with the same intensive chemotherapy.

0.3

0.1

Patients with HIV who receive autologous transplant for NHL or HL have a similar outcome to that of HIV-negative patients treated with Control-Ly an autograft HIV-Ly

0.4

0.0

1.0

P = NS

p=NS 0 1 2 3 4 Years from CR1

The outcome of BL in HIV patients remains very poor in the HAART era when treated with non-intensive chemotherapy schedules such as those used for DLBCL.

Moderate (rather than severe) immunosuppression is associated with HL; hence, the incidence of HL might be increasing in the HAART era. HL presents in HIV patients with B-symptoms, advanced stage, extranodal disease, and high-risk IPS more frequently than in HIV-negative patients. The outcome of patients with HIV infection and HL treated with ABVD chemotherapy is similar to that of the general population.

This graph shows EFS for patients with HL treated with ABVD. A recent study demonstrates that the outcome of patients with HL treated with ABVD is independent of HIV status

REVISION QUESTIONS 1. What is the standard treatment for patients with HIV and relapsed lymphoma? 2. Should patients with BL and HIV infection be treated with DLBCL regimens or with intensive chemotherapy? 3. How does the outcome of HL treated with ABVD in HIV patients compare with the outcome of HL in the general population?

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Post-transplant lymphoproliferative disorders (PTLDs) PTLDs are lymphomas arising in patients who are immunosuppressed after having received a solid organ transplant (SOT) or a bone marrow transplant (BMT). The most important risk factors for PTLD are EBVseronegativity and intense immunosuppression. The risk of PTLD is higher after SOT than after BMT. Early PTLD (<12 mo) is often EBV-driven while lateonset PTLD is usually EBV-negative. The risk of PTLD is higher in children, related to EBV-primary infection.

The incidence of PTLD has a clear bimodal pattern, with a higher incidence shortly after transplant and a subsequent peak thereafter

WHO 2008 classification of PTLD Early lesions Plasmacytic hyperplasia Infectious mononucleosis-like lesion PTLD comprise a wide spectrum of disorders, Polymorphic PTLD from EBV-driven early Monomorphic PTLD lesions to EBV-negative B-cell neoplasms lymphomas (monomorphic Diffuse large B-cell lymphoma PTLDs) resembling those in Burkitt lymphoma immunocompetent Plasma cell myeloma patients Plasmacytoma-like lesion Other T-cell neoplasms Peripheral T-cell lymphoma, NOS Hepatosplenic T-cell lymphoma Other Classical Hodgkin lymphoma-type PTLD

Most patients present with enlarged LN and extranodal involvement (gastrointestinal, lung, liver). B-symptoms and poor PS are common. PTLDs after SOT are usually of host origin and the allograft is often involved (differential diagnosis with rejection). PTLD after BMT is normally of donor origin. The prognosis of PTLD is determined by clinical characteristics (PS, extranodal disease) rather than by latency or pathological subtype.

Reduction of immunosuppression (RI) is the first step in the management of PTLD, resulting in a CR rate of 0-50% (with a lower CR rate in late-onset PTLD). Low-risk patients not responding to RI can be treated with rituximab monotherapy with excellent results, as it kills the EBV-infected B-cells thus eliminating EBV. The addition of rituximab has improved the prognosis of PTLD, with 3-year PFS and OS: 50-60%. High-risk patients should receive immunochemotherapy.

Progression-Free Survival (%)

Risk of PTLD : renal (<1%) < liver/heart (1-2%) < heart-lung/lung/ bowel (>5%) transplant

100 No rituximab Rituximab

75 Some authors recommend to administer rituximab prior to chemotherapy, rather than concurrently, to improve PS

25 P < .0001

100

125

Time (months)

REVISION QUESTIONS 1. What are the most important risk factors for PTLD? 2. Which are the transplant recipients at a higher risk of developing PTLD? 3. What is the first step in the management of PTLD?

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Summary: Lymphomas in the immunocompromised patient • The incidence of NHL and HL is increased in HIV patients • The introduction of HAART has decreased the incidence of some types of NHL • The most common types of NHL in HIV patients are DLBCL and BL • Patients with HIV and DLBCL or HL have more aggressive disease with poor risk features in comparison with non-HIV patients with DLBCL or BL • The outcome of patients with HIV and lymphoma has significantly improved in the HAART era • The outcome of HIV patients with lymphoma is similar to that of HIV-negative patients treated with the same chemotherapy schedules • The management of relapsed lymphoma in HIV patients includes autologous stem cell transplant, as in the general population • PTLD is diagnosed more frequently following SOT than following BMT • The prognosis of patients with PTLD depends on the presence of clinically aggressive characteristics • The treatment of PTLD includes RI and rituximab (with or without chemotherapy)

Further Reading Bower M, Collins S, Cottrill C, et al. British HIV Association guidelines for HIV-associated malignancies 2008. HIV Med 2008; 9:336–388. Bower M, Stebbing J, Tuthill M, et al. Immunologic recovery in survivors following chemotherapy for AIDS-related non-Hodgkin lymphoma. Blood 2008; 111:3986–3990. Díez-Martín JL, Balsalobre P, Re A, et al. Comparable survival between HIV+ and HIV- non-Hodgkin and Hodgkin lymphoma patients undergoing autologous peripheral blood stem cell transplantation. Blood 2009; 113:6011–6014. Evens AM, David KA, Helenowski I, et al. Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era. J Clin Oncol 2010; 28:1038–1046. Kaplan LD, Lee JY, Ambinder RF, et al. Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010. Blood 2005; 106:1538–1543. Lim ST, Karim R, Nathwani BN, Tulpule A, Espina B, Levine AM. AIDS-related Burkitt’s lymphoma versus diffuse large-cell lymphoma in the pre-highly active antiretroviral therapy (HAART) and HAART eras: significant differences in survival with standard chemotherapy. J Clin Oncol 2005; 23:4430–4438. Oriol A, Ribera JM, Bergua J, et al. High-dose chemotherapy and immunotherapy in adult Burkitt lymphoma: comparison of results in human immunodeficiency virus-infected and noninfected patients. Cancer 2008; 113:117–125. Parker A, Bowles K, Bradley JA, et al. Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients – BCSH and BTS Guidelines. Br J Haematol 2010; 149:693–705. Trappe R, Oertel S, Leblond V, et al. Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell posttransplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial. Lancet Oncol 2012; 13:196–206. Xicoy B, Ribera JM, Miralles P, et al. Results of treatment with doxorubicin, bleomycin, vinblastine and dacarbazine and highly active antiretroviral therapy in advanced stage, human immunodeficiency virus-related Hodgkin’s lymphoma. Haematologica 2007; 92:191–198.

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Appendix 1: WHO Classification of Lymphomas

WHO 2008: MATURE B-CELL NEOPLASMS Chronic lymphocytic leukemia/small lymphocytic lymphoma B-cell prolymphocytic leukemia Splenic B-cell marginal zone lymphoma Hairy cell leukemia Splenic lymphoma/leukemia, unclassifiable Splenic diffuse red pulp small B-cell lymphoma Hairy cell leukemia variant Lymphoplasmacytic lymphoma Heavy-chain diseases Plasma cell myeloma Solitary plasmacytoma of bone Extraosseous plasmacytoma Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) Nodal marginal zone lymphoma Pediatric nodal marginal zone lymphoma Follicular lymphoma Pediatric-type follicular lymphoma Primary cutaneous follicle center lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma (DLBCL), NOS T-cell/histiocyte rich large B-cell lymphoma Primary DLBCL of the CNS Primary cutaneous DLBCL, leg type EBV positive DLBCL of the elderly DLBCL associated with chronic inflammation Lymphomatoid granulomatosis Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma ALK positive large B-cell lymphoma Plasmablastic lymphoma Large B-cell lymphomas arising in HHV8-associated multicentric Castleman disease Primary effusion lymphoma Burkitt lymphoma B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma Provisional entities

WHO 2008: PRECURSOR LYMPHOID NEOPLASMS B-lymphoblastic leukemia/lymphoma, not otherwise specified B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities

WHO 2008: MATURE T-CELL AND NK-CELL NEOPLASMS T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Chronic lymphoproliferative disorder of NK cells Aggressive NK-cell leukemia Systemic EBV positive T-cell lymphoproliferative disease of childhood Hydroa vacciniforme-like lymphoma Adult T-cell leukemia/lymphoma Extranodal NK/T-cell lymphoma, nasal type Enteropathy-associated T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides SĂŠzary syndrome Primary cutaneous CD30-positive T-cell lymphoproliferative disorders Lymphomatoid papulosis Primary cutaneous anaplastic large-cell lymphoma Primary cutaneous gamma-delta T-cell lymphoma Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma Primary cutaneous CD4-positive small/medium T-cell lymphoma Peripheral T-cell lymphoma (NOS) Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma (ALCL), ALK positive Anaplastic large cell lymphoma, ALK negative Provisional entities

WHO 2008: HODGKIN LYMPHOMA Nodular lymphocyte predominant Hodgkin lymphoma Classical Hodgkin lymphoma Nodular sclerosis classical Hodgkin lymphoma Lymphocyte-rich classical Hodgkin lymphoma Mixed cellularity classical Hodgkin lymphoma Lymphocyte-depleted classical Hodgkin lymphoma

WHO 2008: HISTIOCYTIC AND DENDRITIC CELL NEOPLASMS Histiocytic sarcoma Tumors derived from Langerhans cells Langerhans cell histiocytosis Langerhans cell sarcoma Interdigitating dendritic cell sarcoma Follicular dendritic cell sarcoma Other rare dendritic tumors Disseminated juvenile xanthogranuloma

Further Reading Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: International Agency for Research on Cancer, 2008.

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Appendix 2: Prognostic indices

Follicular Lymphoma International Prognostic Index (FLIPI) [1] Risk group

Number of adverse factors

% of patients

5-year OS

Low risk Intermediate High risk

0-1 2 3-5

36% 37% 27%

91% 78% 52%

Mantle Cell Lymphoma International Prognostic Index (MIPI) [5] MIPI score: 0.03535 x age (years) + 0.6978 (if ECOG >1) + 1.367 x log10(LDH/ ULN) + 0.9393 x log10(WBC count) Online calculator of MIPI score: http://www.european-mcl.net/en/clinical_mipi.php

Simplified MIPI [5]

Risk factors: age ≥60; LDH >ULN; stage III-IV; Hb <120 g/L; number nodal areas ≥5

Follicular Lymphoma International Prognostic Index 2 (FLIPI 2) [2] Risk group

Number of adverse factors

% of patients

5-year PFS

5-year OS

Low risk Intermediate High risk

0 1-2 3-5

20% 53% 27%

79% 51% 20%

98% 88% 77%

Risk factors: age >60; β2-microglobulin >ULN; BM involvement; Hb <120 g/L; longest diameter of largest node >6 cm

International Prognostic Index for Patients With Aggressive Lymphoma (IPI) [3,4] Risk group

Number of adverse factors

% of patients

4-year PFS*

4-year OS*

Low risk Intermediate-low Intermediate-high High risk

0-1 2 3 4-5

28% 27% 21% 24%

85% 80% 57% 51%

82% 81% 49% 59%

*Data on patients treated with R-CHOP Risk factors: age >60; LDH >ULN; stage III-IV; PS ECOG >2; extranodal sites >2

Age (years)

ECOG

LDH/ULN

WBC, 109/L

0 1 2 3

<50 50-59 60-69 ≥70

0-1 2-4 -

<0.67 0.67-0.99 1-1.49 ≥1.5

<6.7 6.7-9.99 10-14.99 ≥15

Risk group

Number of adverse factors

% of patients

5-year PFS

Median OS

Low risk Intermediate High risk

0-3 4-5 6-11

44% 35% 21%

not reached 51 months 29 months

Risk factors: age; ECOG; LDH; WBC

Prognostic index for PTCL-NOS (PIT) [6] Risk group

Number of adverse factors

% of patients

5-year PFS

5-year OS

Group 1 Group 2 Group 3 Group 4

0 1 2 3-4

20% 33% 26% 21%

62% 53% 33% 18%

Risk factors: age >60; LDH >ULN; PS ECOG ≥2; BM infiltration

International Prognostic Score for Advanced HL (Hasenclever Index) [7]

Revised-IPI# [4] Risk group

Number of adverse factors

% of patients

4-year PFS

4-year OS

Very good Good Poor

0 1-2 3-5

10% 45% 45%

90% 84% 53%

94% 79% 55%

‘Revised-IPI’ includes the same prognostic factors as IPI but differs in the distribution of risk group according to the number of adverse prognostic factors Risk factors: age >60; LDH >ULN; stage III-IV; PS ECOG >2; extranodal sites ≥2 #

Points

Number of adverse factors

% of patients

5-year PFS

5-year OS

0 1 2 3 4 ≥5

7% 22% 29% 23% 12% 7%

84% 77% 67% 60% 51% 42%

89% 90% 81% 78% 61% 56%

Risk factors: age ≥45; male gender; stage IV; Hb <105 g/L; lymphocyte count <0.6 x 109/L; leukocyte count ≥15 x 109/L; albumin <40 g/L

References 1. Solal-Céligny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood 2004; 104:1258–1265. 2. Federico M, Bellei M, Marcheselli L, et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol 2009; 27:4555–4562. 3. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 1993; 329:987–994. 4. Sehn LH, Berry B, Chhanabhai M, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 2007; 109:1857–1861. 5. Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood 2008; 111:558–565. 6. Gallamini A, Stelitano C, Calvi R, et al. Peripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical study. Blood 2004; 103: 2474–2479. 7. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med 1998; 339:1506–1514.

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Appendix 3: Selected treatment schedules

ABVD [1] Hodgkin lymphoma, 1st line Doxorubicin 25 mg/m2 Bleomycin 10 mg/m2 Vinblastine 6 mg/m2 DTIC (Dacarbazine) 375 mg/m2

i.v. i.v. i.v. i.v.

d1 + d15 d1 + d15 d1 + d15 d1 + d15

q 4 wks

(R-)CVP [12] Non-Hodgkin lymphoma, 1st line Cyclophosphamide 750 mg/m2 i.v. Vincristine 1.4 mg/m2 i.v. Prednisone 40 mg/d p.o. ± Rituximab* 375 mg/m2 i.v.

d1 d1 d1–5 d1

q 3 wks

* without rituximab for CD20-negative NHL

ASHAP [2] Non-Hodgkin lymphoma, Hodgkin lymphoma, salvage chemotherapy Doxorubicin* 10 mg/m2/d i.v. d1–4 C.I.* Cisplatin 25 mg/m2/d C.I. i.v. d1–4 Ara-C 1.5 g/m2 i.v. d5 C.I. over 2 h Methylprednisolone 250 mg/m2 i.v. d1–5 q 3 wks x 2/d * via central venous catheter

ChlVPP [3] Hodgkin lymphoma, 1st line/relapse Chlorambucil 6 mg/m2/d p.o. d1–14 Vinblastine 6 mg/m2 i.v. d1 + d8 Procarbazine 100 mg/m2/d p.o. d1–14 Prednisone 40 mg/d p.o. d1–14 BEACOPP [4] Hodgkin lymphoma, 1st line Bleomycin 10 mg/m2 i.v. Etoposide 100 mg/m2/d i.v. Doxorubicin 25 mg/m2 i.v. Cyclophosphamide 650 mg/m2 i.v. Vincristine 1.4 mg/m2 i.v. Procarbazine 100 mg/m2/d p.o. Prednisone 40 mg/m2/d p.o.

d8 d1–3 d1 d1 d8 d1–7 d1–14

BEACOPP escalated [5, 6] Hodgkin lymphoma, 1st line Bleomycin 10 mg/m2 i.v. d8 Etoposide 200 mg/m2/d i.v. d1–3 Doxorubicin 35 mg/m2 i.v. d1 Cyclophosphamide 1250 mg/m2 i.v. d1 Vincristine 1.4 mg/m2 i.v. d8 Procarbazine 100 mg/m2/d p.o. d1–7 Prednisone 40 mg/m2/d p.o. d1–14 Lenograstim 150 μg/m2/d s.c. from d4 or Pegfilgrastim 6 mg s.c. d4 (R-)CHOP-21 [7-9] Non-Hodgkin lymphoma, 1st line Doxorubicin 50 mg/m2 i.v. d1 Cyclophosphamide 750 mg/m2 i.v. d1 Vincristine 1.4 mg/m2 i.v. d1 Prednisone 100 mg/d p.o. d1–5 ± Rituximab* 375 mg/m2 i.v. d1

* without rituximab for T-NHL or CD20-negative NHL

R-DC [14] Waldenström macroglubulinemia, 1st line Dexamethasone 20 mg i.v. d1 Cyclophosphamide 100 mg/m2 x 2/d p.o. d1–5 Rituximab

q 4 wks

375 mg/m2

i.v.

(R-)EPOCH [15] Non-Hodgkin lymphoma, 1st line Doxorubicin 10 mg/m2/d C.I. i.v. d1–4 Etoposide 50 mg/m2/d C.I. i.v. d1–4 Vincristine 0.4 mg/m2/d C.I. i.v. d1–4 Cyclophosphamide 750 mg/m2 i.v. d5 Prednisone 60 mg/m2 /d p.o. d1–5 ± Rituximab* 375 mg/m2 i.v. d1

q 3 wks

* without rituximab for T-NHL or CD20-negative NHL

q 3 wks

Dose-adjusted (R-)EPOCH [16, 17] Non-Hodgkin lymphoma, 1st line Doxorubicin** 10 mg/m2/d C.I. i.v. d1–4 Etoposide** 50 mg/m2/d C.I. i.v. d1–4 Vincristine 0.4 mg/m2/d C.I. i.v. d1–4 Cyclophosphamide** 750 mg/m2 i.v. d5 Prednisone 60 mg/m2 /d p.o. d1–5 ± Rituximab* 375 mg/m2 i.v. d1 Filgrastim 300 mg s.c. from d5 q 3 wks until ANC > 5000/μL

q 3 wks

* without rituximab for T-NHL or CD20 negative NHL ** • if nadir ANC at least 0.5 x 109/L: 20% increase in etoposide, doxorubicin, and cyclophosphamide above last cycle • if nadir ANC less than 0.5 x 109/L on 1 or 2 measurements: same dose(s) as last cycle • if nadir ANC less than 0.5 x 109/L at least 3 measurements: 20% decrease in etoposide, doxorubicin, and cyclophosphamide below last cycle • if nadir platelet count less than 25 x 109/L on 1 measurement: 20% decrease in etoposide, doxorubicin, and cyclophosphamide below last cycle

q 3 wks

* without rituximab for T-NHL or CD20-negative NHL

(R-)CHOEP [10, 11] Non-Hodgkin lymphoma, 1st line Doxorubicin 50 mg/m2 i.v. d1 Cyclophosphamide 750 mg/m2 i.v. d1 Vincristine 1.4 mg/m2 i.v. d1 Prednisone 100 mg/d p.o. d1–5 Etoposide 100 mg/m2/d i.v. d1–3 ± Rituximab* 375 mg/m2 i.v. d1

(R-)DHAP [13] Non-Hodgkin lymphoma, salvage chemotherapy Dexamethasone 40 mg/d i.v. d1–4 Ara-C 2000 mg/m2 x 2 i.v. d2 Cisplatin 100 mg/m2 i.v. d1 ± Rituximab* 375 mg/m2 i.v. d1 q 3–4 wks

(R-)ESHAP [18, 19] Non-Hodgkin lymphoma, salvage chemotherapy Etoposide 40 mg/m2/d i.v. d1–4 Ara-C 2000 mg/m2 i.v. d5 Cisplatin 25 mg/m2/d C.I. i.v. d1–4 Methylprednisolone 250–500 mg/d i.v. d1–4 ± Rituximab* 375 mg/m2 i.v. d1 q 3 wks * without rituximab for T-NHL or CD20 negative NHL

q 3 wks

* without rituximab for T-NHL or CD20 negative NHL

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(R-)FC [20-22] Non-Hodgkin lymphoma, CLL, 1st line/relapse Fludarabine 25–30 i.v. d1–3 mg/m2/d Cyclophosphamide 250–300 i.v. d1–3 mg/m2/d Rituximab 375–500* i.v. d1 q 4 wks mg/m2 * 500 mg/m2 only for CLL (R-)FCM [23] Non-Hodgkin lymphoma, 1st line Fludarabine 25 mg/m2/d i.v. d1–3 Cyclophosphamide 200 mg/m2/d i.v. d1–3 Mitoxantrone 8 mg/m2 i.v. d1 ± Rituximab* 375 mg/m2 i.v. d1

q 4 wks

* without rituximab for CD20 negative NHL

(R-)GDP [24] Non-Hodgkin lymphoma, Hodgkin lymphoma, salvage chemotherapy Gemcitabine 1000 mg/m2 i.v. d1 Dexamethasone 40 mg/d i.v. d1–4 Cisplatin 75 mg/m2 i.v. d1 ± Rituximab* 375 mg/m2 i.v. d1 q 3 wks * without rituximab for T-NHL or CD20-negative NHL

R-Hyper-CVAD [25] Burkitt lymphoma, 1st line Cycles 1, 3, 5 Cyclophosphamide 300 mg/m2 i.v. d1–3 C.I./3 h x2/d Mesna 600 mg/m2/d C.I. i.v. d1–3 Vincristine 2 mg i.v. d4 + d11 Doxorubicin* 50 mg/m2 C.I. i.v. d4 over 24 h* Dexamethasone 40 mg/d p.o. d1–4, d11–14 Rituximab 375 mg/m2 i.v. d1 + d11 G-CSF 10 μg/kg/d s.c. from d6 q 3 wks *** Methotrexate 12 mg i.t. d2 Ara-C 100 mg i.t. d7 * via central venous catheter

Cycles 2, 4, 6 Methotrexate** Ara-C Rituximab G-CSF

1000 mg/m2 C.I. over 24 h 3000 mg2 x2/d 375 mg/m2 10 μg/kg/d

i.v.

d2–3

i.v. i.v. s.c.

d2 + d3 d2 + d8 from d5

Mantle cell lymphoma [26] Cycles 1, 3, 5 Cyclophosphamide 300 mg/m2 i.v. C.I. over 3h x 2/d Mesna 600 mg/m2 C.I. i.v. Vincristine 1.4 mg i.v. Doxorubicin* 16.6 mg/m2/d i.v. C.I. 72 h* Dexamethasone 40 mg p.o.

*via central venous catheter

Ara-C Rituximab G-CSF

1000 mg/m2 C.I. over 24 h 3000 mg/m2 x2/d 375 mg/m2 5 μg/kg/d

i.v.

i.v. i.v. s.c.

d2 + d3 d1 from d5

q 3 wks

** leucovorin rescue

CODOX-M/IVAC (Magrath)*** [27-29] Burkitt lymphoma, 1st line CODOX-M (Cycles 1 and 3) Cyclophosphamide 800 mg/m2 i.v. d1 Cyclophosphamide 200 mg/m2/d i.v. d2–5 Vincristine 1.5 mg/m2 i.v. d1 + d8 (max. 2 mg) (cycle 1) d1 + d8 + d15 (cycle 3) i.v. d10 Methotrexate* 300 mg/m2 loading dose the 1st hour followed by 2700 mg/m2 for the next 23 hours Rituximab 375 mg/m2 i.v. d1 G-CSF 5 μg/kg/d s.c. from d13 Ara-C 70 mg i.t. d1 + d3 Methotrexate 12 mg i.t. d15 Leucovorin 15 mg/dose p.o. d16 ** * leucovorin rescue

IVAC (Cycles 2 and 4) Ifosfamide 1500 mg/m2/d Mesna 1500 mg/m2/d Etoposide 60 mg/m2/d Ara-C 2 g/m2 x2/d G-CSF 5 μg/kg/d Methotrexate 12 mg Leucovorin 15 mg/dose

i.v. i.v. i.v. i.v. s.c. i.t. p.o.

d1–5 d1–5 d1–5 d1 + d2 from d7 d5 d16

** next cycle on the day that the unsupported ANC is >1.0 x 109/L, with an unsupported plated count >75 x 109/L *** for patients <65 years old

q 3 wks ***

** leucovorin rescue *** or earlier if count recovery occurred (at least 14 days apart)

Rituximab G-CSF

Cycles 2, 4, 6 Methotrexate**

375 mg/m2 5 μg/kg/d

i.v. s.c.

d1–3 d1–3 d4 + d11 d4–6 d1–4, d11–14 d1 from d6

(R-)ICE [30, 31] Non-Hodgkin lymphoma, salvage chemotherapy Etoposide 100 mg/m2/d i.v. d1–3 Ifosfamide 5000 mg/m2 i.v. d2 C.I. over 24 h Mesna 5000 mg/m2 i.v. d2 C.I. over 24 h Carboplatin AUC = 5 i.v. d2 (max. 800 mg) Rituximab* 375 mg/m2 i.v. d1 G-CSF 5 μg/kg/d s.c. from d7 q 2–3 wks * without rituximab for T-NHL or CD20-negative NHL

q 3 wks

IGEV [32] Non-Hodgkin lymphoma, Hodgkin lymphoma, salvage chemotherapy Gemcitabine 800 mg/m2/d i.v. d1 + d4 Ifosfamide 2000 mg/m2/d i.v. d1–4 Mesna 2600 mg/m2/d i.v. d1–4 Vinorelbine 20 mg/m2 i.v. d1 Prednisolone 100 mg/m2/d p.o. d1–4 G-CSF 5 μg/kg/d s.c. d7–14

q 3 wks

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Mini (R-)CEOP [33] Non-Hodgkin lymphoma (elderly patients), 1st line Cyclophosphamide 750 mg/m2 i.v. d1 Epirubicin 50 mg/m2 i.v. d1 Vinblastine 5 mg/m2 i.v. d1 Prednisone 60 mg/m2/d p.o. d1–5 Rituximab* 375 mg/m2 i.v. d1 q 3 wks

C+/-P [42] Non-Hodgkin lymphoma Chlorambucil 10 mg/d p.o.

* without rituximab for T-NHL or CD20-negative NHL

F [43] Non-Hodgkin lymphoma Fludarabine 25 mg/m2/d

Gem-P [34, 35] Non-Hodgkin lymphoma, salvage Gemcitabine 1000 mg/m2 i.v. d1 + d8 + d15 Cisplatin 100 mg/m2 i.v. d15 Methylprednisolone 1000 mg/m2/d p.o. d1–5 MTX High dose [36-38] CNS non-Hodgkin lymphoma Methotrexate* 3500/8000 i.v. d1 mg/m2

q 4 wks

R [45] B-cell non-Hodgkin lymphoma Rituximab 375 mg/m2 i.v.

d1–5

q 4 wks

d1–5

q 4 wks

weekly x 4 followed by maintenance

A [46] Chronic lymphocytic leukemia/small lymphocytic lymphoma Alemtuzumab 30 mg* i.v./ weekly 3 x wk s.c. * first dose 3 mg, second dose 10 mg, then 30 mg 3 x wk

q 3 wks

B [47] Non-Hodgkin lymphoma Bendamustine 90 mg/m2

i.v.

d1–2

Gem [48] Non-Hodgkin lymphoma, palliative setting Gemcitabine 1000 mg/m2 i.v. d1 + d8 + d15

SINGLE AGENTS

CB [41] Non-Hodgkin lymphoma Chlorambucil 30 mg/d

i.v.

q 2 wks

* leucovorin rescue

C [40] Non-Hodgkin lymphoma Cyclophosphamide 100 mg/m2/d

50 mg/d

2-CDA [43, 44] Non-Hodgkin lymphoma Cladribine 0.1 mg/kg/d s.c.

* leucovorin rescue

MTX Intermediate dose and high dose Ara-C [39] CNS non-Hodgkin lymphoma Methotrexate* 3500 mg/m2 i.v. d1 Ara-C 2000 mg x2/d i.v. d2–3

+/- Prednisone

for 6 wks, then d1–14 q 4 wks p.o. d1–7

p.o.

daily

d1–4

V [49] Hodgkin lymphoma, palliative setting Vinblastine 6 mg/m2 i.v. d1 weekly for 4 wks, then q 2 wks

q 4 wks

q 2 wks

Etoposide [50] Non-Hodgkin lymphoma, palliative setting Etoposide 50 mg/d p.o. discontinue Tx when WBC <2 G/l or platelets <50 G/l

Abbreviations 2/d: twice a day ANC: absolute neutrophil count C.I: continuous infusion i.t.: intrathecal i.v.: intravenous

NHL: non-Hodgkin lymphoma p.o.: oral s.c.: subcutaneous WBC: white blood cells wk: week

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Image sources

The authors acknowledge with gratitude the following sources of the images used in this publication. Chapter 1 Figure 1. Dranoff G. Nat Rev Cancer 2004; 4:11-22; 2. Kaiser G. http://faculty. ccbcmd.edu/courses/bio141/lecguide/unit4/antigens/u3fg2.html; 4. Fix D. http://www.cehs.siu.edu/fix/medmicro/igs.htm; 5. Berg JM, Tymoczko JL, Styer L. Biochemistry (Sixth edition). WF Freeman and Company; 2007; 7. http://www. talkdesign.org/faqs/Evolving_Immunity.html; 8. Levy N. http://www.dartmouth. edu/~nlevy/pln3.html; 9. Klein U, et al. Nat Rev Immunol 2008; 8:22-33; 10. Hunt R. www.microbiologybook.org; 11. http://en.wikipedia.org/wiki/File: Antigen_presentation.jpg; 12. http://arthritis-research.com/content/6/1/8/figure/ F1; 13. http://www.singulex.com/inflammation_cytokines.html?PHPSESSID=9 7aaf123b8fca071688edefad296c99c; 14. http://www.mda.org/publications/ Quest/q154newdirections.html; 15. Casadevall A, et al. Nat Rev Microbiol 2004; 2:695-703. Chapter 2 Figure 4. Adapted from hematologyoutlines.com. Chapter 3 Figure 7 and 8. Jaffe ES, Harris NL, Vardiman J, Campo E, Arber D. Hematopathology. St. Louis: Elsevier Saunders, 1st edition, 2011. Chapter 4 Figure 1. Healblog.net: http://www.healblog.net/what-indicates-a-swollen-nodein-the-neck; 2. Healthmad: http://healthmad.com/conditions-and-diseases/badbreath-snoring-sleeplessness-ear-infection-and-sore-throat/; 3. Courtesy Andrea Gallamini, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy; 5. Courtesy Martin Hutchings, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 6. Schwarz K. Lymphomation.org: http://www.lymphomation.org/stage.htm; 7. Courtesy Alberto Biggi, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy; 9. Ngeow JY, et al. Ann Oncol 2009; 20:1543-1547 by permission of Oxford University Press; 11. Terasawa T, et al. J Nucl Med 2008; 49:13-21; 12. Jerusalem G, et al. Blood 1999; 94:429–43; 13. Gallamini A, et al. J Clin Oncol 2007; 25:3746-3752;15 (left). Based on data in Radford JA, et al. BMJ 1997; 314:343346; 15 (right). Weeks JC, et al. J Clin Oncol 1991; 9:1196-203; Liedtke M, et al. Ann Oncol 2006; 17:909-913 by permission of Oxford University Press. Chapter 5 Figure 3. Winslow T. http://www.qualityoflife.org/cancer/patientinfo/list/ summary/?id=CDR258030, copyright Terese Winslow; 4. http://en.wikipedia. org/wiki/Nomenclature_of_monoclonal_antibodies; 5. Brody J, et al. J Clin Oncol 2011; 29:1864-1875; 6. Ansell SM. Expert Opin Investig Drugs 2011; 20:99-105; 8. Courtesy T. Illidge, Manchester, UK; 10. Foote M. The Oncologist 1998;3:365368; 13. http://www.makna.org.my/bonemarrow.asp; 14. Gianni AM, et al. Ann Oncol 1993; 4:889-891; 15. Bleakley M, et al. Nat Rev Cancer 2004; 4:371-380. Chapter 6 Figure 2. Hans CP, et al. Blood 2004; 103:275-282; 3. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (ed 4th). Lyon, France: IARC Press; 2008, based on data in: A clinical evaluation of the International Lymphoma Study Group classification of nonHodgkin’s lymphoma. The Non-Hodgkin’s Lymphoma Classification Project. Blood 1997;89:3909-3918; 6. Modified from Shipp MA. Blood 1994; 83:1165-1173; 7. Coiffier B, et al. Blood 2010; 116:2040-2045; 8. Récher C, et al. Lancet 2011; 378:1858-1867; 10. Pfreundschuh M, et al. Lancet Oncol 2006; 7:379-391; 13. Philip T, et al. N Engl J Med 1995; 333:1540-1545; 14. Gisselbrecht C, et al. J Clin Oncol 2010; 28:4184-4190. Chapter 7 Figure 1. Ramnani D. http://www.webpathology.com/image.asp?case=389&n=3; 2. Courtesy A Carvajal-Cuenca and E Campo; 4. Swenson WT, et al. J Clin Oncol 2005; 23:5019-5026; 5. Al-Tourah AJ, et al. J Clin Oncol 2008; 26:5165-5169; 6. Solal-Céligny P, et al. Blood 2004; 104:1258-1265; 7. Ardeshna KM, et al. Lancet 2003; 362:516-522; 8. Peterson BA, et al. J Clin Oncol 2003; 21:5-15; 10. Based on data in Schulz H, et al. J Natl Cancer Inst 2007; 99:706-714; 11. Rummel M et al, submitted; 12. Morschhauser F, et al. J Clin Oncol 2008; 26:5156-5164; 13. Johnson PW, et al. J Clin Oncol 1995; 13:140-147; 15. Hosing C, et al. Ann Oncol 2003; 14:737-744 by permission of Oxford University Press.

Chapter 8 Figure 6. Kröber A et al. Blood 2002; 100:1410-1416; 7. Hallek M et al. Lancet 2010; 376: 1164-1174; 9. Knauf WU, et al. J Clin Oncol 2009; 114:3382-3391; 10. Robak T et al. J Clin Oncol 2010;28:1756-1765; 11. Michallet M et al. Leukemia 2010; 24:1725-1721. Chapter 9 Figure 1 and 2. Yatabe Y, et al. Am J Surg Pathol 1996; 20:1110-1122; 3. Jares P, et al. Nat Rev Cancer 2007; 7:750-762; 4. Ghielmini M, et al. Blood 2009; 114:1469-1476; 5. Hoster E, et al. Blood 2008; 111:558-565; 6. Tiemann M, et al. Br J Haematol 2005; 131:29-38; 8. Hermine O, et al. Ann Oncol 2010; 22 (Supplement 4: 11th ICML): #23; 9. Based on data in Hoster E et al. Onkologie 2010; 33 (Supplement 6): 202. Abstract #V678; 10. Copyright: Marius Pawlitza; 11. Buske C, et al. Leukemia 2009; 23:153-161; 12. Modified from Rummel MJ, et al. J Clin Oncol 2005; 23:3383-3389; 14. Jares P, et al. Nat Rev Cancer 2007; 7:750-762. 15. Hess G, et al. J Clin Oncol 2009; 27:3822-3829. Chapter 10 Photographs kindly provided by: Luca Mazzucchelli (Locarno, Switzerland), Maurilio Ponzoni (Milan, Italy), and Michele De Boni (Feltre, Italy). Figure 15. Zucca et al. Blood (ASH Annual Meeting Abstracts) 2010; 116: Abstract #432. Chapter 11 Figure 3. Vose J, et al. J Clin Oncol 2008; 26:4124-4130; 7. Gisselbrecht C, et al. Blood 1998; 92:76-82; 8. Savage KJ. Hematology Am Soc Hematol Educ Program 2008:280-288; 9. Gallamini A, et al. Blood 2004; 103:2474-2479; 10. Modified from: Abouyabis AN, et al. ISRN Hematol 2011; 2011:623924; 11. d’Amore F, et al. J Clin Oncol 2012 (published online July 30, 2012); 12. Copyright Francesco d’Amore. Chapter 12 Figure 1. Modified from www.medinfographics.com; 2. Ramnani D. http://www. webpathology.com/; 3. Küppers R. Nat Rev Cancer 2009; 9:15-27; 6. Modified from Cancer Research UK: http://info.cancerresearchuk.org/cancerstats/types/ hodgkinslymphoma/survival/hodgkins-lymphoma-survival-statistics; 7. Engert A, et al. N Engl J Med 2010; 363:640-652; 8. von Tresckow B, et al. J Clin Oncol 2012; 30:907-913; 11. Schulz H, et al. Blood 2008; 111:109-111; 12. Sureda A, et al. J Clin Oncol 2008; 26:455-462; 14. Josting A, et al. Clin Oncol 2003; 21:3440-3446; 15. Aleman BM, et al. J Clin Oncol 2003; 21:3431-3439. Chapter 13 Figure 1. Based on data from Globocan 2008: http://globocan.iarc.fr/; 2. Based on data from National Cancer Institute: http://seer.cancer.gov/canques/incidence. html; 3. Ferlay J, et al. Globocan 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: Globocan 2008: http://globocan. iarc.fr/map.asp?selection=18250&title=Non-Hodgkin+lymphoma&sex=0&type=1 &statistic=2&map=5&window=1&size=2&colour=1&scale=0&submit=%A0Exec ute%A0; 4. Based on data from Globocan 2008, IARC; 5. Quesada V, et al. Nature Genet 2011; 44:47-52; 6. Colt JS, et al. Blood 2009; 113:1899-1905; 7. Modified from: Costas L, et al. Cancer Causes Control 2012; 23:195-206; 8. Larsson SC, et al. Eur J Cancer 2011; 47:2422-2430; 9. de Sanjose S, et al. Clin Gastroenterol Hepatol 2008; 6:451-458. Chapter 15 Figure 3. Stamatoullas A, et al. Leukemia 2007; 21:2064-2067; 5. Staudt LM. Trends Immunol 2001; 22:35-40. Chapter 17 Figure 3. Kim YH, et al. Arch Dermatol 2003; 139:857-866; 8 (left). Willemze R, et al. Blood 2005; 105:3768-3785; 8 (right). Rijlaarsdam JU, et al. J Clin Oncol 1996; 14:549-555; Willemze R, et al. Blood 2005; 105:3768-3785; 9 (left). Senff NJ & Willemze R. Br J Dermatol 2007; 157:1205-1211.

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Chapter 18 Figure 1, 2, and 3. Delabie J, et al. Blood 2011; 118:148-155; 4. http://www. pathpedia.com/graphics/Pathpedia-8.png; 5. Kim TM, et al. Blood 2005; 106:3785-3790; 6. Yamaguchi M, et al. J Clin Oncol 2011; 29:4410-4416; 7. Subcutaneous Panniculitis-like T-cell Lymphoma - 1. Marshall Kadin, American Society of Hematology (ASH) Image Bank 2011; 2011-2864. http://imagebank. hematology.org/AssetDetail.aspx?AssetID=2192; 8. Lee HJ, et al. Radiographics 2003; 23:7-26; 9. Saboo SS, et al. Br J Radiol 2012; 85:81-92.

Chapter 21 Figure 1. Aldoss IT et al. Oncology 2008; 22:1508-1517; 2. Tomlins SA, et al. Science 2005; 310:644-648. Image courtesy Gregory Schuler, NCBI, NIH, Bethesda, MD, USA; 3. cancer.iaea.org: http://cancer.iaea.org/newsstory. asp?ft=7. Image courtesy Angela Leuker; 5. Mead GM, et al. Ann Oncol 2002; 13:1264-1274; 7. Lymphoblastic Lymphoma - 5. Marshall Kadin, American Society of Hematology (ASH) Image Bank 2011; 2011-2864. http://imagebank. hematology.org/AssetDetail.aspx?AssetID=2864&AssetType=Asset

Chapter 19 Figure 3. Berger F, et al. Blood 2000; 95:1950-1956; 8. Thieblemont C, et al. Clin Lymphoma 2002; 3:41-47; 9. Marin-Niebla A, et al. High response rate in patients with splenic marginal zone lymphoma treated with rituximab, either as monotherapy or in combination with chemotherapy (379-P), EHA 16, 10 June 2011. http://www.postersessiononline.com/173580348_eu/congresos/16eha/ aula/-P_379_16eha.pdf.

Chapter 22 Figure 3. Ferreri AJ, et al. Lancet 2009; 374:1512-1520; 4 and 5. Zucca E, et al. J Clin Oncol 2003; 21:20-27.

Chapter 20 Figure 2. Naresh KN, et al. Am J Hematol 2011; 86: 31131-31132; 3. Stone MJ. Clin Lymphoma Myeloma 2009; 9:97-99; 4. Dhodapkar MV, et al. Blood 2009; 113:793-796; 5. Morel P, et al. Blood 2009; 113:4163-4170; 6. Dhodapkar MV, et al. Blood 2009; 113:793-796; 7. Dimopoulos MA, et al. J Clin Oncol 2007; 25:3344-349; 8. Kyriakou C, et al. J Clin Oncol 2010; 28:2227-2232; 9. Treon SP, et al. Clin Cancer Res 2007; 13:3320-3325.

Chapter 23 Figure 1. Engels EA, et al. J Acquir Immune Defic Syndr 2010; 54:78-84; 3. Vaccher E, et al. Cancer 2001; 91:155-163; 4. DĂez-MartĂn JL, et al. Blood 2009; 113:6011-6014; 5. Oriol A, et al. Cancer 2008; 113:117-125; 6. Xicoy B, et al. Haematologica 2007; 92:191-198; 8. Quinlan SC, et al. Am J Hematol 2011; 86:206-209; 9. Evens AM, et al. J Clin Oncol 2010; 28:1038-1046.

While every effort has been made to contact the copyright holders of all images, the publisher would be grateful for any additional information about any images where they have been unable to trace or obtain permissions and will be glad to make amendments in future editions.

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Index

ABC subtype, 31, 82 ABT-263, 87 ABVD, 23, 25, 69, 114, 119 acute lymphoblastic leukemia (ALL), 9, 107 acute myeloid leukemia (AML), 71 alemtuzumab, 26, 45, 46, 47, 65, 103, 121 ALK rearrangements, 13 ALK-fusion protein, 62 allogeneic stem cell transplant (allo-SCT), 29, 35, 41, 45, 64, 94, 95, 105 anaplastic large cell lymphoma (ALCL), 9, 13, 26, 61, 63, 64, 65, 117 angioimmunoblastic T-cell lymphoma (AITL), 9, 15, 61, 62, 63 Ann Arbor classification, 20, 68 anthracycline, 25, 51, 111 antibody-dependent cytotoxicity (ADC), 86 antigen-presenting cells (APC), 3, 5 apoptosis, 4, 13, 49, 57, 85, 86, 87 Ara-C (cytarabine), 25, 33–35, 51, 107–110, 119–121 aurora kinase, 65, 87 autoimmune hemolytic anemia (AIHA), 47, 99 autologous stem cell transplant (ASCT) BL, 106 CLL / SLL, 46, 47 DLBCL, 34, 35 extranodal lymphomas, 109 FL, 40, 41 HIV and, 114 HL, 70 MCL, 51, 53 PTCL, 64, 93, 95 treatment principles, 29 WM, 103

B cells, 2, 3, 14, 26, 55, 62, 91, 115 B-cell lymphoma, see also CBCL, DLBCL immunophenotype, 9, 15 treatment principles, 26 WHO classification, 14–16, 117 B-cell receptor (BCR), 3, 4, 46, 87 bcl-2, 13, 37, 87, 105 BCL2, 13, 16, 37, 81 bcl-6, 15, 32, 50, 98, 106 BCL6, 16 BCNU, 25 BEACOPP, 69, 119 BEAM, 70 bendamustine, 25, 35, 39, 40, 45, 46, 52, 53, 102, 121 BIRC3, 57 bleomycin, 25, 119 BNLI classification, 77 bone lymphoma, 111 bone marrow (BM) BL, 107 CLL / SLL, 43 DLBCL, 32 extranodal marginal zone lymphoma of MALT type, 58

FL, 37, 38 histology, 8, 14 HL, 68 immune system and, 1–4 LBL, 107 LPL, 101 MCL, 50 non-MALT marginal zone lymphomas, 97, 98 PTCL, 62 staging and, 19, 22 Borrelia burgdorferi, 56 bortezomib, 51, 53, 103 brentuximab vedotin, 26, 65, 70 B-symptoms, 19, 20, 32, 47, 58, 62, 68, 93–95, 114 BTK, 87 Burkitt lymphoma (BL), 16–75, 105–107, 113–117, 120 busulfan, 25 bystander cells, 87

CAL-101, 46 carboplatin, 120 carmustine, 25 caspases, 13 CCNU, 25 centroblasts, 3, 15, 37, 91 centrocytes, 3, 15, 37, 91 chemokines, 14, 61 chimeric antigen receptor-modified T-cells (CARs), 46 Chlamydophila psittaci, 56 chlorambucil, 25, 39, 45, 52, 90, 102, 119, 121 CHOP DLBCL, 33 extranodal lymphoma, 93–95 FL, 39, 40 MCL, 51, 52 PTCL, 64 treatment principles, 25, 28, 119 chromosomal translocations, 10, 11, 57, 81 chronic lymphocytic leukemia (CLL), 9, 14, 15, 26, 43–49, 73, 74, 117, 120 chronic myeloid leukemia (CML), 73 cisplatin, 119, 120, 121 cladribine, 25, 102, 121 clarithromycin, 58 cluster of differentiation (CD), 9 CNS infiltration, 32, 107, 110 complement, 1, 5, 21, 86 complement-dependent cytotoxicity, 86 corticosteroids, 25 Cotswolds modification, 20 CSF examination, 32 cutaneous B-cell lymphoma (CBCL), 89, 91 cutaneous T-cell lymphoma (CTCL), 89, 90 CVP, 40, 52, 119 cyclin, 49, 87, 97 cyclophosphamide, 25, 28, 39, 45, 102, 103, 106, 119–121 cytogenetics, 10, 83, 98, 107 cytokines (CK), 1, 14, 86

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dacarbazine, 25, 119 DA-R-EPOCH, 33 Deauville’s criteria, 23 dendritic cells, 1, 3, 117 dexamethasone (DXM), 28, 102, 103 DHAP, 35, 53, 70, 119 diabetes, 74 diagnostic principles, 7–12 diffuse large B-cell lymphoma (DLBCL), 31–36, 38, 75, 78, 99, 105, 106, 109–114 cytogenetics, 10 molecular genetics, 82, 83 staging, 19–23 treatment principles, 25 WHO classification, 13–17, 117 DNA microarrays, 11 “double-hit” lymphomas, 16, 82 doxorubicin, 25, 119, 120, 121 DRC, 103 DTIC, 25, 119 dual-color dual-fusion strategy, 10

EBER, 11, 63 endoscopy, 20, 50, 32, 58, 59 enteropathy associated T-cell lymphoma (EATL), 61, 64, 93 epidemiology, principles, 73 epigenetic profiling, 83 epithelial membrane antigen (EMA), 62, 67 EPOCH, 28, 33, 114, 120 Epstein-Barr virus (EBV), 11, 17, 31, 62, 63, 75, 94, 95, 105, 115, 117 erythroderma, 90 ESHAP, 35, 120 etiology, principles, 73 etoposide, 25, 33, 64, 94, 119–121 expression arrays, 83 extranodal lymphomas, 61, 109–111 extranodal marginal zone lymphoma of MALT type, 55–60 extranodal sites, 20, 32, 50, 55

F-18-fluorodeoxyglucose (FDG), 21, 23 filgrastim, 119 fine-needle aspirate (FNA), 7 flow cytometry, 7, 9, 32, 83, 107 fludarabine, 25, 28, 39, 40, 45, 46, 47, 52, 102, 103, 120, 121 fluorescence in situ hybridization (FISH), 10, 16, 44, 46, 81, 82, 83 follicular lymphoma (FL), 37–41, 81 molecular biology, 83, 84 prognostic indices, 120 radiotherapy, 27

staging, 19, 21 WHO classification, 13–17, 119 Follicular Lymphoma International Prognostic Index (FLIPI), 38, 118 fostamatinib, 46

galiximab, 26 G-CSF, 28, 29, 120, 121 gemcitabine, 64, 70, 120, 121 gene expression profile (GEP), 81, 82 gene rearrangement, 10, 63 germinal center (GC), 3, 15, 31, 49 germinal center like B-cell lymphoma (GCB), 31, 35, 82 GPD, 35 graft-versus-lymphoma, 29, 86

Hashimoto’s thyroiditis, 56 hedgehog pathway inhibitors, 87 Helicobacter pylori, 56–59, 75, 111 helper T-cells, 3 hemophagocytic syndrome (HPS), 95 hepatitis B virus (HBV), 19, 26 hepatitis C virus (HCV), 19, 73, 75, 97, 99 hepatosplenic T-cell lymphoma, 61, 95 high-dose steroids, 47 high-dose therapy (HDT), 29, 34, 35, 64, 70, 93, 95, 103, 106, 109 highly active anti-retroviral therapy (HAART), 113, 114 histiocytes, 14 histone deacetylase inhibitors (HDACi), 65, 87 history, 77–79 HIV, 17, 19, 31, 74, 75, 105, 113, 114 Hodgkin lymphoma (HL), 61, 67–75 cytology, 14 HIV and, 113, 114 immunohistochemistry, 8, 9 staging, 19–23 treatment principles, 25–27, 119 WHO classification, 17 human herpes virus (HHV)-8, 75 human T-lymphotropic virus (HTLV)-1, 75 hyper-CVAD, 28, 51, 64, 107, 120 hypergammaglobulinemia, 62 hypogammaglobulinemia, 47

131-iodine, 27 ibritumomab tiuxetan, 41 ibrutinib, 46 ICE, 35, 70, 121 idiotypic vaccine, 86 ifosfamide, 25, 33, 94, 120, 121 IGEV, 35, 70, 121

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immune system, 1–5, 47 immunochemotherapy, 52, 53, 59, 115 immunodeficiency-associated BL, 105 immunoglobulins (Ig), 2, 3, 9, 10 immunohistochemistry (IHC), 9, 11, 44, 58 immunological memory, 1 immunomodulators (IMIDs), 86 immunophenotype, 9, 15, 19, 31, 43, 49, 98, 107 immunosuppression, 74, 75, 95, 114, 115 immunotoxins, 26 indolent lymphoma, 21, 25, 27, 28, 31, 41, 49, 50, 99 induction treatment, 51, 64 innate immune system, 1, 5 inotuzumab ozogamicin, 26 interferon (INF), 89, 99 International Harmonization Project (IHP), 21, 22 International Prognostic Index (IPI), 32, 34, 35, 50, 63, 64, 94, 113, 114, 118 International Prognostic Score for Advanced HL (Hasenclever Index), 118 International Prognostic Scoring System (ISSWM), 102 International Working Formulation (IWF), 78 International Workshop Consensus (IWC), 22

janus kinase (JAK), 67 JC virus (JCV), 26

Ki-67, 50, 105 Kiel classification, 61, 77, 78

L-asparaginase, 94 lenalidomide, 35, 41, 46, 51, 53, 65, 86 lenograstim, 119 leucovorin, 120, 121 lomustine, 25 Lukes & Collins classification, 77 lumbar puncture, 19 lupus erythematosus panniculitis, 95 lymphadenopathy, 44, 68 lymphoblastic lymphoma (LBL), 105, 107 lymphocytes, see B cells, T cells lymphoepithelial lesions, 14, 55 lymphoid tissues (LT), 8 lymphomatoid papulosis, 90 lymphoplasmacytic cells, 101 lymphoplasmacytic lymphoma (LPL), 75, 101, 117 lymph node (LN) BL, 105, 107 CLL / SLL, 43 CTCL, 90 DLBCL, 32

extranodal lymphomas, 55, 94, 110 FL, 37, 38 HL, 67, 68 immune system, 1–3, 8 LPL/WM, 101, 102 non-MALT marginal zone lymphomas, 97, 99 staging, 19–22

macrophages, 1, 5 magnetic resonance imaging (MRI), 20, 32 major histocompatibility complex (MHC), 4, 5 mantle cell lymphoma (MCL), 13–21, 49–53, 61, 117, 120 Mantle Cell Lymphoma International Prognostic Index (MIPI), 50, 118 marginal zone lymphoma (MZL), 14, 55, 75, 97, 98, 109, 117 mast cells, 1, 101 melphalan, 25 methotrexate (MTX), 25, 33, 34, 51, 90, 94, 95, 107, 109, 110, 121 methylprednisolone, 119, 121 metronidazole, 58 microRNA profiling, 83 minimal residual disease (MRD), 82, 83 mitoxantrone, 28, 120 mobilization, 29 monoclonal antibodies (MoAb), 26, 45, 86, 103 monoclonal B-cell lymphocytosis (MBL), 17, 43 monoclonal gammopathy of undetermined significance (MGUS), 102 monoclonality, 55 mTor, 65 Mucosa-Associated Lymphoid Tissue (MALT), 1, 14, 16, 20, 55–59, 97, 111, 117 multiple myeloma (MM), 73 MYC, 10, 16, 32, 82, 105 mycosis fungoides (MF), 89, 90, 117

natural killer (NK) cells, 4, 5, 9, 27, 61, 86, 94, 95, 117 neutrophils, 1, 14 next generation sequencing (NGS), 83 NF-kappaB, 57, 67 NIHG-ALL09/00, 107 nodal marginal zone lymphoma (NMZL), 97 nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), 67, 69, 70 non-Hodgkin lymphoma (NHL), 31, 50, 61, 94, 105, 107, 113 etiology, 73–75 imaging, 20–23 molecular biology, 82 treatment principles, 26–28, 119–121 non-MALT marginal zone lymphomas, 97–99

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obatoclax, 87 obinutuzumab, 26, 41 ofatumumab, 26, 41, 103 onychodystrophy, 90 orchidectomy, 110

palmoplantar hyperkeratosis, 90 paraffin embedding, 7, 9, 16, 81 PARP inhibitors, 87 PAX5, 15 pegfilgrastim, 119 pentostatin, 25 periodic acid-Schiff (PAS), 7 peripheral B-cell lymphomas, 31 peripheral blood stem cell (PBSC), 40 peripheral T-cell lymphomas (PTCL), 9, 15, 20, 61–65, 93–95, 119 phototherapy, 89 PI3K/AKT/mTOR, 87, 103 plasmapheresis, 101, 102 Plasmodium falciparum, 105 platin derivatives, 25 platinum, 35 polymerase chain reaction (PCR), 11, 16, 55, 81, 82, 83 positron emission tomography (PET), 20, 21–23, 32, 34, 35, 38, 63, 69 post-transplant lymphoproliferative disorders (PTLDs), 115 pralatrexate, 65 prednisone, 90, 95, 119 primary CNS lymphoma (PCNSL), 109, 113 primary lymphoid tissue, 1 primary mediastinal large B-cell lymphoma (PMLBCL), 27, 111 procarbazine, 25, 119 prognostic indices, 118 proliferation centers, 43 proteasome inhibitor, 53 protein kinase C (PKC) inhibitors, 87 pruritus, 19, 68 purine analog, 25, 45–47

R-ACBVD, 28 R-ACVBP, 33 radioimmunotherapy (RIT), 26, 27 CBCL, 91 CL, 89, 90 DLBCL, 33, 34 extranodal lymphomas, 59, 94, 110, 111 FL, 39–41 HL, 69–71 LPL/WM, 103 MCL, 52 Rappaport classification, 77 rasburicase, 28, 106

R-CHEOP, 28 R-CHOP, 22, 28, 33, 34, 40, 41, 52, 91, 103, 110, 114, 118 REAL classification, 79 reduced-intensity conditioning regimen (RIC), 29 Reed-Sternberg cells, 14, 67 residual mass, 22, 34, 59 Revised European-American Lymphoma classification, 79 R-FC, 45, 46, 103 ribavirine, 99 Richter’s syndrome (RS), 47 rituximab, 119–121 CLL / SLL, 45, 47 DLBCL, 32–35 extranodal lymphomas, 59, 111 FL, 38–41 HIV, 114, 115 HL, 70 LPL/WM, 102, 103 MCL, 51, 52 non-MALT marginal zone lymphomas, 101 SMZL, 99 treatment principles, 26, 28 R-MACOP-B, 28 romidepsin, 65

salvage therapy, 23, 29, 35, 39, 68, 70, 109, 110 scattergram, 9 Sezary syndrome, 90, 117 SGN-35, 26, 65, 70 sIg, 55 Sjogren’s syndrome, 56 small lymphocytic lymphoma (SLL), 14, 15, 43–47, 117 solid organ transplant (SOT), 115 somatic recombination, 2, 3 splenectomy, 47, 99 splenic infiltration, 98 splenic marginal zone lymphoma (SMZL), 97, 98, 99 splenomegaly, 44, 99, 102 St. Jude/Murphy staging system, 106 staging principles, 19–24 standardized uptake volume (SUV), 21 STAT, 67 statins, 74 subcutaneous panniculitis-like T-cell lymphoma (SPTCL), 61, 95 survivin inhibitors, 87 Syk, 87 systemic anaplastic large cell (sALCL) lymphoma, 61, 62, 63

T cells, 1, 3, 4, 14, 15, 16, 43 T-cell lymphoma (TCL), 9, 11, 14, 15, 61, 89, 90, 93–95 T-cell receptor (TCR), 4, 11, 62, 63, 81 TdT, 15, 105 temozolomide, 25 temsirolimus, 53

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testicular lymphoma, 110 thiotepa, 25 thymidine kinase, 44 thymus, 1, 4, 8 transformation, 31, 38, 41, 55, 57, 99, 102 translocation, 10, 13, 37, 49, 57, 81, 105 treatment schedules, 119–121 trisomy, 44, 57, 98 tumor lysis syndrome, 28, 106

vinblastine, 70, 119 vinca alkaloids, 25 vinorelbine, 120

Waldenström’s macroglobulinemia (WM), 101–103 Waldeyer ring, 19 WHO classification, 13–18, 61, 79, 82, 107, 117 whole brain radiotherapy (WBRT), 109 whole genome association studies (GWAS), 74

90-yttrium, 27, 41

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ESMOEssentials_LymphomasOK.indd 1

9 788890 635922

A: 4xABVD + 30 GY IF-RT B: 4xABVD + 20 Gy IF-RT C: 2xABVD + 30 GY IF-RT D: 2xABVD + 20 Gy IF-RT

ISBN 978-88-906359-2-2

ESMO Press

108

120

ESMO Press

03/09/12 15:08