Simposio Celgene: Nuevas Opciones de Tratamiento en SMD y LM - Dr Pierre Fenaux by sphperu

Nuevos tratamientos en SMD -LMA Pierre Fenaux Hôpital St Louis Université Paris 7 GFM Lima 0ctubre de 2016

Nuevos tratamientos en SMD -LMA •  Retos en el tratamiento de SMD y LMA •  Op6mizar el uso de drogas y tratamientos disponibles (o aprobados) •  Nuevas drogas

Retos en el tratamiento de SMD y LMA •  LMA de adultos jovenes –  Excepto en pacientes con inv(16), t(8;21), mutacion NPM1 aislada, la mayoria de los pacientes sin alotrasplante recaen

•  LMA del anciano, con cariotopo complejo o despues de SMD/SMP –  QT 6ene poco efecto –  Hipome6lantes 6enen un efecto transitorio, y el pronos6co es muy malo en caso de resistenca o recaida –  Alo trasplante raras veces posible, y con muchas recaidas

Mal pronostico de mutaciones de TP53/p53 con todos los tratamientos disponibles TP53 mutations and results of AZA in MDS (Bally,Leuk Res, 2013)

VOLUME 32 ! NUMBER 25 ! SEPTEMBER 1 2014

JOURNAL OF CLINICAL ONCOLOGY Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved. R E P O R T

0.75

Rafael Bejar, Kristen E. Stevenson, Bennett Caughey, R. Coleman Lindsley, Brenton G. Mar, Petar Stojanov, Gad Getz, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, Corey S. Cutler, and Benjamin L. Ebert

Published online ahead of print at www.jco.org on August 4, 2014. Processed as a Rapid Communication manuscript Supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant No. 5K08DK091360 and an American Society of Hematology scholar award (R.B.) and by National Heart, Lung, and Blood Institute Grant No. R01HL082945, a Leukemia and Lymphoma Society scholar award, and the Yellow Diamond Foundation Fund (B.L.E.). Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Benjamin L. Ebert, MD, PhD, Brigham and Women’s Hospital, 1 Blackfan Circle, Karp CHRB 5.211, Boston, MA 02115; e-mail: benjamin_ebert@dfci.harvard.edu. © 2014 by American Society of Clinical Oncology 0732-183X/14/3225w-2691w/$20.00 DOI: 10.1200/JCO.2013.52.3381

Somatic Mutations Predict Survival After Transplantation for MDS

Patients and Methods We used massively parallel sequencing to examine tumor samples collected from 87 patients with MDS before HSCT for coding mutations in 40 recurrently mutated MDS genes. Results Mutations were identified in 92% of patients, most frequently in the ASXL1 (29%), TP53 (21%), DNMT3A (18%), and RUNX1 (16%) genes. In univariable analyses, only TP53 mutations were associated with shorter overall (OS; hazard ratio [HR], 3.74; P ! .001) and progression-free survival (HR, 3.97; P ! .001). After adjustment for clinical variables associated with these end points, mutations in TP53 (HR, 2.30; P " .027), TET2 (HR, 2.40; P " .033), and DNMT3A (HR, 2.08; P " .049) were associated with decreased OS. In multivariable analysis including clinical variables, complex karyotype status, and candidate genes, mutations in TP53 (HR, 4.22; P ! .001) and TET2 (HR, 1.68; P " .037) were each independently associated with shorter OS. Nearly one half of patients (46%) carried a mutation in TP53, DNMT3A, or TET2 and accounted for 64% of deaths. Three-year OS in patients without these mutations was 59% (95% CI, 43% to 72%), versus 19% (95% CI, 9% to 33%) in patients with these mutations. Conclusion Mutations in TP53, TET2, or DNMT3A identify patients with MDS with shorter OS after HSCT. J Clin Oncol 32:2691-2698. © 2014 by American Society of Clinical Oncology INTRODUCTION

Diagnosis and predicted prognosis of patients with myelodysplastic syndrome (MDS) are largely determined by morphologic and clinical measures.1,2 Recurrent somatic mutations, which are drivers of MDS pathogenesis and can be powerfully associated with clinical phenotype, are not currently incorporated into the routine clinical care of patients with this disorder.3,4 Somatic mutations are common in MDS, with # 75% of patients carrying " one abnormality in the 30 most frequently mutated genes.5-7 Abnormalities in specific genes, such as NRAS, RUNX1, and TP53, have been associated with prognostically important variables, including elevated bone marrow blast proportion and severe thrombo-

cytopenia.3 Therefore, it is likely that acquired mutations could also predict response to specific interventions, such as treatment with hypomethylating agents or survival after hematopoietic stemcell transplantation (HSCT).8 Calculation of risks, benefits, and timing of HSCT is often difficult in MDS.9-11 Older age and comorbidities typical of patients with MDS are frequently associated with unacceptable risk of early death after transplantation. Even in younger and generally healthier patients, deciding when HSCT is appropriate can be challenging. In particular, patients with poor prognostic features may be directed to transplantation because they have few treatment options available or because standard therapeutics are not expected to provide durable responses.

A Not complex (n = 59) Complex karyotype (n = 28)

Variable

Entire cohort (N ! 87) Genetic mutation (present v absent) TP53 TET2 Day-100 landmark analysis (n ! 72) 0 Karyotype (complex v other) Genetic mutation (present v absent) TP53 DNMT3A

P = .005

0.8 0.6 0.4 0.2

95% CI

" .001 .037

4.22 2.29

2.30 to 7.76 1.05 to 5.00

2.85

1.35 to 6.47

.013

3.78 2.62

1.81 to 7.89 1.15 to 5.96

" .001 .022

Abbreviations: HR, hazard ratio; OS, overall survival. ! Final model obtained from backward-elimination selection algorithm candidates included variables with univariable P " .20.

Time (months)

B 1.0

Not complex (n = 59) Complex and TP53 unmutated (n = 12) Complex and TP53 mutated (n = 16)

0.8 0.6 0.4 0.2

Time (months)

C 1.0

TP53 mutated (n = 18) TET2 mutated, no TP53 (n = 10) DNMT3A mutated, no TP53 or TET2 (n = 12) No TP53, TET2, or DNMT3A mutations (n = 47)

0.8 0.6 0.4 0.2

Table 3. Multivariable! Models Identifying Independent Significant Risk Factors for OS

1.0

0.00

Overall Survival (probability)

Benjamin L. Ebert, Brigham and Women’s Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.

Overall Survival (probability)

Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and

Purpose Recurrently mutated genes in myelodysplastic syndrome (MDS) are pathogenic drivers and powerfully associated with clinical phenotype and prognosis. Whether these types of mutations predict outcome after allogeneic hematopoietic stem-cell transplantation (HSCT) in patients with MDS is not known.

Overall Survival (probability)

University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin

0.50

Listen to the podcast by Dr Estey at www.jco.org/podcasts Rafael Bejar and Bennett Caughey,

OS selon les mutations de p53 (p =0.0054)

1.00

Somatic Mutations Predict Poor Outcome in Patients With Myelodysplastic Syndrome After Hematopoietic Stem-Cell Transplantation

0.25

O R I G I N A L

2691

Time (months)

TP53

TET2

DNMT3A

Fig 2. Overall survival (OS) by TP53 and DNMT3A mutation status. OS of patients (A) with and without complex karyotype and (B) with complex karyotype stratified by TP53 mutation status and compared with survival of patients with noncomplex karyotype; (C) OS and mutation distribution showing overlap between patients with TP53, TET2, and DNMT3A mutations. Each column indicates individual patient; colored bars represent mutations of genes in that row.

www.jco.org

these genes were found in nearly one half of patients in this cohort. Mutations of other genes associated with poor prognosis in prior studies, such as RUNX1, ASXL1, SRSF2, and U2AF1, were not associated with differences in OS in our cohort of patients who underwent HSCT (Data Supplement).3,22-24 This may have been the result of disease-modifying effects of conditioning and transplantation or because of the fact that the prognostic significance of these gene mutations is more pronounced in lower-risk patients, of whom there were few in this study. In contrast, TP53 mutations have independent prognostic value, even in higher-risk patients with MDS, in whom they are most commonly found.3,21 The DNMT3A and TET2 genes encode epigenetic modifiers that regulate DNA methylation, and both are recurrently mutated in MDS, acute myeloid leukemia, and other hematologic malignancies. In acute myeloid leukemia, mutations of both genes are enriched in patients with intermediate-risk karyotypes and are associated with poor prognosis.25,26 In MDS, the clinical significance of DNMT3A mutations is less clear but also seems to be unfavorable, whereas TET2 mutations are not associated with survival.5,7,18,19,27,28 Both TET2 and DNMT3A mutations are relatively promiscuous and often co-occur with other mutated genes that can predict outcomes. For example, in a study of lower-risk patients with MDS, DNMT3A mutations were not associated with OS in univariable analysis. However, the DNMT3A-mutant/SF3B1-wild-type subgroup did have shorter OS.19 In our transplantation cohort of largely higher-risk patients, SF3B1 mutations were rare, and most DNMT3A-mutant samples were SF3B1 wild type (88%). DNMT3A and TET2 mutations identified in pretransplantation samples were largely from patients without adverse clinical features known to predict poor outcome. Most of these patients did not have a complex karyotype and were not more likely to have an elevated bone marrow blast percentage before transplantation. Nevertheless, we found that patients with a TET2 or DNMT3A mutation were at increased risk of relapse and death after transplantation, particularly when other predictive variables were considered. We conclude that consideration of TET2 and DNMT3A mutation status can help predict the risk of mortality in patients with MDS. In MDS, TP53 mutations have long been known to be associated with karyotype, elevated bone marrow blast percentage, and severe thrombocytopenia.3,29-31 Despite these links with prognostically adverse clinical features, TP53 mutations have strong and independent © 2014 by American Society of Clinical Oncology

2695

500

1000 analysis time MUT

1500

Retos en el tratamiento de SMD y LMA •  SMD de bajo riesgo –  Pacientes con del 5q: el pronos6co no es tan bueno –  Pacientes sin del 5q •  los ASE 6enen un efecto transitorio •  La mayoria de los pacientes 6enen anemia cronica y trasfusiones repe6das •  Tratamiento de la trombopenia es diﬁcil

Trasfusiones de GR o tratamiento de anemia con drogas ?

Hb (g/dL)

Transfusion given

10 Blood transfusion 8

Tratamiento activo

6 4 0

120

Days of treatment

150

180

210

Calidad de vida y tasa de Hb Quality of Life (LASA, mm)

10 11 Hb level (g/dl)

LASA: Linear Analog Scale Assessment

14 Crawford et al. Cancer 2002; 95: 888â&#x20AC;&#x201C;95

3–7 Prognostic p9 factors of erythroid 23 response to ESA have been well identified, rates in 49 with better response 28 patients with no or limited red blood cell (RBC) ANC (G/l) p1.8 16 transfusion 3,4 requirement, low baseline serum 41.8EPO level and IPSS 27 low or int-1. Response to ESA treatment may also be associated with a survival Platelets (G/l) p260 46 benefit compared with transfusional treatment alone, as 4260 20 suggested by two retrospective and one prospective study.4–6

darbepoetin (DAR). Hemoglobin (g/dl)

Patients and outcome definitions

1.00

±granulocyte(g/dl) We recently reported results of ESA (r-Hu-EPO or DAR Hemoglobin 37.8 2 in 403 MDS 0.89–4.52 0.095 colony-stimulating factor (G-CSF)) patients with anemia 28.3 1.00 (treated in centers of the Groupe Francophone des Mye´lodysplasies ANC (G/l)(GFM), 62.3 in GFM trials or according 0.74 to GFM recommendations, 0.31–1.76 either that 0.50 is, hemoglobin o10 g/dl, with or 1.00 without RBC transfusion requirement; Park 31.94 Platelets (G/l) 1). Of those patients, 142 were excluded et NA al. and Supplementary Figure 0.5 0.23–1.11 0.089 from the present analysis because IPSS was int-2/high or could not be

Serum EPO level p100 39 30.7 1.00 Serum EPO level (IU/l) 4100 20 NA 0.38 0.15–0.94 0.036 Groupe Francophone des Mye´lodysplasies (GFM), Service d’He´matologie Clinique, Hoˆpital Avicenne, Assistance Publique des Hoˆpitaux de Paris, Universite´ Paris 13, Bobigny, RBC transfusionFrance. requirement No 37 47.3 1.00 ˆ Correspondence: Dr P Fenaux, Groupe Francophone des Mye´lodysplasies (GFM), Service d’He´matogie Clinique, Hoˆpital Avicenne, Assistance Publique des Ho pitaux de RBC transfusion requirement 29France. 44.9 1.06 0.53–2.10 0.86 Paris, Universite´ Paris 13, 125 rue deYes Stalingrad, Bobigny 93009, Response duration 58 37.8 1.00 E-mail: (months) Pierre.fenaux@avc.aphp.fr. p6 Response duration Results partly presented at the 52nd46 American Society of Hematology Annual Meeting, December 8 62.3 2010. 0.62 0.19–2.04 0.43 Received 3 June 2012; revised 6 January Trisomy 8 No 2013; accepted 9 January 60 2013; accepted article preview 47.3 online 16 January 2013 1.00 Trisomy 8 Yes 2 7.5 10.46 1.15–95.2 0.037

Yes p9 49 p1.8 41.8 p260 4260 p100 4100 No Yes p6 46 No Yes

70 88 61 61 71 69 64 90 70 79 107 104 82 102 7

38.6 44.9 42.2 31.4 53.6 30.0 62.9 38.6 50.8 42.2 40.1 36.7 56.3 42.2 18.0

Abbreviations: ANC, absolute neutrophil count; CI, confidence interval; EPO, erythropoietin; ESA, erythropoiesis-stimulating agents; FAB, French–American– Abbreviations: ANC, absolute neutrophil count; CI, confidence interval; EPO, erythropoietin British; HR, hazard ratio; Int, intermediate; IPSS, International Prognostic Scoring System; NA, not applicable; OS, overall survival; RA, refractory anemia; RAEB, British; HR, hazard ratio; Int, intermediate; IPSS, International Prognostic Scoring System; O refractory anemia with excess blasts; RARS, refractory anemia with ringed sideroblasts; RBC, red blood cell; RCMD, refractory cytopenia with multilineage with excess blasts; RARS, refractory anemia with ringed sideroblasts; RBC, red blood cell; RC dysplasia; WHO, World Health Organization. Health Organization.

Predominant causes of death in patients without ESA failure were heart disease (17%), infections (14%), solid tumors (14%) and miscellaneous (stroke, fall, iatrogenic) (11%). Results based on the ESA or ESA combination received In total, 21%, 43%, 28% and 8% of patients had received EPO (a or b) alone, EPO þ G-CSF, DAR alone and DAR þ G-CSF, respectively. None of the four treatment options affected OS after failure (HR ¼ 1.00; HR ¼ 0.87, 95% CI: 0.53–1.43, P ¼ 0.60; HR ¼ 0.99, 95% CI: 0.63–1.55, P ¼ 0.96; HR ¼ 1.56, 95% CI: 0.83–2.95, P ¼ 0.16, for EPO, EPO þ G-CSF, DAR, DAR þ G-CSF, respectively), but there was an effect, as a trend, on cumulative incidence of AML (at 5 years: 14.7%, 10.5%, 16.9%, 42.6%, respectively, P ¼ 0.058). However, only 15 patients had been treated by the combination of DAR and G-CSF and the trend towards a higher cumulative incidence of AML in that group may have been biased by the small number of patients. In addition, when other prognostic factors for AML (time to failure, RAEB-1) were taken into account, the type of ESA combination lost its prognostic value. Figure 2. OS after failure in patients with early and later failure.

Figure 1. Cumulative incidence of AML after failure in patients with early and later failure.

& 2013 Macmillan Publishers Limited

DISCUSSION To our knowledge, this is the first report analyzing in detail the outcome of lower-risk MDS with primary or secondary failure to ESA. Our main finding in this cohort was that, in the absence of

Leukemia (2013) 1 – 8 Leukemia (2013) 1 – 8

Figure 3. failure.

Nuevos tratamientos en SMD -LMA •  Retos en el tratamiento de SMD y LMA •  Op6mizar el uso de drogas y tratamientos disponibles (o aprobados) •  Nuevas drogas

Op6mizar el uso de drogas y tratamientos disponibles (o aprobados)

•  Quimoterapia •  ASE •  Hipome6lantes •  Lenalidomida •  Alotrasplante

Op6mizar el uso de drogas y tratamientos disponibles (o aprobados)

•  Quimoterapia •  ASE •  Hipome6lantes •  Lenalidomida •  Alotrasplante

•  •  •  •  •

707 pa6ents aged 50y or more (median, 67y) ALFA-9801/9803 trials (DNR/IDA randomiza6on) All pa6ents aged <65y received HD-DNR (240 mg/sqm) Standard Cox models + Cure frac6on model Median follow-up, 7.5y

ALFA!

Op6mizar el uso de drogas y tratamientos disponibles (o aprobados)

•  Quimoterapia •  ASE •  Hipome6lantes •  Lenalidomida •  Alotrasplante

High response rate with darbepoetin alfa with or without filgrastim in lower-risk MDS Kelaidi C Ann Hematol. 2013] •  lower-risk MDS patients with anemia and endogenous EPO <500 IU/L •  DAR 500 µg / 2 weeks for 12 weeks, G-CSF added at week 12 in non-responders •  In 99 patients, erythroid response 48 and 56 % at 12 and 24 weeks. Addition of G-CSF rescued 22 % of nonresponders

EPO treated versus IMRAW cohort (transfusions only):Time to AML progression (Park ,Blood 2008) Comparison between IMRAW and French-EPO cohort restricted to IPSS LOW INT1 patients without unfavorable karyotype (IMRAW n=447 patients, French-EPO= 284)

a) progression to AMLÂ , p= NS

EPO treated versus IMRAW cohort (transfusions only):

Overall survival (Park, Blood 2008)

Early introduction of ESA in low risk MDS patients may delay the need for RBC transfusion: a retrospective analysis on 112 patients ( Park,Leuk Res 2010)

CLINICAL AND MOLECULAR PREDICTORS OF RESPONSE TO ERYTHROPOIESIS STIMULATING AGENTS (ESA) IN LOWER RISK

MDS O KOSMIDER (Haematologica, 2016)

•  N=79 •  Muta6ons : SF3B1 (40.5% pa6ents), TET 2 (35.4%), ASXL1 (31.4%), DNMT3A (20.2%), U2AF1 (10.1%), SRSF2 (8.8%), IDH1/IDH2 (7.4%)

•  none of the most frequent muta6ons had any impact on erythroid response •  Pa6ents with ≤ 2 muta6ons had beker erythroid response (p=0.02)

Early introduction of ESA in low risk MDS patients may delay the need for RBC transfusion: a retrospective analysis on 112 patients ( Park,Leuk Res 2010)

GFM trial submiked:

randomized trial comparing early versus late onset of ESA in lower risk MDS

Op6mizar el uso de drogas y tratamientos disponibles (o aprobados)

•  Quimoterapia •  ASE •  Hipome6lantes •  Lenalidomida •  Alotrasplante

Perspec6vas con hipome6lantes en SMD-LMA •  •  •  •  •  •

En SMD de riesgo alto EN LMA Antes o despues de un alotrasplante Como tratamiento de mantenimiento En SMD de riesgo bajo AZA oral

Perspec6vas con hipome6lantes en SMD-LMA •  •  •  •  •  •

En SMD de riesgo alto EN LMA Antes o despues de un alotrasplante Como tratamiento de mantenimiento En SMD de riesgo bajo AZA oral

Combinations of hypomethylating agents and other drugs

â&#x20AC;˘â&#x20AC;Ż AZA+ Lenalidomide (Sekeres, Blood, 2012): 71% responses, 41% CR

Findings Between Dec 30, 2009, and June, 17, 2013, we enrolled 88 patients (28 in phase 1 and 60 in phase 2). One patient unexpectedly died in the phase 1 study at the highest dose level, six more patients were recruited with no further serious adverse events. We recorded no dose-limiting toxic eﬀects, and the maximum tolerated dose of lenalidomide in combination with azacitidine in patients with acute myeloid leukaemia and myelodysplastic syndrome was initially established at 50 mg per day for 10 days. In the first 20 patients in phase 2, we noted a high rate of myelosuppression and myelosuppression-related toxic eﬀects; therefore, we amended the lenalidomide dose to 25 mg per day for 5 days. We also adjusted the inclusion criteria to include patients with less than 30% blasts to focus mainly on patients with myelodysplastic syndromes. Median overall survival was 75 weeks (IQR 25–not reached) for the 40 patients in phase 2b. The most common grade 3–4 adverse events overall were neutropenic fever (n=27) and pneumonia (n=18).

Prof G Garcia-Manero) and Department of Pathology (Prof C Bueso-Ramos MD, K P Patel MD), The University of Texas MD Anderson Cancer Center, Houston, TX, USA

AZA+ Lenalidomida

Correspondence to: Dr Guillermo Garcia-Manero, Department of Leukaemia, UT MD Anderson Cancer Centre, Houston, TX 77030, USA ggarciam@mdanderson.org

AZA+ Lenalidomide (Sekeres, Blood, 2012): 71% responses, 41% CR

Interpretation We have identified a safe and active sequential treatment combination of azacitidine and lenalidomide for patient with myelodysplastic syndrome and have preliminary evidence that this dose is also safe for patients with acute myeloid leukaemia. Funding MD Anderson Cancer Center and Celgene.

Introduction Myelodysplastic syndromes are malignant clonal disorders characterised by aberrant and ineﬀective haemopoiesis, bone marrow dysplasia, peripheral cytopenias including thrombocytopenia, and a propensity to transform into acute myeloid leukaemia.1,2 Myelodysplastic syndrome is generally stratified according to prognosis by use of various classification schemes based on the number and type of cytopenias, cytogenetic and molecular aberrations, and the percentage of blast cells within the bone marrow.3,4 Irrespective of the classification, overall survival is poor in patients with myelodysplastic syndromes and new agents and eﬀective treatment regimens are urgently needed. www.thelancet.com/haematology Vol 2 January 2015

Azacitidine, a hypomethylating agent, is recommended as first-line treatment for patients with high-risk myelodysplastic syndromes including up to 30% bone marrow blasts, showing improved overall survival compared with acute myeloid leukaemia-type treatment or supportive care options.5 However, true remission is rare in these patients and durable cures with hypomethylating agent monotherapy are unlikely. Although the duration of response to hypomethylating agents is variable, the median eﬀective duration for responding patients is 12–17 months, and patients have universally poor survival after hypomethylating agent failure.6,7 Several combination strategies are under development to improve the results of hypomethylating agent e12

Lancet Hematol, 2015 MTD: :lenalidomide dose to 25 mg per day for 5 days

Combinations of hypomethylating agents and other drugs

•  AZA+ Idarubicin (M Sébert ,ASH 2105) 50% responses (41% CR+PR+ marrow CR)

•  Intensive AZA (5 d /2 weeks) (L Adès, ASH 2015) •  AZA+ deferasirox (O Hermine) •  AZA+ Volasertib

Intensive AZA trial: Response Rate (n=27)

ORR 70%

« escoger el ganador » con AZA (n=320) 5 AZACYTIDINE 75 mg/m2 x 7 jours VALPROIC ACID

5 AZACYTIDINE 75 mg/m2 x 7 jours

IDARUBICIN 5 AZACYTIDINE 75 mg/m2 x 7 jours REVLIMID 5 AZACYTIDINE 75 mg/m2 x 7 jours

6 cycles

« escoger el ganador » con AZA estrategia futura. Cooperacion internacional 5 AZACYTIDINE 75 mg/m2 x 7 jours X

5 AZACYTIDINE 75 mg/m2 x 7 jours

Y 5 AZACYTIDINE 75 mg/m2 x 7 jours Z 5 AZACYTIDINE 75 mg/m2 x 7 jours

6 cycles

estrategia futura : pais A 5 AZACYTIDINE 75 mg/m2 x 7 jours X

5 AZACYTIDINE 75 mg/m2 x 7 jours

Y 5 AZACYTIDINE 75 mg/m2 x 7 jours

6 cycles

estrategia futura : pais B 5 AZACYTIDINE 75 mg/m2 x 7 jours X

5 AZACYTIDINE 75 mg/m2 x 7 jours

Z 5 AZACYTIDINE 75 mg/m2 x 7 jours

6 cycles

estrategia futura : pais C

5 AZACYTIDINE 75 mg/m2 x 7 jours

A 5 AZACYTIDINE 75 mg/m2 x 7 jours

6 cycles

estrategia futura : pais D 5 AZACYTIDINE 75 mg/m2 x 7 jours Y

5 AZACYTIDINE 75 mg/m2 x 7 jours

A 5 AZACYTIDINE 75 mg/m2 x 7 jours

6 cycles

Perspec6vas con hipome6lantes en SMD-LMA •  •  •  •  •  •

En SMD de riesgo alto En LMA Antes o despues de un alotrasplante Como tratamiento de mantenimiento En SMD de riesgo bajo AZA oral

AZA-001: OS with azacitidine in patients with 20â&#x20AC;&#x201C;30% blasts JCO , 2010 1.0

Log-rank p=0.005 HR= 0.47 (95% CI: 0.28â&#x20AC;&#x201C;0.79) Deaths: azacitidine = 24, CCR = 41

0.9

Proportion surviving

0.8

0.7

50.2%

0.6

24.46 months Azacitidine

0.5

0.4

15.9 months

0.3

0.2

0.1

15.9%

CCR

0 0

Number at risk AZA 55 0 CCR 58 0

Time (months) from randomisation 43

Decitabine in AML patients – DACO16 trial •  N= 485 pa6ents aged 65y+

–  Post-MDS or de novo AML –  Intermediate or poor cytogene6cs –  Uneligible for intensive chemotherapy

•  Randomiza6on between

–  BSC or LDAC 20mg/m 2 daily for 10 days –  Decitabine 20mg/m 2 daily for 5 days, every 4 weeks

•  Updated unplanned OS analysis with 446 (92%) deaths –  Median OS, 7.7 versus 5 months. –  HR 0.82 (0.68, 0.99), P=0.037

•  CR + CRp rate

–  18% versus 8% –  OR=2.5 (1.4-4.8), P=0.001 H. Kantarjian et al. J Clin Oncol. 2012 Jun 11. [Epub ahead of print]

RESULTS

Patient Disposition and Treatments Between January 2006 and April 2009, 485 patients were randomized at 65 sites. The primary OS analysis was based on a clinical cutoff date of October 28, 2009, by which time 385 deaths were projected, and 396 deaths occurred. To provide additional clinical data, mature survival and updated safety data (clinical cutoff date, October 29, 2010) were used for an ad hoc mature survival analysis (446 deaths). The efficacy populations comprised 242 patients randomly assigned to the decitabine group and 243 patients randomly assigned to the TC group (cytarabine, n ! 215; SC, n ! 28). The safety population comprised 475 patients (decitabine, n ! 238; cytarabine, n ! 209; SC, n ! 28). At the 2009 cutoff, 211 patients (87.2%) who received decitabine and 228 patients (93.8%) who received TC had discontinued, primarily because of PD (96 and 116 patients, respectively; Fig 1). www.jco.org

Overall Surviv

Log-

60 40 20

Time

No. at risk Decitabine 242 Total TC 243

Overall Survival (%)

log-rank test and HR for OS; and an analysis of OS in which patients who received subsequent disease-modifying therapy were censored on the first day of the first subsequent therapy. Exploratory subgroup analyses assessed primary and secondary end points, including age, baseline bone marrow blasts, type of AML, cytogenetics, and ECOG PS. Effects of these characteristics on OS and PFS were investigated by using a multivariate Cox proportional hazards model; effects on the probability of achieving CR or CRp were investigated by using a logistic regression model. The incidence of CR plus CRp and corresponding CIs were compared between decitabine and TC arms by using Fisher’s exact test. Significance was set at P ! .05.

137 107

65 55

100

Decita TC

Ha Lo

60 40 20

0 No. at risk Decitabine 242 Total TC 243

Time 137 107

78 68

50 35

France; 18Service d’H!ematologie Clinique, Hôpital Henri Mondor, AP-HP and Universit!e Paris 6, Paris, France; 19Service d’H!ematologie, Hôpital Universitaire Lyon Sud, Lyon, France; 20Service d’H!ematologie Clinique, Hôpital Saint-Antoine, AP-HP and Universit!e Paris 6, Paris, France; 21Service d’H!ematologie, Centre Hospitalier Le Raincy-Montfermeil, Montfermeil, France; 22Service d’H!ematologie Clinique, Centre Hospitalier Universitaire, Nancy, France; 23D!epartement d’H!ematologie, Institut Paoli-Calmettes, Marseille, France; 24Service d’H!ematologie Clinique, Hôpital Cochin, AP-HP and Universit!e Paris 5, Paris, France; 25Service d’H!ematologie Clinique, Centre Hospitalier Universitaire, Angers, France

Conflict of interest: Authors declare no competing financial interests. Results presented in part, at the 51st American Society of Hematology meeting † R.I. and S.T. contributed equally to this work. *Correspondence to: Claude Gardin; Department of Hematology, H^opital Avicenne, AP-HP, Paris 13 University 125 Route de Stalingrad, 93000 Bobigny, France. E-mail: claude.gardin@avc.aphp.fr Contract grant sponsor: Celgene. Received for publication: 14 July 2013; Revised: 30 October 2013; Accepted: 19 December 2013 Am. J. Hematol. 89:410–416, 2014. Published online: 21 December 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.23654 C 2013 Wiley Periodicals, Inc. V

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American Journal of Hematology, Vol. 89, No. 4, April 2014

doi:10.1002/ajh.23654

•  From December 2004 to December 2008 , ATU program •  137 patients treated for AML in front line •  Considered unfit for intensive chemotherapy (age, comorbidities, karyotype) •  50 de novo AML, 50 post MDS AML, 37 t-AML •  55% unfavorable karyotype

ALFA!

French ATU: Response • 104 patients received ≥ 3 cycles (78%)

–  Overall response rate: 43% •  19 CR (14%) •  3 CRi (2%) 23% CR/CRi/PR •  10 PR (7%) •  28 HI (20%) •  16 stable disease w/o HI •  28 progression

• Median duration of response, 6.9 months

non-responders, respectively. Median number of AZA courses delivered was 11 (4–31) in CR/CRi/PR patients and 4 (3–26) in non-responders. In Fig. 3B, is depicted the OS of three subsets of patients, i.e., patients who achieved CR/CRi/PR as best response, patients who achieved stable disease with any HI, and patients who only achieved stable disease without HI according to IWG MDS criteria. Achievement of HI in this cohort, if not followed by subsequent achievement of marrow response (i.e., CR, CRi, or PR), was not significantly associated to any survival benefit among stable patients (P 5 0.38, by the log-rank test). RFS of responders is depicted in Supporting Information Fig. S1, showing 33% persisting responses at 1 year (95% CI, 20–47) and a median RFS of 7.7 months (95% CI, 5.5–11). doi:10.1002/ajh.23654

! Discussion

This study of 149 previously untreated high-risk AML received AZA is the largest to our knowledge. A 33% response ra AZA (including CR/CRi/PR) was observed in this patient co despite a median age of 74 years, a high proportion of the related AML, of AML post-MDS, of post-MPN AML and o adverse karyotype. In studies published to date, using AZA, alone [12,18,20,21,3 or in combination [29,32,33] relapsed AML patients after inte

American Journal of Hematology, Vol. 89, No. 4, April 2014 Figure 2. Overall survival. (A) All patients: Median OS was 9.4 months (6.5–10.9) and OS at 1 year was 38% (30–46); (B) Intermediate versus adverse cytogenetics: median OS was 10.8 (7.9–16.8) versus 6.1 months (4.1–9.9) and OS at 1 year was 47% (36–58) versus 25% months (15–36) (P 5 0.0002, by the log-rank test); (C) WBC lower versus higher than 15.109/L: median OS was 10.4 (7.9–12.8) versus 5.3 months (3.4–8.2) and OS at 1 year was 44% (35–53) versus 15% months (5–30) (P 5 0.0008, by the log-rank test); (D) ECOG 21 versus 0–1: median OS was 10.9 (7.9–12.7) versus 6.1 months (3.0–10.1) and OS at 1 year was 44% (34–53) versus 25% months (12–40) (P 5 0.0083, by the log-rank test). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 3. Overall survival by best response. (A) CR/CRi/PR patients versus non-responders, with a 7-month landmark (85% of CR/CRi/PR were reached at 7 months); (B) Patients with stable disease with or without HI versus CR/CRi/PR patients. Achievement of HI, as best response, was not significantly associated to any benefit in survival among stable patients (P 5 0.38, by the log-rank test). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

chemotherapy and/or allogeneic stem cell transplantation predominated, with limited numbers of untreated AML patients being reported [18,20,29–33]. In the present study, the response rate appeared similar to that reported for previously untreated patients in these AML cohorts treated with AZA. 414

American Journal of Hematology, Vol. 89, No. 4, April 2014

Forty percent of responding patients did reach their best response after three courses, and 85% of them did so by 7 months and after a median six courses. The kinetics of response to AZA observed in this AML patient population therefore appears similar to the slow response kinetics described in higher risk MDS [9,12,34,35]. doi:10.1002/ajh.23654

In univariate analysis using the 11 covariates listed in the Met section (Table III), only cytogenetics and an ECOG PS score associated with a worse response to AZA. Results of the multiv analysis, using these 11 covariates listed in the Methods section shown in Table IV. Only adverse cytogenetics was significantly as ated with the achievement of response at any time (40.5% in inte diate and 22% in adverse cytogenetic risk subgroups; P 5 0 while ECOG-PS score !2, WBC count, and marrow blast c above 30% had no significant impact on the response rate (31 patients with marrow blasts <30% versus 35% in those with ma blasts >30%, P 5 0.60).

after receiving other therapies than AZA or having failed AZA.

Response to azacitidine Thirty-five patients received less than three cycles of AZA due to early death (N 5 19), disease progression (N 5 9), or non-fatal severe adverse events (N 5 7) mostly associated to sepsis (N 5 5), and 114 received at least three cycles. Initial response (including CR/CRi/PR according to IWG) was evaluated after a median of three cycles (i.e., around D110), as shown in Table II and Fig. 1. Forty-one of the 149 patients (27.5%) reached an initial response (including 15.5% CR, 7% CRi, 5% PR). Among the 114 patients who received at least three cycles, initial response was 36%, including 20% CR, 6% CRi, and 10% PR. As some patients achieved a response, or improved their response, only after this initial response assessment, we also analyzed responses achieved at any time (best response) as shown in Table II. The best response rate was 33% (49/149 patients, including 19% CR, 412

American Journal of Hematology, Vol. 89, No. 4, April 2014

Overall survival

Median follow-up was 31.5 (28–33.5) months. Median OS o 149 patients was 9.4 months (95% CI, 6.5–10.9) and OS at 1 a years was 38% (95% CI, 30–46) and 17% (95% CI, 11

Figure 3.

doi:10.1002/ajh Overall survival by best response. (A) CR/CRi/PR pa 7 months); (B) Patients with stable disease with or without HI ve ated to any benefit in survival among stable patients (P 5 0.38, wileyonlinelibrary.com.]

chemotherapy and/or allogeneic stem cell transplantation nated, with limited numbers of untreated AML patien reported [18,20,29–33]. In the present study, the resp appeared similar to that reported for previously untreated p these AML cohorts treated with AZA. 414

American Journal of Hematology, Vol. 89, No. 4, April 2014

OS in the matched paired AZA/IC popula6on N= 81 pairs

AZA patients

ICTx patients

HR 1.22 (.86-1.72), P= .26

AML-001: Phase III Study Design (Dombret et al, Blood 2015)

Randomization

AZA (n=240) Older (≥65 years) pts with newly diagnosed AML (>30% BM blasts) (N=480)

•

75 mg/m2/day SC x 7 days every 28 days + BSC, ideally for at least 6 cycles

Investigator preselection of CCR

CCR (n=240) Patients in each arm followed for survival

•  IC (cytarabine 100-200 mg/m2 IV x 7 days + anthracycline IV x 3 days) induction + BSC, with up to 2 subsequent cycles (re-induction or consolidation) •  LDAC (20 mg SC BID x 10 days q 28 days) + BSC •  BSC only

Overall Survival (ITT)

Median [95% CI] OS: AZA = 10.4 mos [8.0, 12.7] vs. CCR = 6.5 mos [5.0, 8.6] Unstra6ﬁed analysis: HR=0.84 ; log-rank p=0.0829 Stra6ﬁed* analysis: HR=0.85 log-rank p=0.1009 10.4 mos

46.5%

1-Year Survival: 46.5% vs 34.2% (Δ 12.3%; 95%CI: 3.5%, 21.0%)

6.5 mos 34.2%

○ = Censored

*Stratified by ECOG PS and cytogenetic risk Median follow-up for OS was 24.4 months. 193 deaths in the AZA arm (80.1%) and 201 deaths in the CCR arm

Pre-planned OS Sensi6vity Analysis Censored for Subsequent AML Tx*

Median [95% CI] OS: AZA = 12.1 mos [9.2, 14.2] vs. CCR = 6.9 mos [5.1, 9.6] Unstra6ﬁed HR=0.75 [95%CI 0.59, 0.95]; log-rank p=0.0147 Stra6ﬁed† HR=0.76 [95%CI: 0.60, 0.96]; log-rank p=0.0190 12.1 mos 6.9 mos

○ = Censored

*67 AZA pts and 75 CCR pts in this sensitivity analysis were censored at the time they received subsequent AML Tx

Induction failure Azacitidine

(P = 0.022) and peripheral blasts >10% (P < 0.0001) at onset of azacitidine were independently predictive of poor prognosis. Combining these two factors, we identified a subgroup of 48% of patients with intermediate risk cytogenetics and peripheral blasts ≤10% and a median OS of 11.3 months. These results warrant further investigation of azacitidine-based regimens in this subgroup of patients. © 2014 Elsevier Ltd. All rights reserved.

1. Introduction ! On behalf of the Groupe Francophone des Myelodysplasies (GFM), the Acute Leukemia French Association (ALFA), and the Groupe Ouest-Est des Leucemies Aigues et Maladies du Sang (GOELAMS). ∗ Corresponding author. Tel.: +33 1 48957051; fax: +33 1 48957058. E-mail address: claude.gardin@avc.aphp.fr (C. Gardin). 1 Equal contribution as first authors.

The majority of acute myeloid leukemia (AML) patients are older than 50 years at diagnosis. In patients older than 50, intensive chemotherapy (IC) remains the standard of care, resulting in complete remission (CR) rates of 50–75%, with limited duration

•  •  •  •

N=130 ORR: 17% (CR: 10%, CRi: 7%) Median OS 8.4 months. Achievement of CR/Cri associated with more prolonged survival (P = 0.0001), whereas HI (36% of pa6ents), did not improve survival.

Induction failure Azacitidine

•  In mul6variate analysis, high risk cytogene6cs (P = 0.022) and peripheral blasts >10% (P < 0.0001) independently predic6ve of poor prognosis •  50% of the pa6ents had intermediate risk cytogene6cs and peripheral blasts ≤10% and a median OS of 11.3 months

Perspec6vas con hipome6lantes en SMD-LMA •  •  •  •  •  •

En SMD de riesgo alto EN LMA Antes o despues de un alotrasplante Como tratamiento de mantenimiento En SMD de riesgo bajo AZA oral

Information aboutwithin ordering may be transplantation. found online at:1 recurrences occurring thereprints first year after a selection bias, as we included only patients in this immune Donorhttp://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#reprints lymphocyte infusions (DLI) are a well-established salvage monitoring study who had received at least four cycles of Aza in therapy in this situation. In contrast to the success seen in chronic order to assure a serial measurement in individual patients. myeloid leukemia,about theirsubscriptions efficacy in AML MDS is restrictedmay to be found During theat:course of treatment, Tregs (CD3 þ CD4 þ CD25 þ Information andor ASH membership online þ somehttp://bloodjournal.hematologylibrary.org/site/subscriptions/index.xhtml patients. In addition, this benefit is also hampered by the FoxP3 ) and lymphocyte subpopulations including T cells substantial risk to induce severe graft-versus-host disease (GVHD), (CD3 þ ), T helper cells (CD3 þ /CD4 þ ), cytotoxic T cells (CD3 þ / 2 especially when DLI are administered early after transplantation. CD8 þ ), NK cells (CD3-/CD56 þ ) and B cells (CD20 þ ) were Recently, the combination of azacitidine (Aza) and DLI has proven measured by flow cytometry using a FACSCalibur (BD Biosciences, to induce sustained remissions in about one-third of the patients Heidelberg, Germany). Data were analyzed with FCS Express V3 with AML or MDS relapsing after allo-SCT.3–5 The incidence and software (De Novo Software, LA, CA, USA). Peripheral blood severity of GVHD following this combined approach has been samples were routinely obtained prior to treatment, after the first reported to be lower in comparison with historical data using DLI (day 6), second (day 34), fourth (day 90) and sixth Aza cycle (day alone.3–7 As a potential mechanism, murine models have sugge146). For staining of Tregs and lymphocyte subsets the FoxP3 sted that Aza upregulates the transcription factor FoxP3, thereby Staining Kit and the Multitest IMK Kit (both from BD Biosciences, þ expanding CD4 regulatory T cells (Tregs), which play an Heidelberg, Germany) were used according to the manufacturer’s important role in the control of GVHD.8–10 This has also been recommendations. The gating strategy to measure Tregs (CD3 þ recently shown in 17 patients with AML receiving Aza maintenance CD4 þ CD25 þ FoxP3 þ ) is shown in Figure 1a. therapy following allo-SCT.11 Data on Tregs in patients who receive Looking at all the patients, we observed a 1.5-fold increase in Aza and DLI to treat relapse are lacking so far. the absolute number of Tregs in the PB after four Aza cycles (day We serially monitored CD3 þ CD4 þ CD25 þ FoxP3 þ Tregs and 0: 8.23/ml vs day 90: 13.26/ml, P ¼ 0.0479), but this increase varied lymphocyte subsets in the peripheral blood (PB) of 13 patients between the individual patients. By grouping the patients on the with AML (n ¼ 8) or MDS (n ¼ 5) who received Aza and DLI as first basis of the median time to relapse (day 446), we found a 3.2-fold salvage therapy for relapse after allo-hematopoeitic SCT. increase in the absolute number (day 0: 4.7/ml vs day 90: 14.8/ml, Detailed demographics as well as relapse characteristics are P ¼ 0.031) as well as a 1.9-fold increase in the frequency of Tregs summarized in Table 1. Seven of these patients were treated (day 0: 6.7% vs day 90: 12.9% of CD3 þ CD4 þ cells, P ¼ 0.06) during within a prospective multicenter phase II study (AZARELA, http:// treatment with Aza in the group of patients who relapsed early clinicaltrials.gov NCT-00795548) and their clinical results have (Figures 1b and c). On the other hand, in those patients who recently been published,5 while the other six patients were treated relapsed late the absolute number (day 0: 12.2/ml vs day 90: 11.9/ accordingly at our institution. All patients gave written informed ml, NS) and frequency (day 0: 4.7% vs day 90: 3.9%, NS) of Tregs in consent and the study was approved by the Institutional Review PB was already higher and remained unchanged during treatment BoardBlood of The Heinrich University Dusseldorf. The treatment (print ISSNHeine 0006-4971, online ISSN 1528-0020), is published weekly by the American Society (Figure 1c). With regard to other lymphocyte subpopulations no of Hematology, 2021 St, NW, Suite Washington DC 20036. schedule contained up to Leight cycles of 900, Aza (Vidaza, Celgene significant changes were observed (Supplementary Figure S1). 2 CopyrightSummit, 2011 by The Society Hematology; reserved. Corporation, NJ, American USA) either 100ofmg/m /day onall rightsThe finding that Aza-induced expansion of Tregs is apparently 2 days 1–5 or 75 mg/m /day subcutaneously on days 1–7 repeated restricted to patients relapsing early after allo-SCT is in line with every 28 days and DLI envisaged after every second Aza data recently published by Goodyear et al.11 They reported a þ cycle (day 34/90/146) with increasing numbers of CD3 cells. significant increase of the Treg numbers (43-fold) in patients Additional DLI were permitted according to the individual treated with Aza as maintenance therapy in comparison to timephysician’s decision.5 matched controls. These patients commenced Aza therapy at 1–7 Hematological relapse occurred after a median of 446 days months following allo-SCT. Similar to the time dependency in our (range: 19–1688 days) following allo-SCT. The median number of study, Goodyear et al.11 observed the greatest effect on Treg Aza cycles was 6 (range: 4–8). DLI were administered in all expansion after three cycles of Aza, reflecting an early period patients, with a median number of 2 DLI per patient (range: 1–4 following allo-SCT, while no difference was observed after six or DLI). Five patients received one DLI, three patients two DLI, four nine cycles.11 patients three DLI and one patient four DLI, resulting in a The expansion of Tregs during Aza treatment might also median total T-cell dose of 5.0 # 106 CD3 þ cells/kg per patient explain the relatively low rate and mild presentation of þ (range: 1–119 CD3 cells/kg) (Table 1). GVHD in our patients despite a dose-escalating DLI schedule.

Puede AZA inducir una respuesta inmune especialmente despues de un alotrasplante ?

Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and VPA in AML and MDS. Goodyear O, Blood. 2010 :1908-18. 8

Accepted article preview online 1 March 2013; advance online publication, 22 March 2013

PATIENTS AND METHODS Study designs This single center retrospective analysis was performed at the University Hospital of Nantes (Nantes, France). Between September 2006 and July

Statistical analysis Median survival and overall survival (OS) were estimated from the date of the relapse using the Kaplan–Meier method. Differences in OS were studied by univariate analysis, using the log-rank test and Cox regression.

Centre Hospitalier et Universitaire (CHU) de Nantes, He´matologie Clinique, Nantes, France; 2INSERM CRCNA, UMR 892, Nantes, France; 3Centre d’Investigation Clinique en Cance´rologie (CI2C), Nantes, France and 4Universite´ de Nantes, Nantes, France. Correspondence: Dr B Tessoulin, Centre Hospitalier et Universitaire (CHU) de Nantes, He´matologie Clinique, 1 Place Alexis Ricordeau, Nantes 44093, France. E-mail: benoit.tessoulin@chu-nantes.fr 5 Current address: Universite´ Pierre and Marie Curie, Hoˆpital St Antoine, Service d’he´matologie clinique et de the´rapie cellulaire, INSERM UMRs 938, Paris, France. Received 26 June 2013; revised 19 November 2013; accepted 26 November 2013; published online 3 February 2014

•  •  •  •  •  •

N=31 median number of 3 cycles (1–12) 39% monosomal or complex karyotypes 35% DLI 35% responses,13% CR. 1 year OS 14%.

an enhanced graft-versus-leukemia effect without provoking graft-versus-host disease (GvHD).

of AML or MDS after allo-HSCT (AZARELA) trial was a prospective, EBMT (European Group for Blood and Marrow Transplantation)-labeled,

Medical Faculty, Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany; 2University Hospital Carl Gustav Carus, Medizinische Klinik I, Dresden, Germany; 3Goethe University, Medizinische Klinik II, Frankfurt, Germany; 4Charite´ Campus Virchow Klinikum, Department of Haematology, Oncology and Tumor Immunology, Berlin, Germany; 5University of Heidelberg, Medizinische Klinik V, Heidelberg, Germany; 6St. Johannes Hospital, Department of Hematology and Oncology, Duisburg, Germany and 7University Hospital Hamburg-Eppendorf, Clinic for Stem Cell Transplantation, Hamburg, Germany. Correspondence: Dr T Schroeder, Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty, Moorenstr. 5, Duesseldorf, Nord Rhine Westphalia, 40225, Germany. E-mail: thomas.schroeder@med.uni-duesseldorf.de Parts of this study have been presented at the 52nd American Society of Hematology (ASH) Annual Meeting, Orlando, FL, 4–7 December 2010, the BMT Tandem Meeting 2011, Honolulu, HI, 17–21 February 2011, the 37th Annual Meeting of the European Group for Bone and Marrow Transplantation (EBMT), Paris, France, 3–7 April 2011 and at the 53rd American Society of Hematology (ASH) Annual Meeting, San Diego, CA, 10–13 December 2011. 8 These authors contributed equally to this work. Received 16 October 2012; revised 16 December 2012; accepted 3 January 2013; accepted article preview online 14 January 2013

•  N= 30 •  up to 8 cycles azacitidine (100 mg/m2/day, days 1–5, every 28 days) followed by DLI after every second azacitidine cycle. •  A median of three courses azacitidine (range 1–8) were administered, and 22 patients (73%) received DLI. •

Overall response rate 30%, including 7 CR ( 23%) and 2 PR (7%). •  5 patients remained in CR for a median of 777 days

“PrevenOve” Post-transplant azacyOdine in very high risk MDS paOents: a phase II prospecOve study (M Robin) Inclusion criteria Patients aged from 18 to 70 years MDS according to WHO with a very complex cytogenetic (according to IPSSR) or TP 53 gene mutation ?

•  Aza (reduced dose) started on day 40 •  Immunosuppression stopped on day 70 •  DLI started on day 100

Perspec6vas con hipome6lantes en SMD-LMA •  •  •  •  •  •

En SMD de riesgo alto EN LMA Antes o despues de un alotrasplante Como tratamiento de mantenimiento En SMD de riesgo bajo AZA oral

A Phase II Study of Post–Remission Therapy with Azacitidine (AZA) in Patients with AML Post-MDS and High-Risk MDS: A GFM Study Claude Gardin, Thomas Prébet, Krimo Bouabdallah, Denis Caillot, Agnès Guerci, Emmanuel Raffoux, Jean Pierre Marolleau, Cecile Pautas, Anne Banos, Chantal Himberlin, Anne-Laure Taksin, Arnaud Pigneux, Xavier Thomas, Tony Jernival, Norbert Vey, Francois Dreyfus, Sylvie Chevret, Hervé Dombret and Pierre Fenaux

ClinicalTrials.gov Identifier:NCT00446303

Patient characteristics (1) •  AZA 60 mg/m2/d x5 •  51 patients included from July 2006 to April 2009 •  46 patients evaluable •  4 patients did not meet CR, CRi or PR criteria •  1 patient had therapy related AML

•  Cytogenetics •  IPSS (fav./int./unfav): 28 / 8 / 8 •  MRC (fav./int./adv.): 0 / 37 / 7 •  Normal karyotype: 28/44 (64%)

Comparison with maintenance chemotharapy â&#x20AC;˘â&#x20AC;Ż Similar PFS and OS from CR

ALFA!

Perspec6vas con hipome6lantes en SMD-LMA •  •  •  •  •  •

En SMD de riesgo alto EN LMA Antes o despues de un alotrasplante Como tratamiento de mantenimiento En SMD de riesgo bajo AZA oral

©2016 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights reserved to the Ferrata Storti Foundation. Copies of articles are allowed for personal or internal use. Permission in writing from the publisher is required for any other use.

918

the azacitidine and azacitidine plus epoetin-β arms, respectively (P=0.38). Mutations of the SF3B1 gene were the only ones associated with a significant erythroid response, 29/59 (49%) versus 6/27 (22%) in SF3B1 mutated and unmutated patients, respectively, P=0.02. Detection of at least one “epigenetic mutation" and of an abnormal single nucleotide polymorphism array profile were the only factors associated with significantly poorer overall survival by multivariate analysis. The transfusion independence rate observed with azacitidine in this lower-risk population, but resistant to erythropoietic stimulating agents, was lower than expected, with no observed benefit of added epoetin, (clinicaltrials.gov identifier: 01015352).

haematologica | 2016; 101(8)

•  93 pts •  Mainly “purely anemic pa6ents” •  Randomized phase II trial AZA+/- EPO beta In patients CLEARLY resistant to ESAs (at least 12 weeks using 60000 U/ w EPO or 250ug/w Darbepoetin)

•  33% responses, transfusion independence in 19% of pa6ents •  AZA+EPO= AZA

Prognos6c factors of erythroid response and OS to AZA Age

P 0.58

IPSS Cytogene6cs

0.73

IPSS

0.56

Relapse vs primary refractoriness to ESA

0.95

Abnormal SNP-A

0.8

SF3B1 mutated vs WT

0.07

95%CI

IPSS int-1 vs low

2.83

1.05 â&#x20AC;&#x201C; 7.64

0.04

Abnormal vs normal SNP-Arrays

2.92

1.26-7.22

0.013

ASXL1 mutated

5.08

1.48-17.48

0.010

Perspec6vas con hipome6lantes en SMD-LMA •  •  •  •  •  •

En SMD de riesgo alto EN LMA Antes o despues de un alotrasplante Como tratamiento de mantenimiento En SMD de riesgo bajo AZA oral

acute myeloid leukemia (AML) or chronic myelomonocytic leukemia, have been reported.5 Part 1 showed once-daily CC-486 administered for the ﬁrst 7 days of 28-day cycles was bioavailable, clinically active and well-tolerated and the maximally tolerated dose with the 7-day schedule was 480 mg/day. In part 2 of this study, extended CC-486 dosing was evaluated in a new cohort of patients with lower-risk MDS.

administration during the treatment cycle could increase the number of diseased progenitor cells exposed to AZA and maximize therapeutic effects. There is some evidence that extending AZA exposure with administration of lower dosages (o 75 mg/m2/day) can enhance therapeutic effects.23 In a recent study, 10-day SC AZA administration at 50 mg/m2/day in patients with MDS or AML showed a slightly higher rate of hematologic

1 Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Yale Cancer Center, New Haven, CT, USA; 3Division of Hematology/Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA; 4Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 5Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA; 6Medicine/Hematology & Oncology, University of Florida, Gainesville, FL, USA; 7 Cancer Centers of The Carolinas, Greenville, SC, USA and 8Celgene Corporation, Summit, NJ, USA. Correspondence: Dr G Garcia-Manero, Department of Leukemia, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Houston, TX 77030-4009, USA. E-mail: ggarciam@mdanderson.org Received 23 July 2015; revised 2 September 2015; accepted 16 September 2015; accepted article preview online 7 October 2015; advance online publication, 5 February 2016

•  300 mg CC-486 once daily for 14 days (n = 28) or 21 days (n = 27) of repeated 28-day cycles •  Response in 36% pa6ents receiving 14-day dosing and 41% receiving 21-day dosing •  RBC TI rates were similar with both dosing schedules (31% and 38%,) •  CC 486 u6lizado de momento en ensayos: –  En SMD resistente a AZA –  Como mantenimiento en LMA

Myelodysplastic syndromes Auto immune disorders

1. Introduction

∗ Corresponding author at: Service de Médecine Interne, Av du 14 Juillet, Hôpital Jean Verdier, APHP, Université Paris XIII, 93140 Bondy, France. E-mail addresses: jeanbaptiste.fraison@aphp.fr, jbfraison@gmail.com (J.-B. Fraison). 1 Contributed equally to this work.

Autoimmune disorders are observed in 10–30% of MDS and CMML, typically diagnosed concomitantly or shortly before or after MDS/CMML [1]. Most common AID associated with MDS/CMML include relapsing polychondritis, vasculitis, non-erosive and seronegative arthritis [2,3] and Sweet’s syndrome [4]. While AID associated with MDS/CMML usually respond to corticosteroids [2], many patients

•  22 patients treated with AZA for autoimmune disorders (AID) associated with MDS/CMML •  Response of AID to Azacitidine in 19 patients (86%) •  Reduction or discontinuation of steroids and/or immunosuppressive therapy possible in 16 cases (73%).

Op6mizar el uso de drogas y tratamientos disponibles (o aprobados)

•  Quimoterapia •  ASE •  Hipome6lantes •  Lenalidomida •  Alotrasplante

Lenalidomide Erythroid Response: lower risk with Del 5q (NEJM List, 2006) No . Patients

148

Erythroid Response Transf -Indep Minor (>50%â&#x2020;&#x201C;) TI +Minor

99 (67%) 13 (9%) 112 (76%)

Time to Response

4.6 wks 1- 49) (

Cytogenetic response in patients with del 5q Variable

, n (%)

Evaluable

104

Cytogenetic

75%

response* Complete (CCR) Minor (â&#x2030;Ľ 50%â&#x2020;&#x201C;)

48% 27%

*All cytogenetic responders achieved an erythroid response. List AF, et al. Updated data presented at ASH Annual Meeting, 2006 [Abstract 251].

Erythroid response in MDS-003/MDS-004 trial joint analysis

Cytogenetic response (joint analysis of MDS 003/MDS 004 studies) 100 90

Patients (%)

LEN 5 mg × 28 days (n = 43, MDS-004) LEN 10 mg × 21 days (n = 50, MDS-004) LEN 10 mg × 28 days (n = 88, MDS-003)

70 60 50 40 30 20 10 0 Complete CyR

LEN, lenalidomide.

Partial CyR

Complete + partial CyR

Duration of RBC-TI (â&#x2030;¥ 26 weeks) by CyR (MDS-003 and MDS-004)

100

Complete CyR Partial CyR No CyR

Patients (%)

0 0

Duration of RBC-TI (months)

MDS-003/004: progression to AML and CyR

•  Achievement of CyR was associated with significantly reduced risk of AML

MDS-003/004: Overall survival and CyR

â&#x20AC;˘â&#x20AC;Ż Achievement of CyR was associated with significantly increased OS

period accident, placebo; thrombocytopenia, 500 μg). Two patients had(cerebrovascular no post-treatment biopsyworsening to confirm or excluderomiplostim the diagnosis of progression to AML. (romiplostim 500 and 750 μg, respectively) had an increase in bone marrow blasts to >20% during treatment, but Conclusions: data suggest that administered had no post-treatmentThese biopsy to confirm or exclude theromiplostim diagnosis of progression to AML. to MDS patients during lenalidomide treatment may decrease thesuggest frequency of doseadministered reductions/delays due to lenalidomide thrombocytopenia. Additional study is needed to Conclusions: These data that romiplostim to MDS patients during treatment may decreasethe the frequency due to thrombocytopenia. Additional study is needed to confirm results of ofdose thisreductions/delays preliminary trial. confirm the results of this preliminary trial.

Trial registration: ClinicalTrials.gov Trial registration: ClinicalTrials.gov NCT00418665

NCT00418665

Keywords: Romiplostim, Lenalidomide, Thrombocytopenia, Myelodysplastic syndromeMyelodysplastic Keywords: Romiplostim, Lenalidomide, Thrombocytopenia,

* Correspondence: eunice.wang@roswellpark.org Figure 3 Median platelet counts during the treatment 1 Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, 50 × 109/L. Elm and Carlton Streets, Buffalo, NY 14263, USA * Correspondence: Full list of author informationeunice.wang@roswellpark.org is available at the end of the article

syndrome

period. Bars of line graph represent standard deviations. Broken horizontal line is at

1 Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, © 2012 Wang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Elm and Carltonsmaller Streets, Buffalo, NYAttribution 14263, USA inunrestricted the placebo group, trended than those in the placebo group during patients Commons License (http://creativecommons.org/licenses/by/2.0), which permits use, distribution, and 9 (64%) in the romiplosany medium, provided thethe original work is properly cited. Full listallofcycles authorexcept information is available at thethe endextension of article forreproduction cycle 2.inDuring period, tim 500 μg group, and 10 (71%) in the romiplostim

median platelet counts generally fluctuated between 50 750 μg group. Serious adverse events were reported in 6 © 2012 Wang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative (67%) patients in the placebo group, 5 (36%) in the romiand 100 × 109/L (Figure 5). Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and plostim 500work μg isgroup, Bleeding events were reported in one inpatient in the reproduction any medium, provided the original properlyand cited.4 (29%) in the romiplostim placebo group, four in the romiplostim 500 μg group, 750 μg group. Only two serious events, cerebrovascular and four in the 750 μg group. The number (95% CI) of accident in one patient in the placebo group and worbleeding events reported per 100 patient-weeks was 4.8 sening thrombocytopenia in one patient in the romiplos(2.1, 9.6) in the placebo group, 2.6 (0.8, 6.1) in the romi- tim 500 μg group, were considered related to treatment. plostim 500 μg group, and 8.1 (4.7, 13.0) in the romi- In the latter patient, worsening thrombocytopenia (platelet count of 10 × 109/L) was noted at the patient’s plostim 750 μg group. end-of-treatment visit, 4 weeks after her last dose of romiplostim during the treatment period. When romiSafety During the treatment period, adverse events were plostim treatment was resumed during the extension reported by all but one patient in the placebo group and period, her platelet counts increased from 17 × 109/L at by all patients in the romiplostim groups (Table 3). The extension week 1 to 86 × 109/L at extension week 16, most frequently reported adverse events were diarrhea, when romiplostim was discontinued because of an adthrombocytopenia, neutropenia, and dizziness in the pla- ministrative decision. cebo group; thrombocytopenia, diarrhea, rash, and conDuring the extension period, the safety profiles of the stipation in the romiplostim 500 μg group; and fatigue, investigational products were similar to those during the diarrhea, rash, and nausea in the romiplostim 750 μg treatment period. Serious adverse events were reported group. Adverse events led to study withdrawal or investi- in 4 (22%) patients. Of these events, only leukocytosis, gational product discontinuation in 3 (33%) patients in reported in one patient who had received placebo during the placebo group, 2 (14%) in the romiplostim 500 μg the treatment period, was considered related to investigroup, and 1 (7%) in the romiplostim 750 μg group. gational product. One patient in the romiplostim 750 μg These adverse events were pancytopenia, asthenia, and group died during the extension period from an cerebrovascular accident in the placebo group; pancyto- intestinal obstruction, which was not considered related penia and rash in the romiplostim 500 μg group; and to investigational product. No patients developed neuthrombocytopenia in the romiplostim 750 μg group. tralizing antibodies to romiplostim or thrombopoietin. Only cerebrovascular accident in the placebo group was For the 37 patients who had available screening and considered related to investigational product. Adverse end-of-treatment bone marrow biopsy data, no patients events of severity grade ≥ 3 were reported in 6 (67%) exhibited changes in trichrome stain indicative of

Inicio temprano de Lenalidomida en SMD de riresgo bajo con del 5q •  Ensayo SINTRA –REV (M Diez Campelo para el GESMD, C Berthon para el GFM) •  Pacientes con Hb <12g, sin requerimiento trasfusional •  LEN o placebo •  Prevencion de la evolucion clonal ?

LEN en SMD de alto riesgo/ LMA con del 5q •  Karyotype generally very complex (and FISH oxen useful to conﬁrm del 5q) •  Very poor response to intensive chemotherapy and HMA

Lenalidomide in higher risk MDS and AML with del 5q :phase I-II trial (Adès,Blood, 2009) •  •  •

LEN 10mg/d 21 days/ month 43 patients evaluable after at least one cycle Overall response 28%

Prognostic factors of CR achievement

isolated del 5q Single cytogeneti addition cs al abn >1

67%

f m

Treatment of higher risk MDS (and AML)with complex karyotypes including del 5q by DNR+AraC + Lenalidomide

InducOon Course

monthly consolidaOons x6

monthly Maintenance

1st Cohort

DNR 45 mg/m2 x3 ARAC 200 mg/m2x7 Lenalidomide 10 mg x 21

DNR 45 mg/m2 x1 ARAC 60 mg/m2x 10 Lenalidomide 10 mg x 14

Lenalidomide 10 mg x 14

2nd Cohort

DNR 60 mg/m2 x3 ARAC 200 mg/m2x7 Lenalidomide 10 mg x 21

DNR 60 mg/m2 x1 ARAC 60 mg/m2x 10 Lenalidomide 10 mg x 14

Lenalidomide 10 mg x 14

3rd Cohort

(L AdĂ¨s, Haematologica, in press)

DNR 60 mg/m2 x3 ARAC 200 mg/m2x7 Lenalidomide 25 mg x 21

DNR 60 mg/m2 x1 ARAC 60 mg/m2x 10 Lenalidomide 25 mg x 14

Lenalidomide 25 mg x 14

Respuesta (82 pacientes) N° pts

46%

CRi

10%

Early Death

•  Overall Response rate 61% •  68% of CR patients achieved complete or partial cytogenetic response

MDS-005:lower risk MDS without del 5q resistant to ESA Pretreatment

Double-blind (DB) treatment

LEN 10 mg, orally, QDa Key inclusion criteria •  Centrally reviewed IPSS Low or Int-1-risk MDS with karyotypes other than del(5q) •  RBC-TD •  Unresponsive or refractory to ESAs

R A N D O M I Z E D

RBC-TI ≥ 8 weeks or erythroid response

Off-treatment Continue DB phase until erythroid relapse or disease progression

Long-term follow-up (≥ 5 years from randomizaOon)

•  Overall survival

•  AML progression

2:1

Matching placebo

pRBC, packed red blood cell; SPM, secondary primary malignancy.

No RBC-TI ≥ 8 weeks or erythroid response

aLEN

•  Subsequent MDS treatments •  SPMs Discontinue DB phase

5 mg for patients with creatinine clearance 40–60 mL/min.

Results ITT population: 239 pts (LEN, n = 160; PBO, n = 79). Baseline characteristics were comparable across treatment groups

Santini, V., et.al., , JCO, 2016

GFM Len-Epo 2008 LEN +/- EPO in lower risk MDS resistant to ESA

Arm LEN LEN 10 mg/d x 21d every 28 days x 4 cycles of 28 days Arm LEN + EPO LEN 10 mg/d x 21days every 28 days + EPO beta 60 000 U/Week Evaluation after the 4th cycle

A Toma , Leukemia, 2015

LEN 10 mg/day x 21days every 28 days RESPONDERS (IWG 2006)

-  Lower risk MDS Low and Int-1 IPSS - Without del 5q -  Transfusion dependency ≥ 4 RBC units during 8 wks before randomization - ESA failure ≥ 12 consecutive wks ≥ 60 000 UI or 250µg /w or relapse after response

RANDOMIZATION

INCLUSION CRITERIA

Until relapse LEN 10 mg/day x 21days every 28 days + EPO beta 60 000 U/Week

IWG 2006 Erythroid response (primary endpoint) and RBC-TI (ITT population, n=129) LEN + EPO N = 65 Erythroid response

(IWG 2006)

40 %

LEN N = 64 23.4 %

RR1.7 p= 0.043

•  Median response duraOon was 18.1 and 15.1 months in the L and LE arms, respecOvely (P = 0.47) •  Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E.

acute myeloid leukemia (AML). In low- or intermediate-risk MDS, treatment with erythropoiesis-stimulating agents (ESAs) aims at correcting anemia. Lenalidomide is another compound approved for treating anemia in lower-risk MDS patients, with deletion of the long arm of chromosome 5 (del[5q]), where it yields red blood cell (RBC) transfusion independence in 60% to 75% of cases and a complete or partial cytogenetic response in 40% to 60%.1-5 In this setting, the

degrades casein kinase 1A, encoded by the CSNK1A1 gene located in the 5q commonly deleted region, which may cause cell death.6 Lenalidomide also yields an erythroid response (hematologic improvement of the erythroid lineage [HI-E]) and RBC transfusion independence in 20% to 30% of MDS patients without del(5q) who are resistant to ESAs.7,8 In this context, the addition of high doses of epoetin was suggested to increase the hematologic response to

Submitted April 11, 2015; accepted November 17, 2015. Prepublished online as Blood First Edition paper, December 1, 2015; DOI 10.1182/blood-2015-04640128.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

The online version of this article contains a data supplement.

BLOOD, 11 FEBRUARY 2016 x VOLUME 127, NUMBER 6

749

•  In a mul6variate analysis including the 4 most frequent muta6ons, and adjus6ng for treatment arm, DNMT3A muta6on was independently associated with beker HI-E (OR, 3.51, P=0 .029). •  Conﬁrmado en el ensayo MDS 005 (San4ni et al, ASH 2016)

Op6mizar el uso de drogas y tratamientos disponibles (o aprobados)

•  Quimoterapia •  ASE •  Hipome6lantes •  Lenalidomida •  Alotrasplante

INTRODUCTION

Although allogeneic blood or marrow transplantation (BMT) is the only potentially curative approach for many patients with hematologic malignancies, the inability to identify a matched donor and the sometimes prohibitive delays with matched unrelated donor BMT1 have historically been major barriers. In contrast, partially HLA-mismatched related, or HLA-haploidentical, donors can be promptly identified for most patients. HLA3152

mismatched allografting used to be associated with excess risks of graft-versus-host disease (GVHD), graft failure, and nonrelapse mortality (NRM).2-7 However, modern approaches to GVHD prophylaxis, such as high-dose post-transplantation cyclophosphamide (PTCy), have greatly reduced the morbidity of HLA-haploidentical BMT (haploBMT), making it a viable alternative for patients lacking HLA-matched donors.8,9 As a pharmacologic form of tolerance induction,10 high-dose PTCy moderates GVHD and graft

•  271 pa6ents with hematologic malignancies, •  NMA, T-cell–replete haplo-BMT with high-dose post- transplant CY •  median age 61 , 27 (10%) age 70 to 75 years •  For age 50s, 60s, and 70s :

–  6-month NRM probabili6es of 8%, 9%, and 7%, respec6vely (P ︎ .20) –  3-year PFS 39%, 35%, and 33% –  3-year OS 48%, 45%, and 44%

•  Aza (reduced dose) started on day 40 •  Immunosuppression stopped on day 70 •  DLI started on day 100

Allogeneic HSCT in lower risk MDS: A prospective multicenter phase II study based on donor availability on behalf of the GFM & SFGM-TC (M Robin) Â

Nuevos tratamientos en SMD -LMA •  Retos en el tratamiento de SMD y LMA •  Op6mizar el uso de drogas y tratamientos disponibles (o aprobados) •  Nuevas drogas

Figure 1. The mechanisms of action of novel agents currently in development. DNMT, DNA methyltransferase; FLT3, FMS-like tyrosine kinase receptor-3; FT, farnesyltransferase; GO, gemtuzumab ozogamicin; HDAC, histone deacetylase; LDAC, low-dose cytosine arabinoside.

induction therapy. In addition, azacitidine and decitabine are recommended low-intensity treatment options for patients with intermediate-2/high-risk MDS by the National Comprehensive Cancer Network (NCCN).20 Because of the achievement of cytogenetic responses in both MDS and AML caused by a p53independent clonal suppression,21 DNA methyltransferase inhibitors represent an interesting treatment option in patients with complex cytogenetics and TP53 mutations in whom response rates to conventional chemotherapy remain very low,22 and in whom responses to azacitidine appear to be independent of TP53 status.23 This is especially the case if toxicities derived from a more intensive treatment approach are also taken into account. Both azacitidine and decitabine are category 1 recommendations. The only alternative low-intensity treatment option is enrollment into a clinical trial (category 2A recommendation).20 Azacitidine. In a phase III, randomized trial investigating azacitidine versus conventional care regimens (CCRs) in patients with intermediate-2 and high-risk MDS, azacitidine was associated with a significant OS benefit.24 Approximately one-third of the patients enrolled into this trial were classified as having AML under World Health Organization (WHO) criteria (20–30% blasts), and an analysis of this older AML subgroup demonstrated a survival benefit of azacitidine compared with CCR.25 Median OS for azacitidine-treated patients was 24.5 months compared with 16.0 months for conventional care-treated patients (P = 0.005). Azacitidine was also well tolerated with patients who received azacitidine, requiring fewer hospital admissions and spending less © 2015 Macmillan Publishers Limited

time in hospital compared with those treated with CCR.25 Preliminary results from an ongoing phase III study of azacitidine versus CCR in patients with AML aged ⩾ 65 years with 430% blasts (NCT01074047/AML-001) were recently presented.26 A total of 488 patients were randomized to azacitidine (n = 241) or CCR (n = 247 including best supportive care (BSC), low-dose cytosine arabinoside (LDAC) and intensive chemotherapy). Median OS, the primary end point, was not significantly different between the two arms: 10.4 months in the azacitidine group compared with 6.5 months in the CCR arm (stratified hazard ratio (HR) = 0.85 (0.69–1.03); P = 0.1009). However, a prespecified sensitivity analysis for OS with patients censored at the start of subsequent AML therapy showed a significant benefit with azacitidine: median OS was 12.1 (9.2–14.2) vs 6.9 (5.1–9.6) months (stratified HR = 0.76 (0.60–0.96), P = 0.019). The 1-year survival was 47% in the azacitidine arm compared with 34% in patients treated with CCR. Grade 3–4 anemia, neutropenia, febrile neutropenia and thrombocytopenia were higher in the azacitidine group compared with BSC, but similar to LDAC and intensive chemotherapy. No difference in 30- and 60-day mortality was found between the different treatment groups. Decitabine. In a phase III trial of decitabine versus supportive care or LDAC in older (⩾65 years) patients with newly diagnosed AML and poor‐ or intermediate-risk cytogenetics, decitabine treatment resulted in improved rates of complete response (CR) and CR without platelet recovery (CRp) compared with treatment choice (17.8% vs 7.8%; odds ratio, 2.5; 95% confidence interval (CI), Leukemia (2015) 760 – 769

Inhibidores de IDH •  Inhibidor de IDH 1: AG 110 •  Inhibidor de IDH 2: AG 221

Safety and Efficacy of AG-221, a Potent Inhibitor of Mutant IDH2 That Promotes Differentiation of Myeloid Cells in Patients with Advanced Hematologic Malignancies: Results of a Phase 1/2 Trial 323

Eytan M. Stein, All(N=181)

RR-AML (N=128)

n (%) ORR CR CRp CRi mCR PR SD PD NE

74 (41) 30 (17) 3 (2) 1 (1) 15 (8) 25 (14) 81 (45) 9 (5) 17 (9)

52 (41) 23 (18) 1 (1) 1 (1) 8 (6) 19 (15) 57 (45) 7 (6) 12 (9)

(aged <60 years) patients with acute myeloid leukaemia can be cured,1 patients who are refractory or relapsing, or not fit for intensive therapy (mainly elderly patients, aged >60 years) have few therapeutic options. Epigenetic deregulation is thought to be an important factor in acute myeloid leukaemia genesis, with many recurrent gene changes aﬀecting transcriptional activity in both acute myeloid leukaemia and myelodysplastic syndromes.2–4 Hypomethylating drugs, including decitabine and azacitidine, were the first epigenetic modulators approved in myeloid malignancies.5–8 Nonetheless, with

chromatin readers that play a major part in the epigenetic regulation of gene transcription.9 Their bromodomainbearing moiety binds to acetylated histone tails, allowing the extraterminal moiety to bring the elongation complex of the transcriptional machinery within proximity of the gene promoter region. Histone acetylation is prevalent at super-enhancer regions that control expression of various oncogenes, rendering them sensitive to bromodomain inhibition.10 Bromodomain inhibitors are small molecules that specifically bind bromodomains,11 preventing BET proteins from binding to chromatin and thereby inhibiting

www.thelancet.com/haematology Vol 3 April 2016

Hospital, Sutton, Surrey, UK (D C Taussig MD); Institute o Cancer Research, Sutton, UK (D C Taussig); Département d Radio-Pharmacologie, Instit Curie, Hôpital René Huguen Saint-Cloud, France (K Rezai PhD, F Lokiec ScD); Oncoethix SA (now Oncoeth GmbH), Lucerne, Switzerlan (P Herait MD); and Oncology Therapeutic Development, Clichy, France (C Kahatt MD)

ALFA

Hedgehog-pathway inhibitors mTor inhibitors Nuclear export inhibitor XPO1 (also called CRM1) inhibitor

1148

n en

Sorafenib Versus Placebo in Addition to Standard Therapy in Younger Patients with Newly Diagnosed Acute Myeloid Leukemia: Results from 267 Patients Treated in the Randomized PlaceboControlled SAL-Soraml Trial Christoph Rรถllig, Lancet Oncol, 2015 age from 18 to 60 years two cycles of induction with DA (daunorubicin 60 mg/m2 days 3-5 plus cytarabine 100 mg/m2 cont. inf. days 1-7), followed by three cycles of high-dose cytarabine consolidation (3 g/m2 b.i.d. days 1, 3, 5)

Patients randomized to receive either sorafenib (800 mg/day) or placebo on days 10-19 of DA I+II or HAM, from day 8 of each consolidation until 3 days before the start of the next consolidation and as maintenance for 12 months after the end of consolidation.

6 The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand)Â PControlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]) ) Richard M. Stone, MD1 717 pts (341 FLT3 ITD-Low, 214 FLT3 ITD-High; 162 FLT3 TKD) were rand to either M (n=360) or P (n=357). CR rate is 59% (M) and 54% (P) (p=0.18).The HRs comparing M to P for OS is 0.77 (one-sided p = 0.007; Figure 1), and for EFS is 0.80 (one-sided p = 0.004; Figure 2).

Retinoic acid

All-trans retinoic acid¶

CXCR4 antagonist

Plerixafor

E-selectin antagonist

GMI-1271

Homoharringtonine derivative

NCT0

Omacetaxine¶

* CRM1 denotes chromosome region maintenance 1, CXCR4 chemoki (K)-specific demethylase 1A, LSD1 lysine-specific demethylase 1, E3 ub of rapamycin, PI3K phosphatidylinositol 3-kinase, PIM1 oncogene PIM † Chinese Clinical Trial Registry numbers begin with ChiCTR-TRC, Clini Controlled Trial numbers begin with ISRCTN, and Netherlands Trial R ‡ This agent is approved by the EMA, but not by the FDA, for patients de novo or secondary AML and who are not candidates for standard § This agent is approved by the FDA and EMA for patients who have n blasts and multilineage dysplasia and who are not candidates for allo ¶ This agent is under investigation in randomized, phase 2 or phase 3 ∥ In 2000, this drug was granted accelerated approval by the FDA for the older than 60 years of age who had AML in first relapse and who did n was withdrawn from the U.S. market because of a negative postapprov

n engl j med 373;12

nejm.org

Sep

•

Gemtuzumab ozogamicin as 3rd agent ALFA-0701 trial (2) ! ALFA CR+CRp rate, 75 vs 81%

(P=0.25) •  Longer EFS, RFS and OS

du Cancer Toulouse Oncopole, Toulouse, France (Prof C Récher MD); and Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK (L Chilton PhD, Prof A V Moorman PhD) Correspondence to: Prof Alan K Burnett, School of Medicine, Cardiff University, Cardiff CF4 14NX, UK BurnettAK@cardiff.ac.uk

986

Statistical analysis for acute myeloid leukaemia have Very few treatments We analysed dataapproval. using standard meta-analytic techgained regulatory One of the few successes 14 niques, with an assumption-free fixed-effect) was the immunoconjugate drug (orgemtuzumab method. Comparisons were NY, made within trial, and ozogamicin (Pfizer, New York, USA), which gained observedinminus expected variance approval the USA in 2000 (o–e) (with aevents dosingand schedule of were obtained forofeach trial (or each stratum 9statistics mg/m² on days 1 and 15 induction chemotherapy) within each trial). The overall o–e results and variance on the basis of data from a non-randomised, phase 2 1,2 statistics (and effect sizes CIs) were calculated study done in hence 142 patients with and relapsed disease. The as therestricted sum for all trials. We also did exploratory label approval to “older patients with stratifi relapseed 1 analyses investigate baseline who weretonot suitable interactions for intensivebetween treatment”. A parameters treatment eff ectiveness, with interactions confi rmatoryand randomised trial was required for full assessed by means of standard heterogeneity and trend approval. tests; we prespecifi ed that was we approved would doin exploratory Gemtuzumab ozogamicin Japan for analyses if signifipop cant heterogeneity detected. We the same patient ulation and with was the same dosing created survival curves using the Early Breast Cancer Trialists’ Collaborative Group’s method,14 wherein o–e results, variance statistics, and the number of personyears at risk during a particular time period are combined to produce a survival curve adjusted for any disparities between groups across trials. We analysed time-to-event outcomes by the log-rank test, producing Peto odds ratios (ORs); for binary

Rolechemotherapy of the fundingregimens, source this schedule resulted in used There wastoxic no eff funding sourcefrom for athis study. The prohibitive ects.3 Results dose-fi nding 4 corresponding author had full accessozogamicin to all the data was in the study in which gemtuzumab study and with had final responsibility the decision combined frequently used for induction and to submit for publication. consolidation chemotherapy regimens provided evidence that a single, lower dose of 3 mg/m² was safe Results and apparently effective. That study was the prelude to 5 identifiedtrial five trials5–8,11 ozogamicin that met our a We randomised inrandomised which gemtuzumab inclusion patient data was added criteria, to diffand erentobtained coursesindividual of chemotherapy. for all 3325 who were enrolledwith in the thefitrials Feasibility was patients established in combination rst (table). All trials were centrally randomised, and third courses of chemotherapy. On the open basislabel, of and had survival as the endpoint. these data,overall two large trials wereprimary done in which For a 5–7 three of the studies published were supplemented gemtuzumab ozogamicin dose ofdata 3 mg/m² was added unpublished data provided inby the investigators; toby induction chemotherapy younger patients in addition to the four trials for which final results had been reported,5–7,11 source data were made available for the www.thelancet.com/oncology Vol 15 August 2014 GOELAMS AML 2006 IR trial.8 Patients’ ages ranged from 15 to 84 years (median 58 years), and 1842 (55%) of the 3325 participants were male. 2927 (88%) of 3325 patients had de-novo disease, 285 (9%) had secondary disease, and 113 (3%) had high-risk myelodysplastic syndrome. Only two trials5,6 included

Events/patients

o−e

Variance

314/478

–20·8

148·8

321/376

–27·2

159·5

635/854

–48·0

308·2

Gemtuzumab ozogamicin group

No gemtuzumab ozogamicin group

MRC AML15

282/466

NCRI AML16

325/396

Subtotal

607/862

3 mg/m2 single dose

Test for heterogeneity between trials χ2=0·1; p=0·8 3 mg/m2 fractionated ALFA-0701

51/113

69/104

–19·1

28·7

Subtotal

51/113

69/104

–19·1

28·7

6 mg/m2 dose Dates of recruitment

MRC AML15†5 2002–06

SWOG S01067 2004–09

NCRI AML166

2006–10

GOELAMS AML 2006 IR8

2007–10

ALFA-070111

2008–10

Number of patients

Eligibility criteria

Median age of patients in years (range)

Cytogenetic grouping by MRC12 classiﬁcation*

Chemotherapy given

Median followDose and dosing schedule up for survival of gemtuzumab ozogamicin

1099

AML, either de novo or secondary; mostly aged <60 years

50 (15–71)

Favourable n=133 (15%); intermediate n=565 (63%); adverse n=196 (22%); unknown n=205

DA (3+10 then 3+8), ADE (3+10+5 then 3+8+5), or FLAG-Ida

3 mg/m² on day 1 of chemotherapy

De-novo AML; aged 18–60 years

47 (18–60)

595

1115

238

278

AML, either de novo or secondary, or high-risk myelodysplastic syndrome; mostly aged ≥60 years

67 (51–84)

De-novo AML, aged 18–60 years

50·5 (18–60)

De-novo AML; aged 50–70 years

62 (50–70)

Time of last follow-up (original publication)

86·0 months January, (IQR 76·6–99·4) 2009

March, 2013

55·2 months February, (IQR 46·0–66·3) 2013

3 mg/m² on day 1 of chemotherapy

45·5 months July, 2011 (IQR 34·3–57·6)

March, 2013

DA (3+7) Favourable n=0; intermediate n=224 (100%); adverse n=0; unknown n=14

6 mg/m² on day 4 of chemotherapy

39·3 months ·· (IQR 29·1–44·4)

January, 2013

DA (3+7)

3 mg/m² on days 1, 4, and 7 of chemotherapy, up to 5 mg per dose

24·1 months (IQR 15·7–32·8)

August, 2011

Favourable n=9 (4%); intermediate n=179 (73%); adverse n=57 (23%); unknown n=33

DA (3+10 then 3+8) or daunorubicin (days 1, 3, and 5) plus clofarabine (days 1–5)

–4·9

22·7

122/222

–2·5

59·9

Subtotal

161/331

170/324

–7·4

82·6

874/1282

–74·4

419·5

Test for heterogeneity between trials χ =0·5; p=0·5 2

819/1306

Test for heterogeneity (five trials) χ2=8·2; p=0·08

June, 2013

Test for heterogeneity between subtotals χ2=7·7; p=0·02

0·1

1·0 Favours gemtuzumab ozogamicin

Favours gemtuzu ozogam

B 3 mg/m2 single dose

August, 2011

129·6

MRC AML15

244/466

275/478

−19·0

NCRI AML16

284/396

289/376

−27·4

141·7

Subtotal

528/862

564/854

−46·4

271·3

Test for heterogeneity between trials χ2=0·1; p=0·7 3mg/m2 fractionated

AML=acute myeloid leukaemia. DA=daunorubicin plus cytarabine. ADE=daunorubicin, cytarabine, and etoposide. FLAG-Ida=ﬂudarabine, cytarabine, G-CSF, and idarubicin. G-CSF=granulocyte colony-stimulating factor. GM-CSF=granulocyte-macrophage colony-stimulating factor. *Percentages exclude those with unknown cytogenetic characteristics. †14 patients in AML15 aged younger than 15 years were excluded from this meta-analysis.

ALFA-0701

35/113

42/104

−9·4

18·6

Subtotal

35/113

42/104

−9·4

18·6

GOELAMS AML2006 IR

33/109

39/102

−4·0

18·0

SWOG 0106

94/222

91/222

2·2

46·2

127/331

130/324

−1·8

64·2

736/1282

−57·6

354·1

6mg/m2 dose

Table: Trials included in the meta-analysis

988

48/102

118/222

Total

DA (3+7) plus G-CSF 6 mg/m² on Favourable n=72 day 4 of (17%); intermediate or GM-CSF chemotherapy n=283 (67%); adverse n=67 (16%); unknown n=173 Favourable n=33 (4%); intermediate n=576 (66%); adverse n=264 (30%); unknown n=242

43/109

SWOG 0106

GOELAMS AML2006 IR

Time of last follow-up (data for meta-analysis)

Subtotal

www.thelancet.com/oncology Vol 15 August 2014

Test for heterogeneity between trials χ2=1·0; p=0·3 Total

690/1306

Test for heterogeneity (five trials) χ2=4·4; p=0·4 Test for heterogeneity between subtotals χ2=3·3; p=0·2

0·1

1·0 Favours gemtuzumab ozogamicin

Favours gemtuzu ozogam

Figure 3: Relapse-free survival (A), and survival after achieving remission (B) The size of the boxes is proportional to the amount of data contained in each data line. o–e=observed minus expected events. *C subtotals, and 99% CIs for individual trials.

992

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Antibody drug conjugate strategies envisage one such novel approach. CD33 is expressed by myeloid blast cells in 480% of patients with AML suggesting that antibodies to CD33 may have specific therapeutic benefit in the treatment of AML.9,10 Gemtuzumab ozogamycin (GO; Mylotarg, Pfizer Inc., New York, NY, USA) is a humanized anti-CD33 monoclonal antibody covalently linked to a semisynthetic derivative of a potent toxin, calicheamicin.11,12 GO has been used in combination with induction therapy in AML with improved outcomes11,13–17 particularly among elderly

AML cells to GO. Prior exposure of AML cells to hypomethylating agent such as decitabine sensitize them to GO by reducing the expression of multidrug resistance protein-1 or by enhancing DNA intercalation by calicheamicin.25 Nand et al.26 evaluated a combination of 5-azacitidine and GO in 133 elderly patients with newly diagnosed myelodysplastic syndrome (MDS) and AML. They divided patients into good-risk (N = 79) and poor-risk (N = 54) groups. The good-risk group included patients who were 60–69 years or had a performance status of 0 or 1; the poor-risk group

Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Division of Hematology, University of Washington School of Medicine, Seattle, WA, USA and 3Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Correspondence: Dr G Borthakur, Department of Leukemia, University of Texas MD Anderson Cancer Center, Unit 0428, 1515 Holcombe Boulevard, Houston, TX 77030, USA. E-mail: gborthak@mdanderson.org Received 10 May 2015; revised 30 June 2015; accepted 3 July 2015; accepted article preview online 14 September 2015

•  decitabine 20 mg/m2 daily for 5 days and GO 3 mg/m2 on day 5. •  Complete remission (CR)/CR with incomplete count recovery was achieved in 39 (35%) pa6ents;

AZA+ gentuzumab (Nand, Blood , 2013): 40% CR

Interpretation Although there was no significant diﬀerence in the primary endpoint between groups, the prespecified secondary analysis stratified by randomisation factors suggests that the addition of vosaroxin to cytarabine might be of clinical benefit to some patients with relapsed or refractory acute myeloid leukaemia. Funding Sunesis Pharmaceuticals.

Introduction The prognosis for patients with relapsed or refractory acute myeloid leukaemia is poor; median survival is less than 1 year.1,2 High-dose cytarabine monotherapy or cytarabine-based combination regimens are often used as salvage therapy with limited eﬃcacy; in a recent randomised trial, salvage chemotherapy with the

investigator’s choice of one of seven commonly used regimens (including high-dose cytarabine) produced complete remission in 12% of patients and a median survival of 3·3 months, with no significant diﬀerence between regimens.3 Toxicity is also a concern, particularly in patients older than 60 years, who constitute the majority of patients with acute myeloid leukaemia.1,4–6

www.thelancet.com/oncology Vol 16 September 2015

Lancet Oncol, 2015

461 Phase I/II Study of Vosaroxin and Decitabine in Newly Diagnosed Older Patients (pts) with Acute Myeloid Leukemia (AML) and High Risk Myelodysplastic Syndrome (MDS) Naval Daver, MD1

The median overall survival (OS) for all pts is 8.3 months

de Bordeaux, Bordeaux, France (Prof A Pigneux MD); Medizinische Klinik und Poliklinik, University Hospital Schleswig-Holstein, Kiel, Germany (Prof H-A Horst MD); Institut Universitaire du Cancer de Toulouse Oncopole, Université de Toulouse III, CHU de Toulouse, Toulouse, France (Prof C Recher MD); Memorial Sloan-Kettering Cancer Center, New York, NY, USA (V M Klimek MD); University of Chicago, Chicago, IL, USA (O Odenike MD); Hôpital

1025

Venetoclax (inhibidor de BCL2 ) + AZA en LMA del anciano Venetoclax + Azacitidine 75mg/m2 D1-7, 28D cycles N = up to 24

Azacitidine +/- Venetoclax 75mg/m2 D1-7, 28D cycles

Phase Ib Safety PK & Dose-ﬁnding

•

Eligibility: Patients ≥ 65 years old with untreated AML and are not eligible for standard induction therapy

Poten6al targe6ng of mutated or inac6vated TP 53 •  MDM2 Inhibitors (Idasanutlin) •  agents « reconforming » a mutated p53 protein (APR 246) •  Others drugs ac6ve independently of p53 (Venetoclax, Vosaroxin) ?

•  •  •  •

Nuevas drogas en SMD

Spliceosome inhibitors (SF3B1, SRSF2) Telomerase inhibitors (Imetelstat) Toll like receptor (TLR) inhibitors TPO agonist receptors –  Romiplos6n –  Eltrombopag

•  Ligand traps of TGF b pathway •  Immune checkpoint inhibitors (directed at PD-1 PD-L1)

ACE-011 (Sotatercept) and ACE-536 (Luspatercept) Novel Ligand Traps for TGFβ Superfamily Ligands ACE-011 Fusion protein with ligand trap acOvity toward the acOvin type 2 receptors Drug does not bind EPO receptors

Heme eﬀect Bone eﬀect

(Sotatercept)

ACE-536 (luspatercept)

Extracellular Domain of ActRIIA

Modified Extracellular Domain of ActRIIB

Fc Domain of human IgG1 Antibody

+ +

+ –

Luspatercept in MDS: Background TGF-β Superfamily Ligands: GDF11, etc.

Luspatercept Fusion protein containing modified activin receptor type IIB (ActRIIB)

Smad2/3 Erythropoiesis

Activin Receptor Domain Human IgG Fc Domain

•  Mechanism is disOnct from erythropoieOn •  Acts on late-stage erythropoiesis to increase mature RBCs in the circulaOon Suragani R, et al. Nature Med 2014 Zhou L, et al., Blood 2008

Sotatercept :Eï¬&#x192;cacy Summary: HI-E Response Rate 0.125-0.5 mg/kg (N=9) n (%)

0.75-1.75 mg/kg (N=17) n (%)

LTB pa6ents (N=7)

0/2 (0%)

2/5 (40%)

HTB pa6ents (N=19)

2/7 (29%)

5/12 (42%)

All pa6ents (N=26)

2/9 (22%)

7/17 (41%)

PaOent Subgroup

HI-E, hematologic improvement-erythroid IWG, InternaOonal Working Group LTB, low transfusion burden; HTB, high transfusion burden

Erythroid Response: Sideroblas6c vs Non-Sideroblas6c MDS

•  In the sotatercept 1.0 mg/kg dose group, HI-E was achieved in 64% of sideroblas6c and 20% of non-sideroblas6c pa6ents (χ2 test P = 0.11) RSa

HI-E by sotatercept dose group and RS status, n/N (%) 0.1 mg/kg

0.3 mg/kg

0.5 mg/kg

1.0 mg/kg

2.0 mg/kg

≥ 15%b

0/6

4/4 (100)

7/13 (54)

7/11 (64)

2/3 (67)

< 15%

0/1

0/2

2/6 (33)

1/5 (20)

0/2

a RS

status is from baseline, where available; RS status was unknown for 6 patients: 2 and 4 patients from the sotatercept 0.5 and 1.0 mg/kg groups, respectively. b Of 37 patients with ≥ 15% RS, 12 had RARS, 24 had RCMD, and 1 had RCUD.

RARS, refractory anemia with RS; RCMD, refractory cytopenia with mul6lineage dysplasia; RCUD, refractory cytopenia with unilineage dysplasia; RS, ring sideroblasts.

Ensayo fase III Sotatercept en ARSI (Celgene) •  ARSI o SMD de riesgo bajo con mutacion SF3B1 •  Luspatercept vs placebo

HL.18 The 9p24.1 amplicon also includes Janus kinase 2, and gene dosage-dependent Janus kinase 2/signal transducer and activator of transcription activity further induces PD-1 ligand transcription.18 These copy-number dependent mechanisms, as well as other less frequent rearrangements,19 lead to genetically determined overexpression of the PD-1 ligands on the RS cell surface. Epstein-Barr virus infection, also common in HL, is another mechanism of PD-L1 overexpression,20 consistent with the known ability of the virus to usurp the PD-1 pathway to allow viral persistence in the host.1 As a result of these two mechanisms (9p24.1 alterations and Epstein-Barr virus infection), a large proportion of classical HL tumors have increased surface expression of PD-L1.21 This strongly suggested that HL may have a genetic dependence on the PD-1 pathway for survival, and that targeting this pathway could effectively cripple the tumor’s ability to escape immune surveillance. HL was therefore included as an independent expansion cohort in both phase 1 studies, and the clinical results resoundingly validated the preclinical hypothesis. Both studies enrolled patients with multiply R/R HL, with a median of 4 to 5 lines of prior systemic therapy; most had had prior brentuximab and prior autologous stem cell transplantation (ASCT). Despite this, single-agent PD-1 blockade yielded overall response rates of 87% (with a complete response [CR] rate of 17%) and 65% (CR rate 5 21%) with nivolumab and pembrolizumab, respectively.16,17 Although the median follow-up is still short, many of the responses appear durable, with some patients now in continued remission for over a year.

Another important finding in both studies was the favorable safety profile in patients with HM, as was also demonstrated by prior studies of another anti–PD-1 mAb, pidlizumab.22-24 This is a salient result, as many patients on those studies had previously received other agents with potential lung toxicity, including radiation, highdose carmustine, and brentuximab vedotin, raising the concern that PD-1 blockade could lead to a high incidence of pneumonitis in this patient population. In fact, the incidence of pneumonitis in those trials, although not negligible, did not appear excessive, with 13 cases (including 3 severe and 1 fatal case) among 134 patients. Overall, the safety profile of PD-1 blockade in HM appeared similar to that in patients with solid tumors; the rate of severe (grade 3) drug-related adverse events was around 20% in both trials, and only 2 life-threatening (grade 4) and 1 fatal treatment-related toxicities were reported among 134 patients.16,17 PD-1 blockade therefore appears to be a tolerable treatment in HM. The clinical results in HL must be confirmed and extended in larger cohorts of patients with R/R disease; those studies are planned or already underway. Naturally, there is also interest in using PD-1 blockade earlier in the treatment course of patients, in an attempt to increase cure rates in high-risk patients, or to diminish the toxicity of treatment in lower-risk patients. In theory, PD-1 blockade, alone or in combination, could be used in frontline therapy or in early salvage, and those studies are highly anticipated.

anuscript

been shown that T cell expression of the immunoinhibitory receptor PD-1 is regulated by DNA methylation. In 12 of 27 patients (44%) PD-1 promoter demethylation was observed in sorted peripheral blood T cells isolated over consecutive cycles of treatment with 5-azacytidine (5-aza). The PD-1 promoter demethylation correlated with an increase in PD-1 expression. Moreover, demethylation of the PD-1 promoter Users may view, print, copy, download text and data- minerate the content in such documents, for the purposes of academic res correlated with a significantly worseand overall response (8% vs. 60%, p = 0.014), subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms and a trend towards a shorter overall survival (p = 0.11) was observed. A significantly Corresponding author: Guillermo Garcia-Manero MD,promoter Department was of Leukemia, University of Texas higher baseline methylation level of the PD-1 observed in T cells of MD Anderson Cancer Ce 1515 Holcombe Blvd., Houston, TX 77030, Phone 713 745 3428, FAX: 713 563 0289, ggarciam@mdanderson.org. non-responding patients compared to healthy controls (p = 0.023).

Conflicts of interest: The authors have nothing to disclose.

Accordingly, in addition to their beneficial function, HMAs induce PD-1 expression is available at Leukemia’s website. on TSupplementary cells in theinformation MDS microenvironment, thereby likely hampering the immune response against the MDS blasts. Thus, we suggest that activation of the PD-1 checkpoint during HMA treatment can be a possible resistance mechanism, which may be overcome by combination therapy with a PD-1 pathway inhibitor.

in patients with higher-risk MDS [2]. 5-azacytidine (5-aza) treatment has also prolonged overall survival (OS) in patients with AML with 20–30% bone marrow blasts [5], and decitabine (5-aza-2’deoxycytidine) has improved the response rates in older patients (> 65 yrs) with newly diagnosed AML [6]. In addition, HMAs are also approved by the U.S Food and Drug Administration and the European Medicines Agency for treatment of chronic myelomonocytic leukemia (CMML). Still, only about 50% of the HMA treated patients achieve a clinical response, the majority will lose response over time [2], and the outcome after HMA failure is poor with a median survival of only

INTRODUCTION Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders, characterized by increased proliferation and aberrant differentiation combined with a high rate of apoptosis [1]. This results in ineffective hematopoiesis and peripheral blood cytopenias as well as an increased risk of developing acute myeloid leukemia (AML). Compared to conventional care regimens, hypomethylating agents (HMAs) have resulted in improved outcomes in MDS [2–4], including delayed leukemic transformation [4] and prolonged survival www.impactjournals.com/oncotarget

9612

Oncotarget

Durvalumab (an6 PD-L1) en SMD-LMA (Celgene) •  Ensayo con AZA +/- Durvalumab en SMD de alto riesgo y LMA •  Ensayo con AZA oral (CC 486) +/- Durvalumab en SMD de alto riesgo resistentes a AZA

Grupo Francofono de las Mielodisplasias •  Activa ensayos clinicos en los SMD (35 centros en Francia y Belgica Suiza,) •  Website: www. gfmgroup.org •  Registro Online de los SMD franceses •  Estrecha cooperacion con: - una asociacion de pacientes con SMD - la International MDS Foundation - el European Leukemia Net

ALFA

contribute to a suppressive microenvironment that protects cancer cells from immune destruction.5–9 This has led to clinical efforts aimed at overcoming immune tolerance in cancer such as the monoclonal antibody (mAb) ipilimumab, a blocking mAb directly against the co-inhibitory T-cell receptor (TCR) cytotoxic T lymphocyte-associated antigen 4 (CTLA4).15 Other co-inhibitory molecules include programmed death-1 (PD-1) and its ligand, programmed death ligand 1 (PD-L1; B7-H1).16 Anti-PD-1 mAbs have produced responses in patients with solid tumors.17

ligands in myeloid leukemia pathogenesis and in mechanism of resistance to HMAs. MATERIALS AND METHODS Cell culture and treatment Human leukemia cell lines HL-60, NB4, THP1, U937, ML1, OCI-AML3 and HEL were cultured in RPMI-1640 medium. KG-1 cell line was maintained in IMDM medium. All cells were obtained from the

Department of Leukemia, University of Texas MD Cancer Center, Houston, TX, USA; 2Department of Hematopathology, University of Texas MD Cancer Center, Houston, TX, USA; Department of Molecular Carcinogenesis, University of Texas MD Cancer Center, Houston, TX, USA; 4Department of Hematologic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China and 5Department of Stem Cell Transplantation, University of Texas MD Cancer Center, Houston, TX, USA. Correspondence: Dr G Garcia-Manero, Department of Leukemia, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030 TX, USA. E-mail: ggarciam@mdanderson.org Received 25 October 2013; accepted 31 October 2013; accepted article preview online 25 November 2013 3

•  N= 124, CD34 + cells . •  upregula6on (x2-fold) of PD-L1,PD-L2,PD-1, CTLA 4 in 34, 14, 15 and 8% of the pa6ents •  Greater increase in MDS/CMML, compared to AML •  HMAs increase expression •  Greater expression associated with resistance to HMA •  Decitabine par6ally demethylates PD-1

the response rates in older patients (> 65 yrs) with newly diagnosed AML [6]. In addition, HMAs are also approved by the U.S Food and Drug Administration and the European Medicines Agency for treatment of chronic myelomonocytic leukemia (CMML). Still, only about 50% of the HMA treated patients achieve a clinical response, the majority will lose response over time [2], and the outcome after HMA failure is poor with a median survival of only

increased proliferation and aberrant differentiation combined with a high rate of apoptosis [1]. This results in ineffective hematopoiesis and peripheral blood cytopenias as well as an increased risk of developing acute myeloid leukemia (AML). Compared to conventional care regimens, hypomethylating agents (HMAs) have resulted in improved outcomes in MDS [2–4], including delayed leukemic transformation [4] and prolonged survival www.impactjournals.com/oncotarget

9612

Oncotarget

•  In 12 of 27 pa6ents , PD-1 promoter demethyla6on in sorted peripheral blood T cells isolated during AZA treatment •  PD-1 promoter demethyla6on correlated with an increase in PD-1 expression. •  demethyla6on of the PD-1 promoter correlated with signiﬁcantly worse response rate (8% vs. 60%, p = 0.014), and a trend towards a shorter overall survival (p = 0.11) •  higher baseline methyla6on level of the PD-1 promoter in T cells of non-responding pa6ents compared to healthy controls (p = 0.023)

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Benjamin L. Ebert, MD, PhD, Brigham and Women’s Hospital, 1 Blackfan Circle, Karp CHRB 5.211, Boston, MA 02115; e-mail: benjamin_ebert@dfci.harvard.edu. © 2014 by American Society of Clinical Oncology 0732-183X/14/3225w-2691w/$20.00 DOI: 10.1200/JCO.2013.52.3381

0.6

INTRODUCTION

Diagnosis and predicted prognosis of patients with myelodysplastic syndrome (MDS) are largely determined by morphologic and clinical measures.1,2 Recurrent somatic mutations, which are drivers of MDS pathogenesis and can be powerfully associated with clinical phenotype, are not currently incorporated into the routine clinical care of patients with this disorder.3,4 Somatic mutations are common in MDS,with#75%ofpatientscarrying"oneabnormality in the 30 most frequently mutated genes.5-7 Abnormalities in specific genes, such as NRAS, RUNX1, and TP53, have been associated with prognostically important variables, including elevated bone marrow blast proportion and severe thrombo-

cytopenia. Therefore, it is likely that acquired mutations could also predict response to specific interventions, such as treatment with hypomethylating agents or survival after hematopoietic stemcell transplantation (HSCT).8 Calculation of risks, benefits, and timing of HSCT is often difficult in MDS.9-11 Older age and comorbidities typical of patients with MDS are frequently associated with unacceptable risk of early death after transplantation. Even in younger and generally healthier patients, deciding when HSCT is appropriate can be challenging. In particular, patients with poor prognostic features may be directed to transplantation because they have few treatment options available or because standard therapeutics are not expected to provide durable responses. © 2014 by American Society of Clinical Oncology

2691

Overall Survival

the Yellow Diamond Foundation Fund (B.L.E.).

(95% CI, 9% to 33%) in patients with these mutations.

TET2 Day-100 landmark analysis (n ! 72) Karyotype (complex v other) Genetic mutation (present v absent) TP53 DNMT3A

0.4 0.2

2.29

2.85

3.78 2.62

Abbreviations: HR, hazard ratio; OS, overall surv ! Final model obtained from backward-eliminatio dates included variables with univariable P " .20

Time (months)

B Overall Survival (probability)

No. R01HL082945, a Leukemia and Lymphoma Society scholar award, and

1.0

Not complex (n = 59) Complex and TP53 unmutated (n = 12) Complex and TP53 mutated (n = 16)

0.8 0.6 0.4 0.2

Time (months)

C Overall Survival (probability)

Heart, Lung, and Blood Institute Grant

1.0

TP53 mutated (n = 18) TET2 mutated, no TP53 (n = 10) DNMT3A mutated, no TP53 or TET2 (n = 12) No TP53, TET2, or DNMT3A mutations (n = 47)

0.8 0.6 0.4 0.2

Time (months) TP53

TET2

DNMT3A

www.jco.org

these genes were found in nearly one half Mutations of other genes associated with studies, such as RUNX1, ASXL1, SRSF2, and ated with differences in OS in our cohort o HSCT (Data Supplement).3,22-24 This may disease-modifying effects of conditioning a cause of the fact that the prognostic signific tions is more pronounced in lower-risk pat few in this study. In contrast, TP53 mut prognostic value, even in higher-risk patie they are most commonly found.3,21 The DNMT3A and TET2 genes encode regulate DNA methylation, and both are rec acute myeloid leukemia, and other hema acute myeloid leukemia, mutations of bo patients with intermediate-risk karyotypes poor prognosis.25,26 In MDS, the clinical mutations is less clear but also seems to be u mutations are not associated with survival.5 DNMT3A mutations are relatively promisc with other mutated genes that can predict o a study of lower-risk patients with MDS, D not associated with OS in univariable DNMT3A-mutant/SF3B1-wild-type subgro In our transplantation cohort of largely hi mutations were rare, and most DNMT3 SF3B1 wild type (88%). DNMT3A and TET2 mutations identi samples were largely from patients withou known to predict poor outcome. Most of th complex karyotype and were not more likel marrow blast percentage before transplan found that patients with a TET2 or DNMT creased risk of relapse and death after tra when other predictive variables were cons consideration of TET2 and DNMT3A mut dict the risk of mortality in patients with M In MDS, TP53 mutations have long be with karyotype, elevated bone marrow bla thrombocytopenia.3,29-31 Despite these link verse clinical features, TP53 mutations hav

© 2010 Elsevier for Ltd. All reserved. response to ESA), was adjusted Hbrights level, serum EPO level, intertype. The lack of response to ESA in our cohort predicted a hig val between diagnosis and onset of ESA and WHO classification. 2.1. Patients of progression to AML and short For duration incidence of response and time to transfusion dependency the survival, suggesting 1. Introduction Anemia, even if it does notmodel requirewas red blood cell (RBC) transfu-EPO level, interval multivariate Cox adjusted on serum ESA resistance is a marker of relatively aggressive disease eve We recently reported results of treatment with ESA between 1998 and May sions, is associated with an increased incidence of cardiac failure between diagnosis and onset of ESA and WHO diagnosis. To iden“Lower risk” myelodysplastic (MDS), that include 2006 in 403 MDS anemic patients (Hb < 10syndromes g/dl, requiring or not RBC transfusions) and lower quality of life in MDS [1,2–4]. In [6,19]. addition, heavily lower risk MDS On the other hand, early or late onset of tifyMDS any patients possiblehave selection effect of increasing duration of diagnosis withBelgian low and intermediate-1 riskFrancophone according todes theMyélodysplasies Internafrom 25patients French and centers of the Groupe transfused low response rates to erythroid intreatment, the report seems have no influence on progressio Scoring System have who relatively prolonged (GFM) tional [6]. WePrognostic selected, in that cohort, de (IPSS) novo cases had never required RBC to treatment time, wepresent added time onset ESA as ato covariate in the stimulating agents (ESA) especially iftothey have high survival. of below cytopenias, especially anemia, and and of no 5q transfusions, hadImprovement serum EPO level 500 U/l, low or int-1 IPSS score endogenous EPO level analysis, [5]. Thusand there is an increasing multivariate comparing patient tendency groups with time to onset AML survival. quality of life are major targets in those deletion. If karyotype (andtherefore thereforethe IPSS) was treatment not available, less than 5% marrow to treat ESA anemia of 1–6, MDS 6–18 patients with ESA than earlier18 in months, the diseaserespectively in the 0–1, and more The higher rate and longer response duration a patients. blasts and isolated anemia (with no other cytopenia) were required (as IPSS in those course, before RBC transfusions are required, in response order to maximize multivariate analysis. patients would be low or int-1, irrespective of karyotype).

2. Patients and methods

ciated with early onset of ESA (within 6 months of diagno appeared to determine the fact that the interval from diagnosi RBC transfusion dependency was longer in those patients. To id tify any possible selection effect of increasing duration of diagn to treatment time, we had added time to onset ESA as a covar in the multivariate analysis, comparing patient groups with t ing to WHO classification (Table0–1, 1). Karyotype was favorable in 80than 18 months, resp to onset ESA 1–6, 6–18 and more patients, intermediate in 15 and not done or a technical failure in tively in the multivariate analysis, and the same tendency 17 patients. IPSS was low in 39 patients, int-1 in 56 and unavailable found with kind17 ofpatients, analysis. Those results were however so (lack of cytogenetics) in the this remaining who had fewer than 5% marrow blasts and isolated anemia (Table 1). may have expected that patie what unexpected. Indeed, one Median interval between diagnosis and onset of treatment with delayed onset of ESA were those who had slower evolu with ESA+/− G-CSF was 5.5 months (range 0–64 months). Median of diagnosis anemia,was slower disease progression and who could have pot follow-up from 99 months. At onset of ESA, median Hb level was 9.2 g/dl responded (range 8.0–10),better median to endogenous EPO level date of onset of ESA tially ESA. Although was 51 UI/l (range 10–397 UI/l) and median serum ferritin level a possible effect of not randomized, this finding could suggest 440 ng/ml (range 46–1396 ng/ml) (n = 86). in slowing down the evolution of anemia in lower risk MDS. prevent apoptosis and sustain erythroid differentiation of 4.2. Responsecan to ESA and its prognostic factors throid precursors [20–22]. In vitro, high levels of rhEPO indu Eighteen (16%) patients received epoetin alfa alone, 29 (27%) significant increase of EPO-sensitive progenitors cells [12,23]. epoetin beta alone, 33 (31%) DAR alone, 12 (10%) epoetin alfa + Gresultsbeta could suggest rhEPO is able to preferentially stimu CSF, 10 (8%) epoetin + G-CSF and 10that (8%) DAR + G-CSF. G-CSF was thereforeresidual used in 32normal (28%) of the patients. cells over abnormal clones in MDS [24], and The response at 12 could weeks was according to IWG 2006 thisrate effect be 63% more pronounced early in the disease cou criteria (and 74.1% according to IWG 2000 criteria, including 57.1% before decrease the normal progenitor compartment is major and 17% minorthe responses). In in univariate analysis, using

the efficacy of ESA and improve quality of life. 112 patients from the original cohort, who fulfilled those criteria, form the basis ESA, although they can improve anemia of lower risk MDS, are of the present study (Fig. 1). Patients were classified using WHO criteria. Treatment ∗ Corresponding author at: UF d’hématologie, Hôpital Cochin, Université Paris 5, 4.considered Results to have no influence on the disease course, generally consisted of epoetin alfa or beta without G-CSF), at weekly doses of 60,000contrary U 27 rue du Fb St Jacques, 75014(with Paris, or France. Tel.: +33 158 412 131; to drugs like hypomethylating agents. We analyzed the fax: +33 158 412 090. or Darbepoetin (DAR, with or without G-CSF), at weekly doses of 300 !g, during outcome at of 112 lower risk MDS patients with anemia treated with 4.1. Baseline patient characteristics E-mail address: (S. according Park). least 12 1weeks, as part sophie.park@cch.aphp.fr of GFM trials [7–9], or to GFM recommendations an ESA before requiring RBC transfusions to see whether early onset For the GFM group (Groupe Francophone des Myélodysplasies). (http://www.gfmgroup.org/). G-CSF was added after 12 weeks, as an add-on in case of no response, and thefront response ESA +Elsevier G-CSFLtd. was after 12 more weeks Median age of the 112 pts was 75 years (range 41–91), including 0145-2126/$ – see matter to © 2010 Allevaluated rights reserved. of treatment. doi:10.1016/j.leukres.2010.05.030 21 RA, 22 RAEB-1, 34 RARS, 19 RCMD, and 16 RCMD-RS accord-

3. Methods 3.1. Endpoints Erythroid response was evaluated after 12 weeks of treatment, using International Working Group IWG 2006 response criteria [10]. Duration of response to ESA was measured, in agreement with IWG 2006 criteria, between achievement of response to ESA and transfusion dependency or reduction in Hb level by >1.5 g/dl. Time to RBC transfusion dependency was measured from diagnosis to first RBC transfusion (not due to concurrent causes). RBC transfusions were to be performed according to French Health agency (AFSSAPS) recommendations (http://www.afssaps.fr/Afssapsmedia/Publications/Recommandations-de-bonne-pratique) e.g. if Hb < 8 g/dl, or higher in case of underlying comorbidities or anemia-related symptoms. However, for the purpose of the present analysis, and in agreement with IWG 2006 response criteria for MDS, only RBC transfusions performed when Hb levels <9 g/dl were considered. AML transformation was defined by the presence of at least 30% marrow blasts or 20% circulating blasts. Time to AML and overall survival (OS) were measured from ESA

IWG 2006 criteria, EPO level < 100 U/l was associated with higher

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Table 2: Prognostic factors at the time of hypomethylating agent failure Parameter at HMA failure

Score

Beta

P-Value

ECOG Performance status > 1

1.0

.56

.01

Very poor Cytogenetic Category

1.0

.57

< .001

> 75 - < 84

1.0

.52

< .001

> 84

2.0

.90

< .001

Bone Marrow Blast > 20 %

.75

.36

.01

Transfusion dependent (yes vs no)

.75

.39

< .001

1.0

.54

< .001

Age at diagnosis, years

•

455 higher-risk disease with HMA failure; 314 (69.0%) were treated with AZA and 141 (31.0%) with DAC •  6 factors predictive of OS at the time of HMA failure •  The new model (the post HMA model) identified two risk groups: Low: score < 2.25, median OS 11.0 months high: score > 2.25 and median OS 4.5 months Platelets

< 30

Marrow CR

0/7

3/5 (60)

3/12 (25)

‡

RBC TI Sustained for 56 days 5/16 (31) 6/16 (38) 11/32 (34) Sustained for 84 days 2/16 (13) 5/16 (31) 7/32 (22) Platelet TI‡ 0/4 0/2 0/6 IWG 2006 criteria28 *Patients are counted only once for Overall Response, but may be counted more than once in individual response categories. Marrow CR (mCR) was not included in Overall Response. Lower-risk 23 July 2015; revised were 2 September 2015; for accepted 16 September 2015; patients with < 5%Received bone marrow blasts at baseline not evaluable CR or PR. Accepted article preview online 7 October 2015 † Subjects who had a CR are not counted for PR, any HI, or marrow CR. ‡ To be evaluated for RBC TI, patients must have been RBC transfusion-dependent at baseline and been on-study at least 56 days. transfusion dependence baselineAll wasrights defined as receipt of ≥ 4 © RBC 2015 Macmillan PublishersatLimited. reserved. units of packed RBC within 56 days of the first dose of CC-486. §To be evaluated for platelet TI, patients must have been platelet transfusion-dependent at baseline and been on-study at least 56 days. Platelet transfusion dependence at baseline was defined as receipt of ≥ 2 platelet transfusions within 56 days of the first dose of CC-486. CR = complete remission; PR = partial remission; HI = hematologic improvement; HI-E = hematologic improvement-erythroid; HI-P = hematologic improvement-platelet; HI-N = hematologic improvement-neutrophil; TI = transfusion independence; IWG = International Working Group.

matopoiesis.1,2 Progressive hematopoietic failure may lead to anemia, thrombocytopenia, and leukopenia. The prognosis of patients with MDS is poor; patients die either from complications associated with cytopenias (infections and bleeding) or from transformation to acute myeloid leukemia (AML), which occurs in 10% to 70% of patients, more commonly in higher-risk patients.3 The median time to 25% AML progression differs by International Prognostic Scoring System (IPSS) risk group: lowrisk patients, 9.4 years; intermediate-1–risk patients,

count " 20 ! 109/L) at presentation has been documented in approximately 12% of patients with low or intermediate-1 risk MDS.5 Platelet function may be abnormal in MDS patients,6,7 making the presence of moderate to severe thrombocytopenia of greater concern.5,6 Thrombocytopenia is an independent adverse prognostic factor for survival in MDS,8 and increased severity of thrombocytopenia correlates with shorter time to AML progression.9 Platelet transfusions are the only current treatment option, © 2009 by American Society of Clinical Oncology

437

•  •  •  •  •

N=44, lower risk MDS platelets <50G/l 300 to 1500 ug/week Evalua6on at week 4 HI-P (IWG 2006) –  if baseline platelets >20 ︎ 109/L: Increase > ︎ 30 ︎ G/ –  if baseline platelets <20 ︎ 109/L: increase by at least 100%. ︎ 8 consecu6ve weeks

1, Hoˆpital Universitaire de Rennes, Rennes, Service de me´decine interne, Universite´ Limoges, Hoˆpital Limoges, Limoges, 5Universite´ Paris Descartes, AP-HP, Hoˆpital Cochin, Centre de re´fe´rence maladies auto-immunes et syste´miques rares, service de me´decine interne, Paris, 6Service de me´decine interne, Hoˆpital Foch, Universite´ Versailles Saint Quentin en Yvelines, Suresnes, 7Service de me´decine interne, Hoˆpital Nantes, Universite´ Nantes, Nantes, 8Service d’he´matologie clinique, Hoˆpital La Tronche, Grenoble, 9Centre Investigation Clinique Biothe´rapie CIC-1431 & Service de rhumatologie, CHU Besanc¸on, Besanc¸on, 10USPC Universite´ Paris 13, INSERM, APHP; UMR 1125, service de rhumatologie; Hoˆpital Avicenne, 125 route de Stalingrad, 93009 Bobigny, 11Service de me´decine interne, CHU Lille, Universite´ Lille II, Lille, 12Service de me´decine interne, Hoˆpital Henri Mondor, Aurillac, 13Service de me´decine interne, Hoˆpital Pitie´ Salpetrie`re, Universite´ Paris 6, AP-HP, Paris, 14Service de me´decine interne et rhumatologie, Groupe hospitalier La Rochelle Re´ Aunis, La Rochelle,15Service de me´decine interne, Hoˆpital de Tours, Universite´ de Tours, Tours, 16Service de me´decine interne et ge´riatrique, CHU Nıˆmes, Nıˆmes, 17Service de me´decine interne, CH Douai, Douai,

Universite´ Nord de France, Lille, 23Service de rhumatologie, CH Croix Saint Simon, 24Service de maladies infectieuses, Hoˆpital Necker, Universite´ Paris 5, AP-HP, Paris, 25Biostatistics, eXYSTAT SAS, Levallois-Perret, 26Service de rhumatologie, CH Romilly/Seine, 27 Service de me´decine interne, Hoˆpital de Rochefort, Rochefort, 28 Service d’he´matologie, Hoˆpital Necker, Universite´ Paris 5, APHP, Paris, 29Service d’he´matologie clinique, Universite´ Rennes 1, Hoˆpital Universitaire de Rennes, Rennes and 30Service d’he´matologie clinique, Hoˆpital Saint-Louis, AP-HP, Universite´ Paris 7, Paris, France.

Submitted 14 November 2014; revised version accepted 16 July 2015 Correspondence to: Olivier Fain, AP-HP, Hoˆpital Saint Antoine, service de medicine interne and Inflammation!Immunopathology!Biotherapy Department (DHU i2B), F-75012 Paris, France. E-mail: olivier.fain@sat.aphp.fr *Pierre Fenaux and Olivier Fain contributed equally to this study.

•  123 patients with both MDS and SAID •  Autoimmune disease : systemic vasculitis (32%), connective tissue disease (25%), inflammatory arthritis (23%), neutrophilic disorder (10%) and unclassified (11%)….Often incomplete features •  MDS occurring, before, after or concomitantly with SAID •  MDS subtypes variable , but younger age, fewer males, more severe features, no RARS •  Survival identical in MDS with and without SAID

11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57

Low risk MDS

High risk MDS Progression

t em c S ation i e gen lant Allo ransp T

Anomalias del sistema inmunologica en SMD Flt3 inh

ibitors

enet Epig

ugs ic dr

T Ca RAI sp L i as nh e i ibi nh t o ib rs ito rs

Apoptosis Th17 TRAIL Caspase

Tregs

ee r

eneti Epig

Immune evasion

Feature(s)

TNF-Îą IL-2

DLI i nf e tokin ti-cy py Ado n A a pt tran ther sfer ive of T regs c drugs Epigeneti

vie w

Tregs

e p ti v p y fusion Cytokine in Ado thera therapy cell NK

Monoclo Ab. ther

IDO inhibit

NK cells

usion s

c dru

en antig e v i t p Ado loaded apy ther C D