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 controlled trials for erythropoiesis-stimulating agents (ESAs) have been performed in the EU32, 33 and these have led to the European licence of EPO-α (Eprex®), but not darbepoetin (Aranesp®), for the treatment of symptomatic anaemia (haemoglobin ≤100 g/l) in adults with IPSS Low- or INT-1 primary MDS who have low serum EPO levels (<200 iu/l). There is a suggestion of survival advantage for responders to ESA therapy, especially if they are non-transfused prior to starting ESA,34-36 and improvements in global QoL scores for responders.32, 37, 38 ESA therapy is considered first-line standard of care for appropriately selected low-risk MDS patients who should have pretreatment variables that predict a response. The validated Nordic score, shown in Table I, has been widely used.37 An alternative model is the ITACA scoring system.39 As the Nordic model more effectively identifies likely non-responders, it remains the preferred model. ESA therapy should be considered in patients with low or INT-1 IPSS (or IPSS-R very low, low or intermediate with a risk score of up to 3·5), in the context of symptomatic anaemia and Hb < 100 g/l. If patients are symptomatic from anaemia at a higher Hb, then starting an ESA is at the clinician’s discretion. Patients should fulfil criteria predictive of response by the Nordic score (score 0–1). There are data to suggest that starting ESA therapy within six months of diagnosis improves response rates and delays the onset of transfusions (80 vs 35 months).34, 40 Patients with higher-risk MDS should not generally be considered for ESA therapy because of poor responses, short survival and the likely use of hypomethylating agents and stem cell transplantation, which require red cell transfusion support. Treatment should be initiated with EPO-α or darbepoetin alone in all patients. The recommended starting dose for EPO-α is 30 000–40 000 units subcutaneous once weekly for eight weeks (mds-europe.eu).32, 41 If there is no response at eight weeks, the dose can be increased to a maximum dose of 60 000 units/week (divided over one or two doses) for a further eight weeks. Doses of >60 000 units/week are not supported by scientific evidence. The starting dose for darbepoetin should be 300 µg once every 14 days or 150 µg once every seven days (mds-europe.eu).42, 43 This can be increased after eight weeks in non-responders to a maximum of 300 µg per week for a further eight weeks.44 The starting dose in the randomised Phase 3 study33 was 500 µg once every three weeks. However, 81% of patients had an increase in the dose to 500 µg every two weeks in the open-label period leading to a higher erythroid response. The starting dose of EPO-α or darbepoetin in low body weight with stable anaemia and always in the case of reduced renal function should be lower (mds-europe.eu). Finally, it is recommended that all patients receive incremental therapy with ESA alone for 16 weeks, as above, and G-CSF is then added to the higher dose in all non-responders for a final eight-week trial.45, 46 G-CSF should be given to approximately double the starting white cell count (WBC) if <1·5 × 109/l, or keep the WBC in the range 6–10 × 109/l. A starting dose of 300 µg per week or in 2/3 divided doses, rising to 300 µg three times per week in non-responders, is appropriate. However, the dosing regimen should be tailored to individual patients according to need and response. Some patients may achieve potentially beneficial longer gaps between transfusions, although this is not a formally recognised response criterion. The risk of thrombosis in MDS patients responding to darbepoetin has been estimated at 2%42 and between 0·3 and 1·1% in meta-analysis.45 However, in the randomised trial of EPO-α there were no grade 3–4 thrombo-embolic or stroke episodes in 85 treated patients.32 In the darbepoetin randomised controlled trial,33 24 weeks of darbepoetin produced no new safety signals and only one thromboembolic event (PE) in the darbepoetin group. Although the risk of thrombosis is low, it seems appropriate to temporarily interrupt ESA therapy if there is a rapid rise in haematocrit, or if the Hb rises above 120 g/l. Lower doses can then be introduced with careful monitoring of response parameters. Luspatercept (Reblozyl) is a recombinant fusion protein that binds transforming growth factor-beta superfamily ligands to reduce SMAD signalling. It acts as an erythroid maturation agent, targeting later stages of erythropoiesis compared with conventional ESAs. Administration is by subcutaneous injection every three weeks. Luspatercept has been shown to reduce the severity of anaemia in patients with lower-risk MDS and ring sideroblasts for whom ESA therapy has not been effective.47 A double-blinded placebo-controlled Phase 3 trial (MEDALIST) reported transfusion independence for ≥8 weeks in 38% of patients in the luspatercept arm versus 13% in the placebo arm (P < 0·001).47 It was generally well tolerated. Luspatercept received approval by the Food and Drug Administration (FDA) in April 2020 for MDS with ring sideroblasts (MDS-RS) patients of very low, low or intermediate-risk IPSS-R risk status who require ≥2 units of red blood cells per eight weeks and have previously failed ESA therapy. Approval by the European Medicines Agency (EMA) followed in June 2020. At the time of writing luspatercept does not have a marketing authorisation in the UK and so cannot currently be recommended for UK use. Patients with MDS are at risk of developing iron overload from transfusion of red cells where iron build-up is inevitable (one unit of red blood cells delivers 200–250 mg iron), and there is also increased intestinal absorption of iron driven by ineffective erythropoiesis,48 mostly relevant to MDS-RS. Excessive iron ultimately leads to secondary end organ damage and cardiac disease remains the main non-leukaemic cause of death in MDS.49, 50 Retrospective studies have shown that OS is significantly shorter in transfusion-dependent MDS patients either through cardiac deaths, hepatic cirrhosis50, 51 or increased leukaemic progression.50 The European LeukemiaNet MDS Registry showed that the risk of death in transfusion-dependent patients with detectable labile plasma iron levels is independent of risk of disease progression.52 Iron overload also increases transplant-related mortality in haematopoietic stem cell transplantation (HSCT) in MDS patients53 and total transfusion burden implied a worse prognosis in a European Society for Blood and Marrow Transplantation (EBMT) study.54 Routine estimations of iron loading can be made by serial monitoring of ferritin and tracking of red cell units transfused. However, there is little correlation between units transfused, or serum ferritin, and the degree of organ iron deposition. Magnetic resonance imaging (MRI) for R2 (liver proton relaxation rate),55 or cardiac and liver T2* assessments56 can be used to help quantify hepatic and cardiac iron loading and its impact on organ function. Effective iron chelation may improve haemopoiesis. The EPIC study57 and the GIMEMA group58 showed an International Working Group (IWG) erythroid response in 15–25% of patients although median response duration was only eight weeks in the EPIC study. Platelet and neutrophil responses were also reported. Desferrioxamine has been shown to lower cardiac iron assessed by MRI measurements59 and deferasirox has been shown to improve alanine transaminase (ALT) levels.60 A German registry study showed that chelation therapy improved survival in almost 200 transfused lower-risk MDS patients,61 supported by prospective data from the EUMDS registry.62 Furthermore, it is now accepted that iron chelation prior to HSCT in congenital anaemia can improve transplant-related mortality.53 Although this is not yet proven to be the case in haematological neoplasms including MDS, a recent EBMT joint expert panel recommended chelation in patients who have received more than 20 units of blood prior to HSCT.63 Desferrioxamine remains the most efficient iron chelator available and is given subcutaneously in overnight infusions, which may decrease the labile iron pool. However, many patients find it uncomfortable and cumbersome, reporting QoL issues. Deferasirox and deferiprone are given orally and are generally well tolerated, although deferiprone is associated with agranulocytosis in around 4% of patients. Deferiprone should not be used routinely in patients with MDS, and only after careful consideration with a haematologist experienced in treating MDS. It should be undertaken with very careful monitoring (weekly blood counts), and should not be used where the baseline neutrophils are <1·5 × 109/l. Deferasirox is the only iron chelator currently licensed for use in MDS patients with proven reduction in labile iron and improved haemopoiesis in some patients.57, 64 It is recommended that all suitable lower-risk patients (IPSS low and intermediate-1; IPSS-R low and very low) should be considered for iron chelation therapy around the time they have received 20 units of red cells, or when the ferritin is more than 1 000 μg/l. Patients should have ferritin levels measured every 12 weeks and have ophthalmological and auditory examinations before commencing therapy and annually while on treatment. Iron chelation with deferasirox should be stopped if the ferritin falls below 500 μg/l and desferrioxamine should be stopped if the ferritin falls below 1 000 μg/l. Patients who are considered suitable for HSCT should have iron levels monitored and iron chelation therapy given prior to transplant, if time allows. Deferasirox is only licensed second line (after desferrioxamine) for the treatment of chronic iron overload due to blood transfusions in patients with anaemia, such as MDS. However, real-world experience is that deferasirox is better tolerated, compliance is far superior and safety data are now mature. For these reasons, expert opinion is that deferasirox is the drug of choice for transfusion-related iron overload in patients with MDS. Desferrioxamine remains an option in those resistant to or intolerant of deferasirox. The two drugs may be combined in exceptional circumstances with heavy cardiac iron overload, but only under the supervision of a haematologist experienced in MDS treatment, although there are no data to support the combination. There is no contra-indication to the use of iron chelation in combination with other disease-modulating treatments such as lenalidomide or azacitidine. MDS with isolated del(5q) is a distinct diagnostic entity that features macrocytic anaemia, normal or high platelet count, characteristic non-lobulated megakaryocytes and <5% bone marrow blasts. A single additional cytogenetic abnormality other than −7 or −7q is permitted within this diagnostic category. It is associated with female preponderance and has a relatively indolent natural history, with a median survival of six years in those with an IPSS score of 0.65 Independent predictors for OS include transfusion dependence, age and thrombocytopenia.66 Responses of patients with del(5q) MDS to ESA are inferior to that seen in low-risk MDS patients lacking del(5q) (39% vs 52%).67, 68 Nonetheless, given the established safety and efficacy data for ESA, ESA should be first-line therapy for symptomatic anaemia in lower-risk MDS patients with del(5q). The MDS004 study compared lenalidomide with placebo in low and INT-1 transfusion-dependent MDS with del(5q); 58%, 42% and 6% of patients receiving lenalidomide 10 mg, 5 mg or placebo, respectively, achieved transfusion independence.69 Cytogenetic responses were also seen in the lenalidomide treatment groups. Lenalidomide is licensed for transfusion-dependent low/INT-1 MDS with isolated del(5q) (with up to one abnormality other than −7/7q) and is recommended for NHS commissioning (NICE TA322) for such patients who have failed or are unresponsive to ESAs. Concerns about the risk of progression to AML with lenalidomide have not been confirmed in retrospective studies,70, 71 post-MDS-004 study monitoring,72, 73 or a recent meta-analysis.74 Rather, improved survival and reduced risk of transformation have been shown. Nonetheless, the MDS-004 study showed that progression to AML was 40% at five years compared to historically reported data of 20%. Follow-up studies have demonstrated that clonal evolution from existing or acquired TP53 mutations result in higher rates of AML transformation in del(5q) MDS patients.75-77 However, some TP53-mutated cases with del(5q) have durable (2–3 years) responses to lenalidomide. Thus, TP53 mutation is not a contra-indication to lenalidomide therapy, but requires careful discussion and monitoring in this subgroup. Thromboprophylaxis should be considered on an individual basis. Approximately 10–20% of MDS patients have decreased marrow cellularity.78 The WHO classification of myeloid neoplasm designates this hypoplastic MDS (h-MDS), although it does not assign it a distinct category.79 Hypocellularity in MDS can present diagnostic difficulties with other bone marrow failure (BMF) syndromes especially aplastic anaemia. A study integrating cytohistological and genetic features in adult patients with hypocellular bone marrows has led to proposed criteria to define h-MDS.78 This separates patients into two distinct groups, one with features highly consistent with a myeloid neoplasm and one more consistent with a non-malignant BMF. The two groups have significantly different risk of blast progression and OS. Flow cytometric immunophenotyping for paroxysmal nocturnal haemoglobinuria should be performed in patients with h-MDS. It would seem reasonable that those patients with h-MDS and features consistent with a myeloid neoplasm should have an MDS management strategy although tolerance and efficacy need to be considered. Allogeneic stem cell transplantation may be considered for eligible patients. Conversely, those with features more in keeping with BMF should be considered for treatment strategies aimed at BMF, such as immunosuppression. The BSH Guidelines for the Diagnosis and Management of Adult Patients with Aplastic Anaemia should be referred to for treatment strategies of BMF.80 See section on allogeneic stem cell transplantation in MDS below. Patients with high-risk MDS (INT-2/high IPSS or high/very high IPSS-R scores) have a significant risk of progression to AML with a median survival of 0·8–1·6 years.81 Some IPSS-R Intermediate Risk Group patients may also have early progression of disease and poor outcomes. Strategies for those suitable for active therapy should be aimed both at improving cytopenias and altering the natural history of disease to delay progression to AML and improve survival. Patients should be given the opportunity to take part in appropriate clinical trials. As allogeneic HSCT is the only therapy with curative potential, clinicians should initially determine at diagnosis whether a patient is a possible transplant candidate and review this regularly. Early discussion with a transplant unit is recommended. An algorithm for the management of high-risk MDS is seen in Fig 2. For patients not eligible for transplantation, intensive AML-style chemotherapy can be used in an attempt to achieve disease response and improve survival. Patients should be entered into clinical trials where possible. The advantages of intensive chemotherapy are the QoL improvement if complete remission (CR) is achieved, and the small possibility of long-term disease-free survival. There have been reported cases of long-term survival (>4 years) in patients with high-risk MDS and lacking an unfavourable karyotype.82 However, older patients frequently have comorbidities, making intensive regimens less well tolerated. Overall, remission rates are lower (40–60%) than in de novo AML, remission duration is often shorter (median duration 10–12 months) and therapy-related complications of marrow aplasia (infection and haemorrhage) more frequent.82-85 Analysis of 160 patients over the age of 60 years with high-risk MDS or AML showed an early death rate of 10% and an inability to deliver consolidation chemotherapy in 40 of the 96 (42%) patients who achieved CR.84 Compared to those with a normal karyotype who had a median survival of 18 months, those with a high-risk karyotype (involving 3 or more unrelated abnormalities or chromosome 7 abnormality) had a median survival of four months. The largest study of intensive chemotherapy for high-risk MDS broadly supports these data.86 For this reason, it is recommended that cytogenetic results are available before committing to intensive chemotherapy in older patients with MDS, as there is no evidence to suggest this delay in treatment would be detrimental.87 Hypomethylating agents (azacitidine, decitabine) offer an alternative to intensive treatment in high-risk MDS. They are not curative but may result in transfusion independence, improved QoL and survival benefit and are well tolerated in the elderly and in patients with comorbidities. Azacitidine is recommended by NICE and the Scottish Medicines Consortium as a treatment option for adult patients with MDS not eligible for HSCT (IPSS INT-2 or High) and for AML with 20–30% blasts and lineage dysplasia. The recommended dose is 75 mg/m2 for seven consecutive days, repeated at 28-day intervals. The AZA001 study88 showed that azacitidine significantly increased OS compared to conventional-care regimens (median OS 24·5 vs 15·0 months).88 Azacitidine also resulted in haematological responses; 45% of patients became transfusion-independent compared to 11% receiving conventional care. In a subgroup analysis of patients ≥75 years, azacitidine also significantly improved two-year OS compared to conventional care (55% vs 15%), suggesting that this is the treatment of choice in older higher-risk MDS patients with good performance status.89 Even patients with poor-prognosis cytogenetic profiles may benefit from azacitidine treatment.90 Reliable molecular predictors of response have not been identified, although patients with poor-prognosis indicators, including TP53 mutations, may respond. However, the presence of increasing numbers of mutations may be associated with a lower likelihood of response.91 Practical guidance for the delivery of azacitidine has been published.92 Patients who receive less than six cycles or who fail to respond after six cycles have poor outcomes.93, 94 In the absence of progression and where azacitidine is tolerated, a minimum of six courses is recommended, with continued therapy for as long as response is maintained. Patients should have a marrow examination before starting treatment, after six courses (to assess response) and subsequently at clinician discretion should disease progression be suspected. In selected younger patients who achieve a CR with azacitidine and have good performance status, the option of HSCT should be re-visited. Ongoing studies are exploring the combination of azacitidine with other agents in high-risk MDS. The benefits of azacitidine have largely (but not uniformly) been confirmed in ‘real-world’ studies. However, OS in four large data sets has not matched that reported in the original pivotal trial.88 The Canadian, Spanish and French Groups reported OS for azacitidine-treated patients with higher-risk MDS of 12·4, 13·4 and 13·5 months, respectively.93-95 Alternative dosing schedules for azacitidine include 75 mg/m2 for five days, no treatment