British Society for Haematology guidelines for the management of adult myelodysplastic syndromes

Abstract

This document represents an update of the British Society of Haematology Guideline published in 2014 due to advances in understanding the biology and therapy of the myelodysplastic syndromes (MDS).1 The objective of these guidelines is to provide healthcare professionals with clear guidance on the management of adult patients with MDS. Individual circumstances may dictate an alternative approach. A separate British Society for Haematology (BSH) guideline covers the Diagnosis and Evaluation of Prognosis of Adult MDS which is published alongside this Guideline. A separate good-practice paper detailing the management of patients with chronic myelomonocytic leukaemia (CMML) will follow and is not considered in these Guidelines. These Guidelines were compiled according to the BSH process https://b-s-h.org.uk/media/16732/bsh-guidance-development-process-dec-5-18.pdf. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. The guideline group was selected to be representative of UK medical experts and the manuscript was reviewed by the UK MDS Patient Support Group. Recommendations are based on a review of the literature using Medline/Pubmed searches. Search terms included: myelodysplasia, MDS, myelodysplastic, refractory an(a)emia, refractory cytopenia, deletion 5q, del(5q), management, treatment, transfusion, supportive care, iron chelation, growth factors, erythropoietin, TPO agonists, thrombopoietin agonists, romiplostim, eltrombopag, immunosuppression, lenalidomide, azacitidine, decitabine, chemotherapy, luspatercept, bone marrow transplantation, stem cell transplantation. Only English language publications from 2012 to December 2020 were included in the literature search. Additional searches using subsection heading terms were conducted by members of the writing committee at the time of final submission to the British Journal of Haematology. Titles and/or abstracts of publications obtained from the database searches described were curated and manually reviewed by members of the writing committee. Review of the manuscript was performed by the BSH Guidelines Committee Haemato-oncology Task Force, the BSH Guidelines Committee and the haemato-oncology sounding board of the BSH. It was also posted on the members section of the BSH website for comment. This guideline has also been reviewed by patient representatives from the MDS UK Patient Support Group (https://mdspatientsupport.org.uk). These organisations do not necessarily endorse the contents. The myelodysplastic syndromes are a group of clonal bone marrow neoplasms characterised by ineffective haematopoiesis and manifested by dysplasia of haematopoietic cells and by peripheral cytopenia(s).2 They have a variable predilection for the development of acute myeloid leukaemia (AML). The incidence of MDS in the UK is 3·72/100 000 population/year;’ it is predominantly a disease of the elderly (median age at diagnosis 75·7 years) and more common in men (approximately 2:1).3 Patients with suspected MDS should be assessed by a haematologist with a specialist interest in the disease. They should be referred for a second opinion to a regional or national centre when required by the clinician, or requested by the patient. All patients with a diagnosis of MDS must be discussed at a multidisciplinary team meeting (MDT), which should include allogeneic stem cell transplant representation. All patients diagnosed with MDS should be reported to the National Cancer Registry, via the MDT, and to MDS-specific registries if appropriate. Management recommendations for MDS have largely evolved and been driven through the International Prognostic Scoring System (IPSS) and its revised version IPSS-R. ‘Low-risk’ MDS includes patients with IPSS Low/Intermediate-1 (INT-1) and IPSS-R very low, low and intermediate up to 3·5 points.4 ‘High-risk’ MDS includes those with IPSS intermediate-2 (INT-2)/high and IPSS-R intermediate (>3·5 points), high and very high. Patients should be managed according to their individual clinical and biological characteristics and by patient and physician preferences. The IPSS-R should be used to evaluate prognosis in all patients. Where available, all patients should be offered clinical trials and/or prospective registry programmes to maximise information about the natural history and treatment of MDS in order to benefit future patients. Supportive care, including transfusions and antibiotics, is central to the management of MDS patients. Red cell transfusion dependency is associated with decreased overall and leukaemia-free survival in MDS, and reduced quality of life (QoL).5-7 Transfusion therapy is associated with well-recognised complications including risks of alloimmunisation.8, 9 Antibodies to Rh and K antigens appear the most common,10 but the exact role and cost effectiveness of extended red cell phenotyping remains unknown and local practices vary.11 Irradiated blood products are recommended after a stem cell transplant or treatment with antithymocyte globulin (ATG), in keeping with the current BSH Guidelines on the use of irradiated blood components.12 Although the severity of anaemia has a major impact on QoL in MDS patients,13 the degree to which this may be ameliorated by different policies for red cell transfusion is not known. Clinicians may choose to apply a policy for red cell transfusion that is individualised and targeted to symptoms, although in practice specific haemoglobin (Hb) thresholds are often applied. A common haemoglobin threshold of around 80 g/l was identified by a UK national audit, a survey in Australia14 and findings from the European MDS Registry (EUMDS).13 The only randomised trial of transfusions in MDS patients compared two transfusion thresholds (80 g/l, to maintain Hb 85–100 g/l against 105 g/l, maintaining 110–125 g/l).15 In an exploratory analysis, the five main QoL domains were improved for participants in the liberal compared to restrictive arm. National Institute for Health and Care Excellence (NICE) has published guidelines for the prevention and management of neutropenic sepsis in cancer patients (CG151 published September 2012).16 The use of prophylactic granulocyte-colony stimulating factor (G-CSF) may be considered in patients with recurrent infections who have low-risk MDS and may be used (with prophylactic antibiotics) to support the delivery of azacitidine in selected higher-risk patients. Although a randomised centre study showed that in patients undergoing chemotherapy, posaconazole prevented invasive fungal infections more effectively than did either fluconazole or itraconazole and improved overall survival (OS),17 there is no evidence to suggest that this should be routinely given to all patients with MDS. The American Society of Clinical Oncology and Infectious Diseases of America guidelines suggest that a mould-active triazole is recommended for patients who are at risk of profound, protracted neutropenia (defined as <0·1 × 109/l ≥ 7 days, or other risk factors).18 There is common but variable practice of platelet transfusion in MDS. There are no similar studies in MDS, but a retrospective study in patients with stable chronic severe aplastic anaemia described a ‘no-prophylaxis’ platelet transfusion approach.19-21 Avoiding unnecessary platelet transfusions in patients without signs of bleeding reduces the need for outpatient attendance improving QoL and may reduce the risk of platelet refractoriness. Patients with chronic thrombocytopenia presenting with bleeding of World Health Organisation (WHO) grade 2 or above should receive platelet transfusions. Alternative agents to platelet transfusions include the antifibrinolytic drug tranexamic acid and should be considered as a symptomatic measure in mucous membrane bleeding in appropriate patients with MDS, although randomised trial evidence is lacking.22 Thrombopoietin receptor agonists (TPO-RA), specifically romiplostim and eltrombopag, have been evaluated in randomised placebo-controlled studies in both low-risk MDS and high-risk MDS (the latter in combination with either chemotherapy, hypomethylating agents or lenalidomide).23-29 There were fewer bleeding episodes and fewer platelet transfusion episodes in the romiplostim arm in the Low/INT-1 study, although this study was halted prematurely because of concerns about increasing blast cell counts in patients receiving active drug.25 A subsequent meta-analysis of several such studies did not find a significant difference in transformation to AML between intervention with TPO-RAs and placebo.30 A moderate reduction in bleeding events compared with placebo controls was noted, but with no improvement in mortality. Ongoing studies are evaluating the safety and efficacy of eltrombopag in Low/INT-1 MDS with severe thrombocytopenia (<30 × 109/l), and interim analysis has shown platelet responses in 47% of the eltrombopag group compared to 3% in the placebo group.31 Although their use in high-risk MDS cannot be recommended, the results are promising for TPO-RA with platelet responses in low or intermediate-1 risk MDS (47–65%).24, 31 TPO-RA are not currently licenced for use in MDS and although these agents should ideally be accessed within clinical trials, the overall safety data now with longer follow-up is reassuring. The diagnosis of MDS is often overwhelming to the patient and his or her family. It can be a difficult diagnosis for the patient to understand, and there may be many treatment options (both active and supportive) to consider, including clinical trials. All patients should be offered support by a local Clinical Nurse Specialist with experience in MDS. Support groups such as the UK MDS Patient Support Group (www.mdspatientsupport.org.uk), Leukaemia Care (www.leukaemiacare.org.uk) or Blood Cancer UK (www.bloodcancer.org.uk) are valuable resources for all patients and relatives, both at diagnosis and during their treatment pathway. There is evidence that disease-specific patient information should be re-discussed regularly with patients, at least on an annual basis.5 The clinical sequelae encountered in low-risk MDS patients relate to the depth of cytopenias. An algorithm for the management of lower-risk MDS is shown in Fig 1. It is only recently that randomised trials for agents have been performed in the and these have to the European of but not for the treatment of symptomatic anaemia in with IPSS or MDS who have low levels There is a of survival for to if are to and in QoL for therapy is considered of for selected low-risk MDS patients who should have that a The shown in has been An alternative is the the more effectively it remains the therapy should be considered in patients with low or IPSS IPSS-R very low, low or intermediate with a risk of up to in the of symptomatic anaemia and Hb patients are symptomatic from anaemia at a an is at the Patients should criteria of by the There are data to suggest that therapy within of diagnosis and the of transfusions (80 Patients with higher-risk MDS should not be considered for therapy because of survival and the use of hypomethylating agents and stem cell transplantation, which red cell transfusion should be with or in all patients. The recommended for is 000 for there is no at the can be to a of 000 or two for a of 000 are not by The for should be or This can be after in to a of for a The in the randomised was of patients an in the to two in the to a The of or in low with stable anaemia and in the of reduced should be it is recommended that all patients receive therapy with for as and is to the in all for a final should be given to the cell if × or the in the × A of or in to in is appropriate. the should be to individual patients according to need and patients may longer between although this is not a The risk of in MDS patients to has been at and between and in in the randomised trial of there were no grade or episodes in In the randomised of no safety and only in the Although the risk of is low, it appropriate to therapy if there is a in or if the Hb above can be with of is a that growth to reduce It as an of compared with is by has been shown to reduce the severity of anaemia in patients with lower-risk MDS and for therapy has not been A placebo-controlled trial reported transfusion for in of patients in the arm in the placebo arm It was by the and in 2020 for MDS with patients of very low, low or IPSS-R risk who of red blood cells and have by the European in the time of writing not have a in the UK and cannot currently be recommended for UK Patients with MDS are at risk of iron from transfusion of red cells iron is of red blood cells and there is also of iron driven by ineffective to iron to and disease remains the main of in studies have shown that is in MDS patients either through or The European MDS Registry showed that the risk of in patients with iron levels is of risk of disease also in haematopoietic stem cell in MDS and transfusion a prognosis in a European Society for Blood and of iron can be by of and of red cell there is between or and the degree of iron for or and can be used to and iron and its impact on iron may The and the showed an International Group in of patients although was only in the and responses were also has been shown to iron assessed by and has been shown to A registry study showed that therapy improved survival in lower-risk MDS by prospective data from the it is now that iron to in anaemia can Although this is not to be the in neoplasms including MDS, a recommended in patients who have more than of blood to remains the most iron and is given in which may the iron many patients find it and QoL and are given and are although is associated with in around of patients. should not be used routinely in patients with MDS, and only after with a haematologist in MDS. It should be with very blood and should not be used the are × is the only iron currently for use in MDS patients with reduction in iron and improved in It is recommended that all lower-risk patients low and IPSS-R low and very should be considered for iron therapy around the time have of red or when the is more than 000 Patients should have levels and have and therapy and on with should be if the and should be if the 000 Patients who are considered for should have iron levels and iron therapy given to if time is only second for the treatment of chronic iron due to blood transfusions in patients with such as MDS. experience is that is is and safety data are now these opinion is that is the drug of for iron in patients with MDS. remains an in those to or of The two may be in circumstances with iron but only the of a haematologist in MDS treatment, although there are no data to support the There is no to the use of iron in combination with other such as or MDS with is a that or high platelet and bone marrow A other than or is within this It is associated with and has a natural with a survival of in those with an IPSS of for include transfusion age and of patients with MDS to are to that in low-risk MDS patients given the safety and efficacy data for should be therapy for symptomatic anaemia in lower-risk MDS patients with The study compared with placebo in low and MDS with and of patients receiving or transfusion responses were also in the treatment is for MDS with (with up to other than and is recommended for for such patients who have or are to about the risk of to AML with have not been in retrospective study or a improved survival and reduced risk of transformation have been the study showed that to AML was at five compared to reported data of studies have that clonal from or in of AML transformation in MDS with have years) responses to is not a to but and in this should be considered on an individual of MDS patients have decreased marrow The of myeloid this MDS although it not it a in MDS can with other bone marrow syndromes aplastic A study and in adult patients with bone has to criteria to This patients two with with a myeloid and more with a The two groups have different risk of blast and for should be performed in patients with It that those patients with and with a myeloid should have an MDS management although and efficacy need to be stem cell may be considered for patients. those with more in keeping with should be considered for treatment at such as The BSH Guidelines for the Diagnosis and Management of Adult Patients with should be referred to for treatment of section on allogeneic stem cell in MDS Patients with high-risk MDS IPSS or high IPSS-R have a significant risk of to AML with a survival of IPSS-R Group patients may also have of disease and for those for active therapy should be both at improving and the natural history of disease to to AML and Patients should be given the to in appropriate clinical trials. allogeneic is the only therapy with should at diagnosis a patient is a transplant and review this with a transplant is An algorithm for the management of high-risk MDS is in Fig patients not for transplantation, can be used in an to disease and Patients should be clinical trials The of are the QoL improvement if is and the of There have been reported of survival years) in patients with high-risk MDS and an patients have are than in is often (median and complications of marrow and more of patients the age of with high-risk MDS or AML showed an of and an to in of the patients who to those with a who a survival of those with a high-risk or more or 7 a survival of The study of for high-risk MDS these this it is recommended that results are to in patients with MDS, as there is no evidence to suggest this in treatment be agents an alternative to treatment in high-risk MDS. They are not but may in transfusion improved QoL and survival benefit and are in the elderly and in patients with is recommended by and the as a treatment for adult patients with MDS not for or and for AML with and The recommended is for days, at The showed that azacitidine compared to (median also in of patients compared to receiving In a analysis of patients azacitidine also improved compared to that this is the treatment of in higher-risk MDS patients with patients with may benefit from azacitidine of have not been although patients with including may the of increasing of may be associated with a of guidance for the delivery of azacitidine has been Patients who receive than or who to after have In the of and azacitidine is a of is recommended, with therapy for as as is Patients should have a marrow treatment, after assess and at should disease be In selected patients who a with azacitidine and have the of should be Ongoing studies are the combination of azacitidine with other agents in high-risk MDS. The of azacitidine have largely not been in in data has not that reported in the The and reported for patients with higher-risk MDS of and Alternative for azacitidine include for five days, no treatment for two days, and two of treatment on a or for five In the study of high-risk patients there was no difference in for patients with azacitidine for compared with the and this is as the alternative if the is studies for with supportive in MDS have shown that patients or study showed significant improvement in In the study of patients receiving for five of and red cell and platelet transfusion were survival was prospective randomised studies azacitidine with have been reported in MDS. is the and the only for use in the Although has in high-risk MDS, the of azacitidine in the study therapy in high-risk MDS. therapy be considered for use in a group of patients, those with an of in a marrow with a for no alternative active therapy is and/or appropriate. The of such patients will with of will a second but for a patients are All MDS patients should be discussed with a transplant physician at a MDT, both at diagnosis and with disease The to transplant should be on a evaluating and disease to transplant The time to transplant patients with lower-risk MDS remains an of transplant for the patients is not recommended due to subsequent reduction in life in the IPSS the the use of other such as transfusion dependency of blood significant platelet × × or very Transfusion and iron levels with in MDS patients should be considered the patient iron if there is a to transplant iron should be Patients with disease such as increasing blast cells or of should be considered for for to or lenalidomide, a prognosis and should of patients with and an associated have a prognosis and of patients should be considered for in their disease Patients with MDS and severe bone marrow experience compared with or those the of should transplant ideally to to severe allogeneic a survival in higher-risk MDS and patients should be referred to a transplant survival for patients with at the time of transplant have been It remains to transplant of blast In the of prospective patients with may be considered for or hypomethylating agents to is not should be considered are in patients with other and Patients with a or of with up to may also be considered for transplant as may with the of data from randomised trials, patients should be offered a clinical The support in patients with of data from the study patient due to or suggest that the of should be patients receiving chemotherapy, may treatment should ideally be a has been identified a to therapy is Patients with a are more to to their prognosis and that all patients with are for is associated with to and In are treatment with hypomethylating agents for MDS patients with or Patients with in the of who a reduction in blast should be considered for clinical trials as there is no clear evidence to suggest or is in this It is clear that with and after allogeneic of the of The are in patients with or in with a and transplant is not recommended for this group of patients of clinical trials. patients with a in the of a or those with a and should be considered for in the and have also been shown to with and studies are required to the role and of for such patient Patient age is not a factor for of patients years) with and low haematopoietic cell Patients with high-risk MDS and high ≥ have the and alternative should be survival to may be options for patients with high-risk disease a The trial showed no significant difference in survival or incidence of at two with or A similar prospective trial for to trial In keeping with high-risk patients with in may be for for there are no recommendations of therapy for and this is not discussed in this Guideline. patients may be managed through clinical trials All the to the writing of these Guidelines. The writing committee to the team of MDS experts at the MDS UK Patient Support Group for their review of the manuscript on of the UK MDS Patient for her in the literature also the BSH Haemato-oncology the BSH sounding board and the BSH Guidelines Committee for their support in this Guideline. All and the UK MDS Patient Support Group have a of to the BSH and Task which may be on of the writing group will the writing if evidence that the strength of the recommendations in this document or it The document will be and from the BSH current guidelines website if it recommendations are an will be published on the BSH Guidelines website the and information in this guidance is to be and at the time of to the the BSH the for the of this

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