Myelodysplastic syndromes (MDS) include a group of clonal myeloid neoplasms characterized by cytopenias due to ineffective hematopoiesis, abnormal blood and marrow cell morphology, and a risk of clonal evolution and progression to acute myeloid leukemia (AML). Because outcomes for patients with MDS are heterogeneous, individual risk stratiﬁcation using tools such as the revised International Prognostic Scoring System (IPSS-R) is important in managing patients—including selecting candidates for allogeneic hematopoietic stem cell transplantation (ASCT), the only potentially curative therapy for MDS. The IPSS-R can be supplemented by molecular genetic testing, since certain gene mutations such as TP53 inﬂuence risk independent of established clinicopathological variables. For lower risk patients with symptomatic anemia, treatment with erythropoiesis-stimulating agents (ESAs) or lenalidomide (especially for those with deletion of chromosome 5q) can ameliorate symptoms. Some lower risk patients may be candidates for immunosuppressive therapy, thrombopoiesis-stimulating agents, or a DNA hypomethylating agent (HMA; azacitidine or decitabine). Among higher risk patients, transplant candidates should undergo ASCT as soon as possible, with HMAs useful as a bridge to transplant. Non-transplant candidates should initiate HMA therapy and continue if tolerated until disease progression. Supportive care with transfusions and antimicrobial drugs as needed remains important in all groups. Overview germline HFE mutations associated with hereditary Myelodysplastic syndromes (MDS) are deﬁned by inef- hemochromatosis may have an elevated risk of organ fective hematopoiesis resulting in blood cytopenias, and toxicity from iron overload with repeated red cell trans- clonal instability with a risk of clonal evolution to acute fusions. Functional defects in neutrophils or platelets may 1,2 myeloid leukemia (AML) . Patients with MDS collec- result in an infection or bleeding risk that is dispropor- tively have a high symptom burden and are also at risk of tionate to the degree of cytopenias . death from complications of cytopenias and AML . The Three drugs have been approved by the Food and Drug goals of therapy for patients with MDS are to reduce Administration (FDA) for use in MDS-related indications: disease-associated symptoms and the risk of disease pro- the orally administered immunomodulatory drug lenali- gression and death, thereby improving both quality and domide, and two parenterally administered nucleoside 4–6 quantity of life . analogs that are DNA hypomethylating agents (HMA), Because the median age at diagnosis of MDS is ~70 azacitidine, and decitabine. In addition to these agents, years, patients frequently have comorbid conditions that there is extensive off-label use of the erythropoiesis- 7,8 may inﬂuence outcomes and treatment approaches . For stimulating agents (ESA) epoetin and darbepoetin in instance, patients with established cardiovascular or pul- MDS, which is supported by National Comprehensive monary disease tolerate anemia poorly, while those with Cancer Network (NCCN) guidelines and therefore reim- 10,11 bursed by Medicare as a compendium use . No new drugs have been approved for MDS-related indications Correspondence: David P. Steensma (David_steensma@dfci.harvard.edu) since decitabine’s FDA approval in 2006 , underscoring Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to theCreativeCommons license, and indicate if changes were made. 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Blood Cancer Journal 1234567890():,; 1234567890():,; Steensma Blood Cancer Journal (2018) 8:47 Page 2 of 8 Table 1 2012 revised international prognostic scoring system for MDS (IPSS-R) Parameter Categories and Associated Scores (Scores in italics) Cytogenetic risk group Very good Good Intermediate Poor Very Poor 01 2 3 4 Marrow blast proportion ≤2.0% >2.0–<5.0% 5.0–<10.0% ≥10.0% 01 2 3 Hemoglobin ≥10 g/dL 8–<10 g/dL <8 g/dL 0 1 1.5 9 9 Absolute neutrophil count ≥0.8 × 10 /L <0.8 × 10 /L 0 0.5 9 9 9 Platelet count ≥100 × 10 /L 50–100 × 10 /L <50 × 10 /L 0 0.5 1 Risk group Total Proportion of patients in Median survival (survival data Time until AML progression (AML data score category (%) based on n= 7012) (years) available based on n = 6485) (years) Very low 0–1.0 19 8.8 Not reached Low 1.5–3.0 38 5.3 10.8 Intermediate 3.5–4.5 20 3.0 3.2 High 5.0–6.0 13 1.5 1.4 Very high >6.0 10 0.8 0.7 Cytogenetic risk group, very good: -Y, del(11q); good: normal; del(5q) ± 1 other abnormality del(20q), or del(12p); intermediate:+ 8, i(17q), del(7q), + 19, any other abnormality not listed including the preceding with 1 other abnormality; poor: −7 ± del(7q), inv(3)/t(3q)/del(3q), any 3 separate abnormalities; very poor: more than 3 abnormalities, especially if 17p is deleted or rearranged Sum scores on a 0–10 point scale Source: adapted from Greenberg P et al, Blood 120(12):2454–65 the importance of clinical trial enrollment; currently only series have been published assessing the prognostic a small proportion of patients with MDS are enrolled in importance of individual mutations, the IWG-PM is prospective interventional studies. currently assessing the utility of speciﬁc mutations in 14,15 more than 3000 patients . Among DNA sequencing Risk stratiﬁcation series already reported, TP53, NRAS, ASXL1, and EZH2 The most commonly used tool for risk stratiﬁcation in mutations are consistently associated with poor outcomes MDS is the 2012 revised International Prognostic Scoring while SF3B1 mutations are associated with more favorable 16–18 System (IPSS-R; Table 1), which was based on a multi- outcomes . variate assessment of clinicopathological variables and The IPSS-R has several limitations in addition to its lack outcomes in more than 7000 patients, conducted by the of molecular genetic information. For example, the IPSS- International Working Group for Prognosis in MDS R is only validated for adult patients with de novo disease (IWG-PM) . The IPSS-R takes into account the number at the time of diagnosis, and it describes expected out- 19,20 and degree of cytopenias, proportion of blasts in the comes for those treated with supportive care alone . marrow, and risk of the speciﬁc cytogenetic abnormalities Future prognostic tools will hopefully be validated for a present. The IPSS-R stratiﬁes patients into 5 risk groups; broader range of patients and will be dynamic, able to be collectively, the 2 lowest risk groups are often referred to applied at any time in the disease course. as ‘lower risk MDS’, while the 2 higher risk groups are Patients with therapy-related disease (t-MDS) asso- described as ‘higher risk MDS’. ciated with prior genotoxic exposure frequently have The intermediate risk IPSS-R group is heterogeneous, TP53 mutations or PPM1D mutations and a complex with some patients having a more indolent natural history karyotype . These patients were excluded from the IPSS- similar to lower risk MDS and others more aggressive R and should be considered to have very high risk disease. disease. This heterogeneity can be partly resolved by the Some patients with MDS have features of myeloproli- use of molecular genetic sequencing. While a number of ferative neoplasms, such as monocytosis (especially in Blood Cancer Journal Steensma Blood Cancer Journal (2018) 8:47 Page 3 of 8 chronic myelomonocytic leukemia) or extensive marrow discontinued early by a data safety monitoring committee ﬁbrosis. These patients have a distinct pathbiology, with because of excess leukemia and other disease progression over-representation of mutations such as JAK2, SRSF2, in the active treatment arm, a more recent update with SETBP1, CSF3R, and BCOR compared to patients with ﬁve-year follow-up shows no difference in outcomes MDS without proliferative features, and require a spe- between patients treated on that study with romiplostim cialized treatment approach that is not discussed further or placebo . A randomized trial with eltrombopag in 22,23 here . Patients with secondary MDS after another combination with azacitidine in a similar patient popu- marrow failure syndrome (acquired aplastic anemia, par- lation also showed a slight increase in progression in the oxysmal nocturnal hemoglobinuria, or a germline dis- active treatment arm . The dose of TPO mimetic order like Fanconi anemia or dyskeratosis congenita) also required to improve platelet count is typically higher in require a specially tailored approach. MDS than in the labeled indication of immune thrombocytopenia . Lower risk MDS Because growth factors have somewhat limited efﬁcacy Some patients with MDS have mild cytopenias and are in MDS, anti-T cell immunosuppressive therapy (IST; e.g., asymptomatic at the time of diagnosis. Early treatment of antithrombocyte globulin, corticosteroids, and cyclos- MDS is not known to be beneﬁcial in terms of preventing porine or tacrolimus) or HMA are frequently considered clonal evolution or death. Therefore, observation is for these patients, especially after failure of ESA or lena- appropriate for asymptomatic lower risk patients until lidomide. Selection of appropriate patients for IST is their cytopenias worsen or they become more challenging, as published reports are inconsistent about symptomatic. parameters that predict a higher likelihood of response; For patients with lower risk disease and anemia asso- however, excess blasts, therapy-related disease, and a ciated with MDS, two parameters are important in complex or monosomal karyotype predict lower like- treatment choice (Fig. 1). First, the serum erythropoietin lihood of response to IST . (sEPO) level reﬂects endogenous renal response to anemia A recent multicenter analysis of more than 300 MDS and is a strong predictor of the likelihood of clinical patients treated with IST other than corticosteroid response to ESA . Patients with lower risk MDS who monotherapy demonstrated that marrow cellularity less have a sEPO < 100 U/L have a greater than 70% chance of than 20% and blast proportion less than 5% were asso- responding to ESA, while for those patients with sEPO > ciated with a higher likelihood of transfusion indepen- 500 U/L, a trial of ESA is usually not warranted because dence and improved survival after immunosuppressive the response rate is <10%. Second, the presence of a therapy . In this multicenter series, information about clonally restricted deletion of the long arm of chromo- mutations that might predict response to IST such as some 5 including band q31 (del5q) is associated with a BCOR was not consistently available, but the presence of high erythroid response rate to lenalidomide (65–70% a paroxysmal nocturnal hemoglobinuria (PNH) clone or transfusion independence, and 30–40% cytogenetic HLA DR15 status, which had been found to be of value in 25,26 remission) . Patients with a complex karyotype that predicting response in smaller (mostly single-center) includes del5q and those with excess marrow blasts series, did not predict IST response. A trial of IST is respond less well to lenalidomide treatment than those reasonable in a lower risk patient who lacks excess blasts whose disease lacks these features. Lower risk MDS or a complex karyotype and who either has (1) anemia patients with anemia who lack del5q have a 26% response that has not responded to ESA or lenalidomide, or has (2) rate to lenalidomide therapy, and a brief trial of lenali- another severe cytopenia that either has not responded to domide is reasonable in such patients, although this usage growth factors or where the clinician elects not to use 27,28 is off-label . growth factors or the patient’s insurance will not pay for For patients with lower risk MDS who have other severe growth factors. IST is a particularly attractive considera- cytopenias beyond anemia, the most appropriate treat- tion if the marrow is hypocellular for age. ment approach is less clear . Neutropenia in patients Recently, results were reported from a multicenter with MDS often does respond to use of myeloid growth adaptive randomization clinical trial of a reduced schedule factors, but these have never been shown to improve HMA (i.e., three days of azacitidine 75 mg/m2/d per survival in MDS and have minimal effect on reducing month, or three days of decitabine 20 mg/m2/d per 11 39 infection risk . The thrombopoiesis-stimulating agents month) in lower risk MDS and MDS/MPN . The overall (thrombopoietin (TPO) mimetics) eltrombopag (oral) or response rate in this series was higher with decitabine romiplostim (injectable) can reduce platelet transfusion (32% transfusion independence rate and 70% overall needs and clinically signiﬁcant bleeding events in some response rate) than with azacitidine (16% transfusion 30–33 patients with severe thrombocytopenia . Although a independence rate and 49% overall response rate), so the randomized trial of romiplostim in lower risk MDS was adaptive randomization resulted in 65% of enrolled Blood Cancer Journal Steensma Blood Cancer Journal (2018) 8:47 Page 4 of 8 Fig. 1 MDS treatment algorithm as described in the text. Clinical trials should be considered for all patients, but is recognized that many patients will not have access to trials or will not be eligible for available trials or will not want to go on trials, especially those requiring travel to a major center. In fact only a very small proportion of patients with MDS are currently enrolled on prospective interventional trials. However, increased trial enrollment is an important goal given the continued poor outcomes with MDS. EPO erythropoietin, ESA erythropoiesis-stimulating agent, HMA DNA hypomethylating agent, IST immunosuppressive therapy (anti-thymocyte globulin, cyclosporine, or tacrolimus) patients being treated with decitabine compared to 35% anemia and ring sideroblasts. Luspatercept has not yet been well studied in patients without ring sideroblasts. with azacitidine. It is possible that three days of azaciti- dine represents underdosing even in lower risk patients and a randomized trial (NCT02269280) comparing ﬁve Higher risk MDS days of azacitidine to three days of decitabine or a sup- For patients with higher risk MDS, the ﬁrst question portive care strategy is ongoing. The optimal dose and that must be answered is whether the patient is a candi- schedule of HMA in both higher risk and lower risk MDS date for allogeneic hematopoietic stem cell transplanta- is unknown, and the doses and schedules of decitabine tion (ASCT). Two mathematical modeling analyses based and azacitidine used for patients with higher risk MDS are on Center for International Blood and Marrow Transplant myelosuppressive and may have a less favorable risk- Research (CIBMTR) data—one analysis focused on con- beneﬁt balance for those patients with lower risk MDS. Of ventional myeloablative transplant, the other inclusive of note, this trial of ‘lower risk’ patients enrolled 18% patients aged 60–70 years treated with a reduced-intensity patients with t-MDS and 19% with MDS/MPN overlap conditioning (RIC) approaches—show that life expectancy syndromes, who should not be considered lower risk. is improved by early transplant in this subgroup, if fea- 41,42 Clinical experience has shown that patients who fail to sible . Increased availability of alternate donors, respond to HMA rarely respond to IST, so IST after HMA including haploidentical donors and cord blood, mean is unlikely to be of value. that larger proportion of patients have the opportunity to Luspatercept is a fusion protein that binds to ligands of undergo SCT. Patients up to age 75 routinely undergo the activin II receptor, altering transforming growth factor transplant now, and in the future age may not be a lim- beta signaling and resulting in improved erythropoiesis in itation to ASCT if performance status remains excellent. some patients with lower risk MDS . A randomized trial While details about conditioning regimens for ASCT, of luspatercept versus placebo in patients with MDS and graft-versus-host prophylaxis and management, and post- ring sideroblasts (MEDALIST; NCT02631070) completed transplant infectious disease prophylaxis and pre-emptive accrual in 2017; if this trial is positive, it is likely that management are beyond the scope of this review, a recent luspatercept will be the next drug FDA approved for CIBMTR/Clinical Trials Network randomized trial of RIC MDS, and would be useful in lower risk patients with compared with myeloablative conditioning (MAC) is worth noting . This study enrolled patients aged 18–65 Blood Cancer Journal Steensma Blood Cancer Journal (2018) 8:47 Page 5 of 8 years with a low transplant comorbidity index and <5% however, if 5-day decitabine or azacitidine would be as marrow blasts, and randomly assigned them to receive effective as 10 day decitabine, and 10 day decitabine is MAC (n = 135) or RIC (n = 137) followed by ASCT from highly myelosuppressive with a high frequency of HLA-matched related or unrelated donors. While overall opportunistic infections. survival at 18 months was slightly higher with MAC, this HMA can decrease clonal burden and may therefore difference was not statistically signiﬁcant. RIC resulted in result in improved hematopoiesis, but do not eradicate transformed stem cells, so relapse is inevitable. The lower treatment-related mortality but at the cost of higher relapse rates compared with MAC. These data support mechanism of action of HMA is unclear, and may result the use of MAC as the standard of care for patients with from a combination of conventional cytotoxic, DNA MDS who are able to tolerate more intense conditioning. hypomethylation (no speciﬁc signature), and immune- It is not clear whether treatment of higher risk MDS related mechanisms including changes in interferon sig- prior to ASCT is beneﬁcial, but pre-transplant bridging naling and presentation of neoantigens as epitopes to the 52,53 therapy is often considered to cytoreduce disease, espe- immune system . This has led to difﬁculty in predict- cially for those patients who are going to go on to get RIC ing responders, and available molecular genetic assays do approaches and those who have more than 10% marrow not differentiate responders versus non-responders to an blasts . Pre-transplant cytoreductive therapy can also be extent that inﬂuences treatment selection. considered in those for whom there will be a delay in Once an HMA fails the patient, either via intolerance, transplant due to lack of donor availability or insurance resistance, or relapse after favorable response, there is no approval. In the past, intensive AML-type induction approved second-line therapy and the outlook is poor 54–56 chemotherapy was commonly used for pre-transplant with a median survival of less than six months . cytoreduction in MDS, but today HMA therapy is used far Addition of the bcl-2 inhibitor venetoclax (an off-label more frequently and outcomes are at least as good with use) can recapture response and a subset of patients for HMA as with intensive chemotherapy . whom HMA alone is inadequate, and ongoing trials are For those patients who are not transplant candidates, evaluating venetoclax both after HMA failure HMA therapy is most appropriate. In a randomized trial (NCT02966782) and in treatment-naïve patients of 358 higher risk MDS patients, azacitidine treatment (NCT02942290) . The immune checkpoint (PD1, PDL1, was associated with a median survival of 24 months CTLA4) inhibitors, despite their high rate of efﬁcacy in compared to 15 months in patients treated with intensive certain solid tumors, are of limited use as monotherapy in chemotherapy, low-dose cytarabine, or best supportive MDS, but are being evaluated in more than 10 different 46 58 care . A similar survival improvement has not been seen trials as combination therapy with HMA . Other com- in decitabine randomized studies, but these trials enrolled bination approaches including lenalidomide plus azaciti- a higher risk subgroup of patients and treated patients for dine and histone deacetylase inhibitors plus HMA have a shorter period of time, so that the trials are not com- not resulted in improved outcomes compared to HMA parable to the azacitidine study. These agents are con- alone despite in vitro synergy, largely due to excess 59–62 sidered comparable by most clinicians, with treatment myelosuppression and early treatment withdrawal .In choice left up to individual providers based on con- January 2018, it was announced that the ongoing INSPIRE siderations such as regional licensing of drug or local cost trial of the multikinase inhibitor rigosertib versus best considerations. Some studies of ‘real world’ experience supportive care in IPSS-R high and very high risk patients with azacitidine have not been able to replicate the sur- after HMA failure (NCT02562443) would increase its vival outcomes seen in the randomized trial, so the actual accrual goal because of promising early results. If the beneﬁts of HMA may be less than has been commonly results are favorable, rigosertib would be the ﬁrst drug presented . approved for second-line therapy in MDS. The optimal dose and schedule for each HMA is unclear; the best studied schedule of azacitidine is 75 mg/ Supportive care m per day for seven days every 28 days, whereas the most Support of patients with severe symptomatic anemia commonly used decitabine schedule for higher risk MDS with red cell transfusions and severe thrombocytopenia is 20 mg/m per day for ﬁve days every 28 days, which with platelet transfusions is a mainstay of therapy for 48–50 avoids weekend dosing . Lower doses have been stu- MDS. Fevers in patients with MDS must be taken ser- died in MDS but are not approved from a regulatory iously, and antimicrobial protocols for febrile neutropenia standpoint, and it is unclear if response rates mirror that followed carefully, as infection is the leading cause of 63,64 seen with the most widely studied regimens. Recently, a death in MDS . The beneﬁt of prophylactic anti- very high response rate was reported with 10-day deci- microbials is controversial. tabine treatment in patients with higher risk MDS or For patients with thrombocytopenia who are refractory AML associated with a TP53 mutation . It is not clear, to platelet transfusions, the TPO agonists mentioned Blood Cancer Journal Steensma Blood Cancer Journal (2018) 8:47 Page 6 of 8 above may be of help, and the antiﬁbrinolytic agents majority of patients diagnosed with MDS in 2018 will die epsilon-aminocaproic acid or tranexamic acid can reduce of complications of cytopenias . bleeding in some of those with recurrent mucosal 65 Acknowledgements hemorrhage . Androgens such as danazol or oxymetho- D.P.S. is supported by the Edward P. Evans Foundation. lone may improve hemoglobin or platelet count in a minority of patients, but liver tests must be monitored Conﬂict of interest Data safety monitoring committee: Janssen, Onconova, Takeda. Research during therapy and some older men may have difﬁculty support: H3 Biosciences, Celgene. Advisory board: Otsuka, Amphivena. with urinary retention due to an increase in prostate hyperplasia . Patients who receive repeated transfusions with red cells Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in may accumulate excess iron, which can cause tissue injury published maps and institutional afﬁliations. via generation of reactive free radicals. Iron chelation therapy with deferasirox or deferoxamine may be helpful Received: 29 January 2018 Revised: 9 February 2018 Accepted: 15 February in selected cases, but the effect of chelation on outcomes 2018 is controversial and such therapy is expensive (defer- asirox) or inconvenient (deferoxamine) . A randomized trial of deferasirox versus placebo in lower risk MDS References patients with red cell transfusion dependence and a serum 1. Tefferi, A. & Vardiman, J. W. Myelodysplastic syndromes. N. 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Published: May 24, 2018
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