Special Report – Haematological Malignancy

SPECIAL REPORT

Haematological Malignancy Watch and Wait vs. Palliative Therapy and Supportive Care Treatment Options for Patients with Newly-Diagnosed Haematological Malignancy Practice Points Haematological Malignancies: A Primary Care Perspective Leukaemia Lymphoma Diagnostic Awareness

Published by Global Business Media

Leukaemia & Lymphoma Research is the only UK charity solely dedicated to research into blood cancers, including leukaemia, lymphoma and myeloma.

Our life-saving research is focused on finding causes, improving diagnosis and treatments and running groundbreaking clinical trials for all blood cancer patients. Blood cancers including leukaemia, lymphoma and myeloma affect people of all ages from babies to grandparents. We need to be sure that we reach all those touched by leukaemia, lymphoma and myeloma and give them the best possible chance of survival.

Leukaemia & Lymphoma Research 39-40 Eagle Street, London WC1R 4TH Tel: 020 7405 1010 Fax: 020 7405 3139 Email: info@beatbloodcancers.org www.beatbloodcancers.org Press team: Tel: 020 7269 9019 Email: press@beatbloodcancers.org

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SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY

SPECIAL REPORT

Haematological Malignancy Watch and Wait vs. Palliative Therapy and Supportive Care

Contents

Treatment Options for Patients with Newly-Diagnosed Haematological Malignancy Practice Points Haematological Malignancies: A Primary Care Perspective Leukaemia

FOREWORD

2

Martin Richards, Editor

Lymphoma

WATCH AND WAIT FOR HAEMATOLOGICAL MALIGNANCY

Diagnostic Awareness

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Ken Campbell, Clinical Information Officer, Leukaemia & Lymphoma Research, London Published by Global Business Media

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Watch and Wait vs. Palliative Therapy and Supportive Care Treatment Options for Patients with Newly-Diagnosed Haematological Malignancy Indolent Haematological Malignancies Leukaemia Non-Hodgkin Lymphoma Myeloma Myelodysplastic Syndromes and Myeloproliferative Neoplasms Prodromal Conditions Practice Points

References HAEMATOLOGICAL MALIGNANCIES: A PRIMARY CARE PERSPECTIVE

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Ken Campbell, Clinical Information Officer, Leukaemia & Lymphoma Research

Epidemiology The Diseases Leukaemia Lymphoma Other HM Diagnostic Awareness Children Adults Indolent Haematological Malignancies Aggressive Haematological Malignancies Myeloma

Liaison with Secondary and Tertiary Care Facilities Clinical Management of Patients in the Primary Care Setting References

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SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY

Foreword

E

ach year in the UK, several thousand patients are diagnosed with blood cancers but are told that they will not receive any treatment,

possibly for many years or even decades. Some patients will never require treatment; in other cases the disease will eventually show signs of progressing indicating a need to start treatment. Most patients in this situation will have chronic lymphocytic leukaemia or indolent lymphoma – a smaller proportion will have very early stage myeloma. The common feature is that, unlike most solid tumours, these conditions are widely disseminated at the time of diagnosis and there is no point at which early treatment has a high chance of eradicating the disease and achieving cure.

Even in the case of lymphoma where there are discrete anatomical lesions, there are malignant cells within the circulation even at the earliest stages.

The practice of deferring treatment, known as watch and wait, should be distinguished from palliative care. Patients who are on watch and wait have treatable conditions and the decision not to treat is based on good quality studies indicating no benefit from early treatment. Palliative care is intended purely to suppress symptoms and signs of the condition, although this may prolong survival, it has no direct impact on the disease process. In patients who transition from watch and wait to active treatment, their treatment is in almost all cases, definitive therapy.

Patients being managed on a watch and wait may experience stress, as may family members. They will need careful monitoring for signs of progression and may have disease-related problems such as fatigue or relative immunosuppression. Primary care practitioners can offer valuable support, both in psychosocial care and in medical monitoring of these patients.

Martin Richards Editor

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SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY

Watch and Wait for Haematological Malignancy Ken Campbell, Clinical Information Officer, Leukaemia & Lymphoma Research

Although there are exceptions, for most solid cancers there is a consensus that early treatment is indicated; this is particularly the case in cancers with a high risk of metastasis. If the cancer is removed while disease is localised there is a much higher cure rate than when secondary tumours are present.

Watch and wait refers to deferred treatment

Leukaemia & Lymphoma Research is the only UK charity solely dedicated to research into blood cancers, including leukaemia, lymphoma and myeloma.

for a condition, usually based on published data showing that there is no clear benefit from early treatment

F

or a number of haematological malignancies a policy of “watch and wait” is preferred. Even though this approach is based on high quality clinical studies which show no survival benefit from early treatment, patients still may be anxious about by being told that they have a cancer diagnosis but that they are to receive no treatment. Many patients refer to this as “watch and worry”. Alternative terms are sometimes used to reduce anxiety; examples are “watchful monitoring” or “active monitoring” or “expectant management”.

This article will discuss the basis for watch and wait and the difference between this and palliative care; briefly describe those haematological malignancies for which a watch and wait policy is commonly applied; describe the criteria for when to start treatment and indicate what special considerations may apply to primary care of such patients.

Watch and Wait vs. Palliative Therapy and Supportive Care The distinction between watch and wait and palliative and supportive therapy is critically

important. Watch and wait refers to deferred treatment for a condition, usually based on published data showing that there is no clear benefit from early treatment; it does not relate to the fitness of the patient to undergo treatment.

Palliative therapy is offered to a patient for whom the potential benefits of more disease-directed treatment are insufficient to offset the sideeffects of definitive treatment. Palliation (from Latin palliare – to cloak) is aimed at alleviating symptoms of the disease. Supportive care refers to treatments such as transfusion (RBC or platelet) or infection prophylaxis or treatment.

Supportive care often forms a major part of palliative therapy, but is also a key element of definitive treatment. Much of the improvement in survival for haematological malignancy is thought to derive from improvements in supportive care lowering the treatment-related mortality (TRM).

Palliative therapy may be offered to a patient with an aggressive malignancy if the patient is too unfit, through advanced age and/or comorbidity, to receive definitive therapy. It may also be offered if a patient is deemed unlikely to survive for long, even with definitive treatment.

The central consideration in palliative therapy is

Our life-saving research is focused on finding causes, improving diagnosis and treatments and running groundbreaking clinical trials for all blood cancer patients. Blood cancers including leukaemia, lymphoma and myeloma affect people of all ages from babies to grandparents. We need to be sure that we reach all those touched by leukaemia, lymphoma and myeloma and give them the best possible chance of survival.

Leukaemia & Lymphoma Research 39-40 Eagle Street, London WC1R 4TH Tel: 020 7405 1010 Fax: 020 7405 3139 Email: info@beatbloodcancers.org www.beatbloodcancers.org Press team: Tel: 020 7269 9019 Email: press@beatbloodcancers.org

Scotland Office Leukaemia & Lymphona Research 24D Milton Road East, Edinburgh EH15 2NJ Tel: 0131 669 7862

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On the basis of their natural history, haematological malignancies can be broadly divided into aggressive and indolent conditions.

to maintain quality of life; palliative therapy will, in many cases, prolong survival, but this is not the principal objective. It is important to emphasize to patients that palliative therapy and end of life care are not synonymous – a patient may sometimes spend a prolonged period receiving palliative therapy before entering the terminal phase of their condition.

Treatment Options for Patients with Newly-Diagnosed Haematological Malignancy • Definitive Therapy – Directed at the underlying disease process, whether or not aimed at cure – Typically a higher toxicity than palliative care; may not be feasible for some patients • Palliative Therapy – Aimed at controlling symptoms – May prolong survival but this is not the primary aim – Quality of life is typically the deciding factor in choice of treatment • Supportive Care – Aimed at limiting adverse effects of disease and/or treatment – Prevention and effective therapy for anaemia, infections, etc.

– Component of both definitive and palliative therapy – Effective supportive care is crucial in reducing mortality and morbidity • Watch and wait – Evidence-based elective decision to defer initial therapy – Not therapeutic nihilism, based on risk/benefit analysis not on cost or availability of therapy – A patient receiving palliative or supportive care is not, by definition, on watch and wait Confusion may be caused by the use of the term “watch and wait” to cover monitoring of patients who have received definitive therapy. Here the choice is between consolidation treatment, also called maintenance, and observation. In this article the term always refers to management of the newly diagnosed patient.

Indolent Haematological Malignancies The principal considerations in deciding whether watch and wait is appropriate are the natural history of the patient’s condition and the 4 | WWW.PRIMARYCAREREPORTS.CO.UK

evidence base for benefit (or harm) from early treatment. On the basis of their natural history, haematological malignancies can be broadly divided into aggressive and indolent conditions.

Acute leukaemias and certain forms of nonHodgkin lymphoma (NHL) tend to develop rapidly and, if not effectively treated, will progress rapidly.

Before the development of effective treatments patients with these conditions rarely survived longer than a few months. Int contrast, indolent malignancies develop slowly and, even without treatment, they progress slowly with patients commonly surviving for years or even decades.

The indolent group includes; • Chronic lymphocytic leukaemia, • Low-grade NHL, • Smouldering myeloma • Most cases of myelodysplastic syndromes (MDS) and • Most cases of myeloproliferative neoplasms (MPN).

Watch and wait is appropriate for many patients with indolent malignancies; a proportion of patients with more aggressive disease may also qualify for watch and wait. The essence of the treatment approach is not therapeutic nihilism; it is to only treat early where clinical trials have shown benefit from so doing.

Both myeloma and chronic lymphocytic leukaemia are preceded by clinically silent prodromal conditions, monoclonal gammopathy of undetermined significance (MGUS) and monoclonal B-lymphocytosis (MBL) respectively.

Although monitoring of these conditions is not defined as watch and wait, they are briefly described here for completeness and because there may be some overlap with early stage myeloma or CLL respectively.

Leukaemia Although there are many sub-types of leukaemia, these all fall within four major groups: • Acute lymphoblastic leukaemia • Acute myeloid leukaemia • Chronic lymphocytic leukaemia • Chronic myeloid leukaemia Acute leukaemia may be managed palliatively if a patient is frail elderly or has co-morbidities which would preclude offering definitive therapy; it is never managed on a watch and wait basis. If the patient is fit enough to receive treatment then this will commence soon after diagnosis. An attempt to manage acute leukaemia by watch and wait would result in early and severe morbidity; even if palliative care may not extend survival it can mitigate morbidity due to the leukaemia.

Chronic myeloid leukaemia is also never managed by watch and wait, even though the natural history of the disease is indolent – prior to the introduction of effective definitive

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Typical morphology of CLL cells in peripheral blood (http://www.flickr.com/photos/euthman/2869815349)

chemotherapy using imatinib median survival was on the order of 7 years. The reason for not delaying therapy is the fact that, when left untreated, the disease will enter a more aggressive phase which is less responsive to chemotherapy. It is not possible to predict when an individual patient’s condition will progress. Disease transformation may occur within the first year after diagnosis – for this reason it is normal to start treatment very soon after diagnosis. The side-effect profile of imatinib and related drugs is sufficiently mild that even frail patients will usually be given definitive treatment.

Chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia in the Western population and is the only form of leukaemia for which watch and wait is recommended. There are about 3 300 cases each year in the UK. Most patients with CLL have an indolent form of the disease and a significant proportion of patients never require treatment. An oft-used description of CLL is that, “Many patients die with CLL, not from it.” A number of studies have reported that there is no survival benefit from early treatment.

A recent review in Blood1 by John Gribben offers a detailed description of management of newly diagnosed CLL. Gribben describes CLL thus, “CLL is extremely heterogeneous in its clinical course; some patients live for decades with no need for treatment for their disease, whereas others have a rapidly aggressive clinical course.” One of the questions posed in this review was whether watch and wait should continue to be the preferred management for most newly diagnosed patients. A metaanalysis of trials enrolling more than 2 000 patients showed no benefit from early vs. deferred treatment; there was a slight trend to poorer survival in the early treatment group2. A

caveat to this finding is that the patients in the trials analysed were treated with alkylating agents whereas the preferred up front treatment now uses newer drugs with lower systemic toxicity.

A second consideration is the developing use of biomarkers to predict which patients will experience early progression – a discussion of this is beyond the scope of this article – see the recent reviews by Bockstaele et. al. and Butler and Gribben.3 Treatment is normally initiated in response to; • Symptomatic disease, • Bulky lymphadenopathy and/or splenomegaly, • Risk of local compressive disease, • Marrow compromise, or • Rapid disease progression.

It is possible that practice will change with increasing availability of prognostic screening tests which may enable earlier recognition of patients who disease is likely to progress rapidly. In Europe the most widely used staging system is called the Binet system and the earliest recognized is stage A, in the US the Rai system is more widely used, in which the earliest stage is stage 0. Watch and wait would be reserved for stages A or 0; some stage A/0 patients would now be identified as having MBL rather than CLL – MBL is discussed below as a prodromal condition.

Patients who have CLL and are being managed on watch and wait are normally seen around every 3 to 4 months initially, then less frequently if their condition remains stable. Between haematology consultations the primary care health team should be alert for any indications that their condition may be progressing. Gribben specifically mentions: • development of night sweats, • increasing adenopathy at one site, or • elevated lactate dehydrogenase

Leukaemia & Lymphoma Research is the only UK charity solely dedicated to research into blood cancers, including leukaemia, lymphoma and myeloma.

Our life-saving research is focused on finding causes, improving diagnosis and treatments and running groundbreaking clinical trials for all blood cancer patients. Blood cancers including leukaemia, lymphoma and myeloma affect people of all ages from babies to grandparents. We need to be sure that we reach all those touched by leukaemia, lymphoma and myeloma and give them the best possible chance of survival.

Leukaemia & Lymphoma Research 39-40 Eagle Street, London WC1R 4TH Tel: 020 7405 1010 Fax: 020 7405 3139 Email: info@beatbloodcancers.org www.beatbloodcancers.org Press team: Tel: 020 7269 9019 Email: press@beatbloodcancers.org

Scotland Office Leukaemia & Lymphona Research 24D Milton Road East, Edinburgh EH15 2NJ Tel: 0131 669 7862

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Many clinicians would offer all eligible patients an opportunity to take part in a clinical trial if they are eligible.

Cut surface of lymph node replaced by follicular lymphoma (http://en.wikipedia.org/wiki/File:Lymphoma_macro.jpg)

Non-Hodgkin Lymphoma Non-Hodgkin lymphoma is the fifth most common cancer in the developed world – in the UK there are about 9000 newly diagnosed patients with NHL each year. A broad, clinically based, classification of the many sub-types is between indolent (low-grade) and aggressive (high-grade).

• Indolent – Slow onset; often diagnosed at late stage – Long survival period without therapy (many years) – Frequently a rapid response to treatment – Typically relapses with shortening duration of intermission – Not curable in the majority of cases • Aggressive – Rapid onset; commonly presents at early stage – Progress rapidly without effective therapy – High probability of cure if chemo/ radio-sensitive The WHO classification of blood cancers4 is the most widely used; within this schema the indolent forms of NHL are: • Follicular lymphoma • Small lymphocytic lymphoma • Marginal zone B-cell lymphoma, mucosa-associated lymphoid tissue type • Marginal zone B-cell lymphoma, nodal type • Lymphoplasmacytic lymphoma Together, indolent forms make up about one-third of all NHL. The standard of care for patients with newly diagnosed indolent NHL is “expectant 6 | WWW.PRIMARYCAREREPORTS.CO.UK

management for asymptomatic patients with low-bulk disease”; and to “initiate treatment in patients with symptomatic disease, bulky lymphadenopathy or splenomegaly or both, risk of local compressive disease, marrow compromise, or rapid disease progression”5.

Many clinicians would offer all eligible patients an opportunity to take part in a clinical trial if they are eligible. It may be confusing for patients that their options may consist of “do nothing” or undergo relatively high-risk treatment such as a stem cell transplant; support from the primary care team can be of great value.

Patients on expectant management would typically be reviewed in clinic at 3-monthly intervals with history, physical examinations and bloods including LDH. Clinical indicators of possible transformation from indolent to aggressive NHL include fast growing of lymph nodes, pleural effusions or superior cave vein syndrome6. Transformation is an indication for immediate initiation of treatment so the primary care team should treat any suspicion of this as grounds for an immediate emergency referral.

Myeloma Myeloma is about as common as indolent NHL with about 3 500 new cases in the UK each year.

As with several other conditions, there is an increasing trend for early, incidental diagnosis as more people undergo “well-person” medical reviews, which means that many patients are asymptomatic at diagnosis. A recent “review of reviews” stated that “The results from the overview show that early treatment does not offer survival benefit.”7 The crucial considerations for initial management of myeloma are whether the patient is symptomatic and whether there is

SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY

Plasma cells in peripheral blood (http://en.wikipedia.org/wiki/File:PCL.jpg)

evidence of myeloma related organ or tissue damage (ROTI). ROTI includes hypercalcaemia, renal damage, anaemia and bone lesions – easily remembered by the acronym CRAB. Standard management for a patient who is asymptomatic and has no ROTI is watch and wait8. Monitoring is usually at three-monthly intervals. Symptoms which may indicate progression, and therefore justify emergency referral include: • Bone disease • Impaired renal function • Anaemia • Hypercalcaemia • Recurrent or persistent bacterial infection • Hyperviscosity Spinal cord compression, hypercalcaemia and renal failure are medical emergencies requiring immediate investigation and treatment. Signs of spinal cord compression include9: • pain (both local and radicular), • weakness, • paraesthesias,

Leukaemia & Lymphoma Research is the only UK charity solely dedicated to research into blood cancers, including leukaemia, lymphoma and myeloma.

• loss of bladder or bowel function • ataxia

Myelodysplastic Syndromes and Myeloproliferative Neoplasms The myelodysplastic syndromes are “…clonal bone marrow disorders that lead to underproduction of normal blood cells.

The consequent cytopenias result in infections and bleeding complications. MDS transform to acute myeloid leukemia in one-third of patients.”10 Almost all MDS patients will require transfusional support at some supportive rather than disease-oriented. The deciding factor for a change from watch and wait to treatment is, therefore, usually the development of anaemia severe enough to impinge upon performance status.

The myeloproliferative neoplasms (MPN) are essential thrombocythaemia (ET), polycythaemia vera (PV) and primary myelofibrosis (MF). For both PV and ET thrombosis is the primary MPN

Our life-saving research is focused on finding causes, improving diagnosis and treatments and running groundbreaking clinical trials for all blood cancer patients. Blood cancers including leukaemia, lymphoma and myeloma affect people of all ages from babies to grandparents. We need to be sure that we reach all those touched by leukaemia, lymphoma and myeloma and give them the best possible chance of survival.

Leukaemia & Lymphoma Research 39-40 Eagle Street, London WC1R 4TH Tel: 020 7405 1010 Fax: 020 7405 3139 Email: info@beatbloodcancers.org www.beatbloodcancers.org Press team: Tel: 020 7269 9019 Email: press@beatbloodcancers.org

Scotland Office Leukaemia & Lymphona Research 24D Milton Road East, Edinburgh EH15 2NJ Tel: 0131 669 7862 Dysplastic megakaryocyte in marrow of patient with myelodysplastic disorder

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The wider use of laboratory testing of apparently healthy individuals is likely to lead to an increasing number of patients being diagnosed with precursor syndromes or early stages of a haematological malignancy.

related causes of death11; for this reason, even asymptomatic patients are likely to be started on prophylactic medication and thus cannot be considered to be on watch and wait. Patients with MF are dealt with in essentially the same way as MDS patients; at such time as they develop anaemia which limits activities of daily living (ADL) they are started on a transfusion regimen. Until transfusion becomes necessary, which it almost always does, they are actively monitored.

Prodromal Conditions As mentioned, both CLL and myeloma are preceded by non-malignant clonal proliferations; monoclonal B cell lymphocytosis (MBL) and monoclonal gammopathy of undetermined significance (MGUS) respectively. It is part of the definition in both MBL and MGUS that the condition is asymptomatic at the time of diagnosis.12;13 There is a degree of overlap between MBL and early CLL and between MGUS and early myeloma; despite this it is not normally considered that MBL or MGUS patients are on watch and wait. It is recommended that patients with prodromal syndromes should be monitored as there is a rate of conversion to clinically frank disease of about 1% per annum in each case.

For each condition there is a recent review which discusses the clinical implications and follow-up.

Practice Points Psychological Considerations Many patients being managed on watch and wait are, understandably, often very anxious.

As such, they may benefit from reassurance that the deferment of treatment is based on clinical grounds. The primary care team should offer explicit reassurance that neither cost nor availability of treatment has played any part in their treatment planning. It is possible that, with the introduction of new systems for commissioning, patients may be more likely to fear that treatment decisions are based on cost. In this case the GP can explain that the issue of payment for treatment has not arisen because the evidence base supports watch and wait. Again, it may help to assure the patient that there will be no problem with funding payment if, and when, this is indicated.

Availability hints at another reason for patient anxiety, the perception that they are not being treated because there is nothing that can be done. This can best be dealt with using positive rather than negative assurances; it should be made clear that, if and when treatment becomes necessary, there are options available.

In the case of particularly anxious patients the primary care team may be able to act as go-betweens; this will involve liaison with 8 | WWW.PRIMARYCAREREPORTS.CO.UK

the haematology care team. A primary care practitioner, with a long-standing therapeutic relationship with the patient, may be better able to communicate clinical information in an understandable and reassuring fashion.

Infection Prophylaxis and Management Patient with haematological malignancy commonly suffer some degree of immunoparesis, even when not being treated; evidence is equivocal on whether, despite this, they benefit from prophylaxis such as flu vaccination. Despite the lack of definitive evidence it is generally recommended that they should be included in vaccination programs.

Indications for Referral As previously indicated, the wider use of laboratory testing of apparently healthy individuals is likely to lead to an increasing number of patients being diagnosed with precursor syndromes or early stages of a haematological malignancy.

It is likely that most practices will have at least one patient being managed on a watch and wait basis for haematological malignancy. A prudent approach would be to develop a protocol for referral of such patients between planned reviews.

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References: 1

Gribben, J. How I treat CLL up front. Blood 115, 187-197. 20102010.

2

CLL Trialists’ Collaborative Group. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. J Natl Cancer Inst. 91(10), 861-868. 19991999.

3

Butler T, Gribben JG. Biologic and clinical significance of molecular profiling in Chronic Lymphocytic Leukemia. Blood Rev. 2010;24:135-141.

4

Swerdlow SH, Campo E, Harris NL et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.

Lyon: IARC; 2008.

5

Gribben JG. How I treat indolent lymphoma. Blood 2007;109:4617-4626.

6

Gine E, Montoto S, Bosch F et al. The Follicular Lymphoma International Prognostic Index (FLIPI) and the histological subtype are the most important factors to predict histological transformation in follicular lymphoma. Ann.Oncol.

2006;17:1539-1545.

7

Kumar A, Galeb S, Djulbegovic B. Treatment of patients with multiple myeloma: an overview of systematic reviews.

Acta Haematol. 2011;125:8-22.

8

British Committee for Standards in Haematology in conjunction with the UK Myeloma Forum (UKMF). Guidelines on the diagnosis and management of multiple myeloma. 20102010.

9

Chakraborti C, Miller KL. Multiple myeloma presenting as spinal cord compression: a case report. J Med.Case.

Reports. 2010;4:251.

10

Barzi A, Sekeres MA. Myelodysplastic syndromes: a practical approach to diagnosis and treatment. Cleve.Clin.J Med. 2010;77:37-44.

11

Guglielmelli P, Vannucchi AM. Recent advances in diagnosis and treatment of chronic myeloproliferative neoplasms.

F1000.Med.Rep. 2010;2:

12

Rawstron AC, Hillmen P. Clinical and diagnostic implications of monoclonal B-cell lymphocytosis. Best.Pract.Res.Clin.

Haematol. 2010;23:61-69.

13

Landgren O. Monoclonal gammopathy of undetermined significance and smoldering myeloma: new insights into pathophysiology and epidemiology. Hematology.Am.Soc.Hematol.Educ.Program. 2010;2010:295-302.

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Haematological Malignancies: A Primary Care Perspective Ken Campbell, Clinical Information Officer, Leukaemia & Lymphoma Research, London

GPs may underestimate the incidence of blood cancer in the general population – in part because of the way in which cancer statistics are usually presented, with leukaemia, lymphoma, myeloma and other types listed separately.

GPs can offer a unique supportive role for patients with haematological malignancies (and to their families). In most cases the GP will be the first doctor to suspect a haematological malignancy. Once the diagnosis has been made they can act as a qualified go-between to assist the patient in getting information and understanding the implications of this information. An increasing number of patients with blood cancer are spending much of their time in the community, rather than as inpatients, and an informed GP will be better able to serve their special needs.

T

HE HAEMATOLOGICAL malignancies represent a wide spectrum of disorders from illness so benign that most diagnoses are chance findings in clinically well individual, to aggressive disease, which will kill within days or weeks without effective therapy. They all, however, reflect the same underlying problem; “a genetic change in a particular group (clone) of blood cells (or its precursor) that leads these cells to develop incorrectly and multiply in a disorganised and uncontrolled manner, crowding out cells that are essential to normal function”1.

There are substantial overlaps between different haematological malignancies and they are dealt with in the same hospital units, which justifies grouping them together in some contexts.

There are three key issues in primary care for patients with haematological malignancies; • Diagnostic awareness • Liaison with secondary and tertiary care facilities • Clinical management of patients in the primary care setting This article will briefly review the haematological malignancies will give guidance on clinical indicators of these illnesses and will then summarise ways in which the primary health care team may contribute to care of the patient with a haematological malignancy.

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Epidemiology Each year, over 25 000 people in the UK are diagnosed with a leukaemia, lymphoma, myeloma or a related condition. This represents about 10% of all cancer diagnoses and means that a practice of 2,000 patients might be expected to see a new case once every two years.

GPs may underestimate the incidence of blood cancer in the general population – in part because of the way in which cancer statistics are usually presented, with leukaemia, lymphoma, myeloma and other types listed separately. This recognizes non-Hodgkin lymphoma (NHL) as the fifth most common cause of cancer deaths but shows the mortality as around one-third that of prostate cancer (the 4th most common). If the haematological malignancies are considered together, they account for almost as many deaths as prostate cancer. It should be stressed that within this overall picture, there are many specific types which are rare, for example Burkitt lymphoma and hairy cell leukaemia, each with only about 200 cases a year in the UK, and juvenile chronic myelomonocytic leukaemia, with literally a handful of cases a year.

The Diseases It is generally agreed that the current definitive classification of HM is the WHO “Blue Book”, which has the formal title WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues2.

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The major disease categories are leukaemia, lymphoma, myeloma, myeloproliferative neoplasms and myelodysplastic syndromes.

Detailed information on each of these diseases can be found on the Leukaemia Research web site at www.lrf.org.uk. For many of the conditions the British Committee for Standards in Haematology (BCSH) has produced detailed evidence-based management guidelines, these can be downloaded from http://www. bcshguidelines.com/.

Leukaemia There are many types of leukaemia described in the Blue Book but these can be grouped into 4 major types. These are; • Acute myeloid (AML) o This is the type most often seen in young adults although leukaemia is rare overall in this age-group.

• Acute lymphoblastic (ALL) o This is the only type commoner in children than in adults.

• Chronic myeloid (CML) o This is not generally considered curable but is eminently treatable with a new class of drugs called tyrosine kinase inhibitors.

• Chronic lymphocytic (CLL) o This is the commonest form of leukaemia in the Western world, although it is rare in Asians; it is typically indolent and many patients have a long survival.

Lymphoma Lymphomas are solid tumours of lymphoid tissue; they may arise in lymph nodes, or extranodally.

Lymphoma of superficial nodes presents as (typically) painless localized lymphadenopathy whereas extranodal or deep nodal LAD may produce any of a wide range of symptoms.

Lymphomas may occur at any age but like other haematological malignancies they are more common with increasing age. A key difference between lymphoma and other haematological malignancies is that the marrow is rarely involved in early stages of lymphoma. There are two major types; • Hodgkin Lymphoma (HL) o This is characterized by presence of distinctive Reed-Sternberg giant cells. It is very responsive to treatment in young patients who have a high cure rate.

• Non-Hodgkin Lymphoma (NHL) o There are many subtypes of NHL; these are broadly grouped into indolent (low-grade) and aggressive (high-grade).

Other HM Several other conditions fall under the general rubric of haematological malignancies; the

most important of these are the myelodysplastic syndromes and the myeloproliferative neoplasms; • Myelodysplastic syndromes (MDS) o This is a group of conditions linked by a typically hyperplastic marrow with low cell counts, there is a wide clinical spectrum from asymptomatic, laboratory-diagnosed cases to severe transfusion-dependent cytopenias.

• Myeloproliferative neoplasms (MPN) o Until recently, these were referred to as myeloproliferative disorders; the change of name reflects progress in understanding of the conditions. o The MPNs are • Polycythaemia vera (PV) with raised numbers of red cells • Essential thrombocythaemia (ET) with excess numbers of platelets • Myelofibrosis (MF) with excess production of marrow fibrin.

Leukaemia & Lymphoma Research is the only UK charity solely dedicated to research into blood cancers, including leukaemia, lymphoma and myeloma.

Diagnostic Awareness The National Institute for Health and Clinical Excellence (NICE) has published guidelines for referral of patients with suspected cancer3 http://www.nice.org.uk/guidance/CG27.

Children Leukaemia and lymphoma together make up about 40% of all childhood cancers.

There are about 10 new diagnoses a week in the UK.It is a difficult judgement call when to suspect haematological malignancy in a young child, because thankfully this is so rare that most GPs will not see a case in their professional lifetime.

Recognition of Childhood Leukaemia and Lymphoma4 • Leukaemia should be suspected if – Persistent vague symptoms are accompanied by evidence of: • Abnormal bleeding • Bone pain • Lymphadenopathy • Hepatosplenomegaly – Beware NAI misdiagnosis which may cause great distress – Trust parental instinct – if a normally calm parent insists the child is ill, listen • Lymphoma may present as – One or more painless masses, often in the neck, accompanied by • Signs and symptoms of local compression and • Systemic disturbances, such as fever and weight loss

Our life-saving research is focused on finding causes, improving diagnosis and treatments and running groundbreaking clinical trials for all blood cancer patients. Blood cancers including leukaemia, lymphoma and myeloma affect people of all ages from babies to grandparents. We need to be sure that we reach all those touched by leukaemia, lymphoma and myeloma and give them the best possible chance of survival.

Leukaemia & Lymphoma Research 39-40 Eagle Street, London WC1R 4TH Tel: 020 7405 1010 Fax: 020 7405 3139 Email: info@beatbloodcancers.org www.beatbloodcancers.org Press team: Tel: 020 7269 9019 Email: press@beatbloodcancers.org

Scotland Office Leukaemia & Lymphona Research 24D Milton Road East, Edinburgh EH15 2NJ Tel: 0131 669 7862

WWW.PRIMARYCAREREPORTS.CO.UK | 11

SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY

Many patients with

Adults Indolent Haematological Malignancies

low-grade disease

Indolent haematological malignancies which include chronic leukaemias and indolent lymphomas, are often chance findings in routine health screens. Where symptoms are present, these are usually lowgrade and non-specific; they include fatigue, due to anaemia; frequent and persistent infection due to neutropenia and immunoparesis; and bruising/bleeding due to thrombocytopenia. In almost all cases of leukaemia a simple full blood count is diagnostic, although further investigations may be needed to confirm this.

The full blood count is an inexpensive test, capable of indicating pathology of many systems of the body. a potential drawback is that, as with PSA and prostate disease, it may reveal many pathological defined haematological malignancies which would never have become clinically problematic and thus generate anxiety.

Lymphoma diagnosis may be straightforward, with excision biopsy of superficial node(s) leading to a definitive diagnosis. Where the disease arises in other anatomical sites diagnosis may be challenging;it should be recognised that lymphoma may present through virtually any department of a hospital.

Ev en when a b i o ps y i s a v a i l a b l e , expert histopathological review may be necessary to differentiate reactive nodes from malignant transformation.

In most cases early diagnosis has no impact on disease progression or on outcome, indeed, early stage low-grade disease typically does not require treatment. The exception to this principle is CML, which always requires immediate treatment; this is because if untreated, the condition may transform to an accelerated phase, which is much less responsive to treatment. Although indolent HM patients usually have a long survival, cure is less likely than for the aggressive forms.

are managed by “watch and wait”, which many patients describe as “watch and worry”.

Aggressive Haematological Malignancies Aggressive haematological malignancies, which include acute leukaemia and aggressive lymphomas, are typically symptomatic at diagnosis, and will always trigger immediate treatment. Early diagnosis is unlikely to have the same impact on survival as for solid tumours. This is because most haematological malignancies arise in cells that normally traffic between anatomical sites and are thus disseminated at diagnosis – in solid tumours metastasis is a late event with negative 12 | WWW.PRIMARYCAREREPORTS.CO.UK

prognostic impact. Survival in solid tumours diagnosed prior to metastasis is much higher than for later stage disease. The only HM in which anatomical spread is featured in staging are the lymphomas.

Myeloma Myeloma may present as an indolent neoplasm, known as smouldering myeloma, or as a relatively aggressive condition. Even smouldering myeloma requires urgent assessment. Patients with myeloma may suffer renal damage as a consequence of high levels of serum paraprotein (abnormal immunoglobulins); renal damage when it occurs is often irreversible, but may be prevented by early diagnosis. NSAIDs should not be given to any patient whose differential diagnosis includes myeloma, as they may exacerbate renal damage.

• About 1% of unexplained lymphadenopathy seen in primary care is malignant5.

• Lymphadenopathy lasting less than two weeks or more than one year with no progressive size increase has a very low risk of being neoplastic6.

Exceptions to this rule are low-grade Hodgkin’s and non-Hodgkin’s lymphomas and, occasionally, chronic lymphocytic leukaemia.

Liaison with Secondary and Tertiary Care Facilities Although haematological malignancies make up just 10% of all cancers, they account for more in-patient bed days than any other cancer.

Hospital episode statistics show that HM account for about 17,000 in-patient bed days per million population per year, but the actual figure could be substantially higher than this1.

The implications for fund-holding practices are clear; Low et. al have pointed out that “Most haematological malignancies are chronic disorders with a simple clinical management plan, requiring periodic clinical monitoring.”7. In the same paper, they comment “Only a minority of cases require care in specialist hospital haematology units; the majority can be managed using community-based haematological follow-up care.” This is important because a significant majority of HM patients are over 65 years of age and benefit from receiving treatment as close to home as possible. Clearly, GPs can help this patient group by liaising with specialist physicians to achieve local care, and by providing such additional support as

SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY

may be needed to keep patients in the community. GPs can help to keep patients out of hospital by monitoring for changes in clinical status, by arranging for routine investigations and by management of problems arising in the primary care setting.

Patients often comment that they do not understand what hospital doctors are telling them, or that they find it difficult to get information from the specialist, or that they find it difficult to get different specialists to agree on what is the most likely cause of a particular symptom. In each of these cases the GP is uniquely well placed to act as the patient’s agent in obtaining and interpreting information.

This role may be particularly valuable to patients with one of the rarer haematological malignancies and to patients with significant co-morbidities.Clinical management in these groups may be complex and it is less likely that patients will be able to obtain written information on their illness.

Many patients with low-grade disease are managed by “watch and wait”, which many patients describe as “watch and worry”. This group may benefit from reassurance from the primary care team. The GP should also be alert to any change in clinical status in this group, as this may indicate a need to move to active treatment.

At the other end of the spectrum there are patients who have a limited life expectancy; support from the primary care team may be decisive in determining whether such patients are able to die at home or at a hospice or community hospital, rather than in an acute unit.

Clinical Management of Patients in the Primary Care Setting “Most haematological malignancies are chronic disorders with a simple clinical management plan, requiring periodic clinical monitoring.8” An increasing number of patients are being diagnosed with haematological malignancies that are not curable, but which are associated with a long survival; in some cases long survival is the natural course of the illness (CLL, indolent NHL), whilst in others it results from drug therapy (CML). In either situation, the typical patient lives a near-normal life style.

Other patients will be receiving treatment with curative intent, involving hospital stays, but also spending a high proportion of their time in the community. All of these patients will be subject to the normal ailments of their age group but have additional needs for surveillance, prophylaxis and prompt response to complications of their haematological malignancy or therapy.

Early recognition, and appropriate management, of infection in immunocompromised patients is imperative; for example prompt management of URTI may reduce the risk of pneumonia leading to admission to HDU and IV antibiotic therapy.

“Pulmonary disease in the immunocompromised host remains a major cause of morbidity and has a high mortality9.” It may be helpful to discuss infection prophylaxis and management in this group with the microbiologist at the centre treating their haematological malignancy.

Infections may present atypically in patients who are neutropenic; they may not show typical signs such as; • Redness • Swelling • Pus formation (at the site of an injury or incision) • Cough • Sputum • Nasal drainage (from a sinus or respiratory infection) Most cancer patients experience at least one oncological emergency during the course of their illness10, the most common and critical of which are; • Febrile neutropenia • Tumor lysis syndrome • Hypercalcemia of malignancy • Superior vena cava syndrome • Spinal cord compression • Hyperviscosity • Strokes and seizures • Treatment-related emergencies.

Emergencies may initially present in the primary care setting – early recognition and prompt referral may prevent serious morbidity or fatal complications. A detailed description of these is beyond the scope of this paper but several reviews are available10-14.

A 2005 Forum in Lancet Oncology offers a review of the role of the primary care physician in oncology from the perspective of, variously, an oncology specialist, a GP, a (physician) patient and a service co-ordinator15.

An increasing group of patients are those who have completed their treatment.Although discharged by their haematologist/oncologist, this group are often not finished with their illness. There may be late effects of treatment.

In order for the GP to monitor this group they need to be aware of the increased risk of certain conditions. A particularly valuable resource is the “Therapy Based Long Term Follow Up” Practice Statement produced by the Childhood Cancer and Leukaemia Group (CCLG) – this can be downloaded from http:// www.cclg.org.uk/researchandtreatment/ content.php?3id=29&2id=19. Although this is written from a paediatric perspective,

Leukaemia & Lymphoma Research is the only UK charity solely dedicated to research into blood cancers, including leukaemia, lymphoma and myeloma.

Our life-saving research is focused on finding causes, improving diagnosis and treatments and running groundbreaking clinical trials for all blood cancer patients. Blood cancers including leukaemia, lymphoma and myeloma affect people of all ages from babies to grandparents. We need to be sure that we reach all those touched by leukaemia, lymphoma and myeloma and give them the best possible chance of survival.

Leukaemia & Lymphoma Research 39-40 Eagle Street, London WC1R 4TH Tel: 020 7405 1010 Fax: 020 7405 3139 Email: info@beatbloodcancers.org www.beatbloodcancers.org Press team: Tel: 020 7269 9019 Email: press@beatbloodcancers.org

Scotland Office Leukaemia & Lymphona Research 24D Milton Road East, Edinburgh EH15 2NJ Tel: 0131 669 7862

WWW.PRIMARYCAREREPORTS.CO.UK | 13

SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY

All patients who have, or have been treated for, a haematological malignancy should be encouraged to have regular check-ups to ensure early detection

as one would expect, much of its content is relevant for patients of any age. It will offer valuable guidance to GPs and other members of the primary health care team on what late effects are associated with which treatments, and on what follow up surveillance may be advisable. Anthracyclines are widely used in treatment of haematological malignancies but unfortunately, they may be associated with cardiac damage, this is discussed in a recent Lancet Oncology review16. All patients who have, or have been treated for, a haematological malignancy should be encouraged to have regular check-ups to ensure early detection of any late effects of treatment or recurrence of disease.

Leukaemia & Lymphoma Research is the only UK charity solely dedicated to research into blood cancers, including leukaemia, lymphoma and myeloma.

of any late effects of treatment or recurrence of disease.

Our life-saving research is focused on finding causes, improving diagnosis and treatments and running groundbreaking clinical trials for all blood cancer patients. Blood cancers including leukaemia, lymphoma and myeloma affect people of all ages from babies to grandparents. We need to be sure that we reach all those touched by leukaemia, lymphoma and myeloma and give them the best possible chance of survival.

Leukaemia & Lymphoma Research 39-40 Eagle Street, London WC1R 4TH Tel: 020 7405 1010 Fax: 020 7405 3139 Email: info@beatbloodcancers.org www.beatbloodcancers.org Press team: Tel: 020 7269 9019 Email: press@beatbloodcancers.org

Scotland Office Leukaemia & Lymphona Research 24D Milton Road East, Edinburgh EH15 2NJ Tel: 0131 669 7862

14 | WWW.PRIMARYCAREREPORTS.CO.UK

SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY

References: 1

National Institute for Health and Clinical Excellence. Improving outcomes in haematological cancers. 2003. London, NICE. Guidance on Cancer Services.

2

Eds. Jaffe, E. S., Swerdlow, S. H., Campo, E., Pileri, S. A., Thiele, J., Harris, N. L., Stein, H., & Wardiman, J. W.(2008) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (IARC Press, Lyon).

3

National Institute for Health and Clinical Excellence. Referral guidelines for suspected cancer. 27. 2005. London, NICE. NICE Clinical Guidelines.

4

Young, G., Toretsky, J. A., Campbell, A. B. & Eskenazi, A. E. (2000) Recognition of common childhood malignancies Am. Fam. Physician 61, 2144-2154.

5

Fijten, G. H. & Blijham, G. H. (1988) Unexplained lymphadenopathy in family practice. An evaluation of the probability of malignant causes and the effectiveness of physicians’ workup J. Fam. Pract. 27, 373-376.

6

Bazemore, A. W. & Smucker, D. R. (2002) Lymphadenopathy and malignancy Am. Fam. Physician 66, 2103-2110.

7

Low, J., Smith, A., George, S., Roderick, P. & Davis, C. (2002) How many patients with haematological malignancy need the facilities offered by a district general hospital? J Public Health Med 24, 196-199.

8

Low, J., Smith, A., George, S., Roderick, P. & Davis, C. (2002) How many patients with haematological malignancy need the facilities offered by a district general hospital? J Public Health Med 24, 196-199.

9

El Mahallawy, H. A., Ibrahim, M. H., Shalaby, L. & Kandil, A. (2005) Community respiratory viruses as a cause of lower respiratory tract infections following suppressive chemotherapy in cancer patients J. Egypt. Natl. Canc. Inst.

17, 121-126.

10

Krimsky, W. S., Behrens, R. J. & Kerkvliet, G. J. (2002) Oncologic emergencies for the internist Cleve. Clin. J. Med. 69, 209-4, 216.

11

Zojer, N. & Ludwig, H. (2007) Hematological emergencies Ann. Oncol. 18 Suppl 1, i45-i48.

12

Halfdanarson, T. R., Hogan, W. J. & Moynihan, T. J. (2006) Oncologic emergencies: diagnosis and treatment Mayo Clin. Proc. 81, 835-848.

13

Higdon, M. L. & Higdon, J. A. (2006) Treatment of oncologic emergencies Am. Fam. Physician 74, 1873-1880.

14

Cervantes, A. & Chirivella, I. (2004) Oncological emergencies Ann. Oncol. 15 Suppl 4, iv299-iv306.

15

Wong, J. E. L., Hall, S., Finegan, W. C. & Holmberg, L. (2005) The role of the primary-care physician in oncology care.

Forum Lancet Oncol 6, 118-119.

16

Altena, R., Perik, P. J., van Veldhuisen, D. J., de Vries, E. G. & Gietema, J. A. (2009) Cardiovascular toxicity caused by cancer treatment: strategies for early detection Lancet Oncol. 10, 391-399.

WWW.PRIMARYCAREREPORTS.CO.UK | 15

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