special report – haematological malignancy
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Primary Care – Special Report on Haematological MalignancyTRANSCRIPT
Haematological Malignancy
S P E C I A L R E P O R T
Published by Global Business Media
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
www.msinstruments.co.uk
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 fi nding 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 Research39-40 Eagle Street, London WC1R 4TH
Tel: 020 7405 1010 Fax: 020 7405 3139 Email: [email protected] www.beatbloodcancers.org
Press team: Tel: 020 7269 9019 Email: [email protected]
Scotland Offi ceLeukaemia & Lymphona Research
24D Milton Road East, Edinburgh EH15 2NJ Tel: 0131 669 7862
SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY
Published by Global Business Media
Global Business Media Limited 62 The Street Ashtead Surrey KT21 1AT United Kingdom
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EditorMartin Richards
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Contents
FOREWORD 2Martin Richards, Editor
WATCH AND WAIT FOR HAEMATOLOGICAL MALIGNANCY 3Ken Campbell, Clinical Information Offi cer, Leukaemia Research Trust, London
Watch and Wait vs. Palliative Therapy and Supportive Care 3
Treatment Options for Patients with Newly-Diagnosed Haematological Malignancy 4
Indolent Haematological Malignancies 4
Leukaemia 4
Non-Hodgkin Lymphoma 6
Indolent
Aggressive
Myeloma 6
Myelodysplastic Syndromes and Myeloproliferative Neoplasms 7
Prodromal Conditions 8
Practice Points 8
Psychological Considerations
Infection Prophylaxis and Management
Indications for Referral
REFERENCES 9
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Haematological Malignancy
S P E C I A L R E P O R T
Published by Global Business Media
Sponsored by
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
Foreword
Each 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 benefi t 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, defi nitive 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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2 | WWW.PRIMARYCAREREPORTS.CO.UK
SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY
WWW.PRIMARYCAREREPORTS.CO.UK | 3
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 fi nding 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 Research39-40 Eagle Street, London WC1R 4TH Tel: 020 7405 1010 Fax: 020 7405 3139
Email: [email protected] www.beatbloodcancers.org
Press team: Tel: 020 7269 9019
Email: [email protected]
Scotland Offi ceLeukaemia & Lymphona Research24D Milton Road East, Edinburgh
EH15 2NJ Tel: 0131 669 7862
Watch and Wait for Haematological MalignancyKen Campbell, Clinical Information Offi cer, Leukaemia Research Trust, London
For 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 CareThe 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 benefi t from early treatment; it does not relate to the fi tness of the patient to undergo treatment. Palliative therapy is offered to a patient for whom the potential benefi ts of more disease-directed treatment are insufficient to offset the side-effects of defi nitive 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 defi nitive 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 unfi t, through advanced age and/or co-morbidity, to receive defi nitive therapy. It may also be offered if a patient is deemed unlikely to survive for long, even with defi nitive treatment. The central consideration in palliative therapy is
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
for a condition, usually
based on published data
showing that there is
no clear benefi t from
early treatment
SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY
4 | WWW.PRIMARYCAREREPORTS.CO.UK
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
• Defi nitive 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/benefi t analysis not on cost or availability of therapy
– A patient receiving palliative or supportive care is not, by defi nition, 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 defi nitive 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 MalignanciesThe principal considerations in deciding whether watch and wait is appropriate are the natural history of the patient’s condition and the
evidence base for benefi t (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 non-Hodgkin 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 benefi t 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.
LeukaemiaAlthough 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 leukaemiaAcute leukaemia may be managed palliatively if a patient is frail elderly or has co-morbidities which would preclude offering defi nitive therapy; it is never managed on a watch and wait basis. If the patient is fi t 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
On the basis of
their natural history,
haematological
malignancies can be
broadly divided into
aggressive and
indolent conditions.
SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY
WWW.PRIMARYCAREREPORTS.CO.UK | 5
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 fi nding 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 Research39-40 Eagle Street, London WC1R 4TH Tel: 020 7405 1010 Fax: 020 7405 3139
Email: [email protected] www.beatbloodcancers.org
Press team: Tel: 020 7269 9019
Email: [email protected]
Scotland Offi ceLeukaemia & Lymphona Research24D Milton Road East, Edinburgh
EH15 2NJ Tel: 0131 669 7862
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 profi le of imatinib and related drugs is suffi ciently mild that even frail patients will usually be given defi nitive 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 signifi cant 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 benefi t 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 meta-analysis 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 fi nding 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 identifi ed 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 specifi cally mentions:• development of night sweats, • increasing adenopathy at one site, or • elevated lactate dehydrogenase
Typical morphology of CLL cells in peripheral blood (http://www.fl ickr.com/photos/euthman/2869815349)
SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY
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Non-Hodgkin LymphomaNon-Hodgkin lymphoma is the fi fth 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, classifi cation 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 classifi cation 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 lymphomaTogether, indolent forms make up about one-third of all NHL.
The standard of care for patients with newly diagnosed indolent NHL is “expectant
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.
MyelomaMyeloma 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 benefi t.”7
The crucial considerations for initial management of myeloma are whether the patient is symptomatic and whether there is
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)
SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY
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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 fi nding 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 Research39-40 Eagle Street, London WC1R 4TH Tel: 020 7405 1010 Fax: 020 7405 3139
Email: [email protected] www.beatbloodcancers.org
Press team: Tel: 020 7269 9019
Email: [email protected]
Scotland Offi ceLeukaemia & Lymphona Research24D Milton Road East, Edinburgh
EH15 2NJ Tel: 0131 669 7862
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,
• loss of bladder or bowel function• ataxia
Myelodysplastic Syndromes and Myeloproliferative NeoplasmsThe 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 myelofi brosis (MF). For both PV and ET thrombosis is the primary MPN
Plasma cells in peripheral blood (http://en.wikipedia.org/wiki/File:PCL.jpg)
Dysplastic megakaryocyte in marrow of patient with myelodysplastic disorder
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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 ConditionsAs 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 defi nition 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 PointsPsychological ConsiderationsMany 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
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 ManagementPatient with haematological malignancy commonly suffer some degree of immunoparesis, even when not being treated; evidence is equivocal on whether, despite this, they benefi t from prophylaxis such as fl u vaccination. Despite the lack of definitive evidence it is generally recommended that they should be included in vaccination programs.
Indications for ReferralAs 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.
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.
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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 signifi cance of molecular profi ling in Chronic Lymphocytic Leukemia. Blood Rev. 2010;24:135-141.
4 Swerdlow SH, Campo E, Harris NL et al. WHO Classifi cation 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 signifi cance and smoldering myeloma: new insights into pathophysiology and epidemiology. Hematology.Am.Soc.Hematol.Educ.Program. 2010;2010:295-302.
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