The role of hematopoietic cell transplantation as therapy for myelodysplasia. Another oral DAC combination (ASTX727) includes the cytidine deaminase inhibitor cedazuridine, which is being tested in first-line treatment (NCT03306264). Patients with a very high MDS transplantation risk score, based on combination of advanced age, high HCT-CI, very poor-risk cytogenetic and molecular features, and high IPSS-R score have a low chance of cure with standard HSCT and consideration should be given to treating these patients in investigational studies.
In the future, a change of the current observational strategy in this subgroup of patients may be called for when novel and safe treatments capable of modifying the natural history of “very early MDS” disease become available. Priorities of therapeutic interventions in patients with MDS according to disease stage. *Not presently approved.

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However, a phase 3 placebo-controlled study in intermediate-1 risk MDS patients with RBC-TD and thrombocytopenia (NCT01566695) has recently been prematurely terminated because of toxicity.40. Allogeneic stem cell transplantation in MDS: how? The expert panel could not recommend a specific method to evaluate iron overload in the transplant setting. A comprehensive diagnostic workup, nowadays including a panel of molecular abnormalities,3  is mandatory and can provide important prognostic (detailed in scoring systems) and predictive factors for a subsequent response to a given therapy, as is the case for del(5q) and lenalidomide.4. 2020 May 27;4(3):e357.

USA.gov. Alternative Stem Cell Sources. The outcome of higher-risk MDS patients and poor-risk cytogenetics was inferior when patients were transplanted in CR, compared with comparable patients who received upfront HSCT. In patients with lower-risk disease, HSCT may be best carried out when progression occurs to intermediate-1 risk (by IPSS) or intermediate risk by WPSS.64  Several poor-risk factors, including frequent RBC transfusions (≥2 units per month), life-threatening cytopenias (neutrophil counts, <0.3 × 109/L or platelet counts, <30 × 109/L) and very-poor prognostic cytogenetic markers might be identified both in lower-risk and in intermediate-risk patients and justify HSCT early after diagnosis (Figure 1). Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial, Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial, Karyotype evolution and acquisition of FLT3 or RAS pathway alterations drive progression of myelodysplastic syndrome to acute myeloid leukemia, H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers, Preliminary results show flotetuzumab well-tolerated and effective in relapsed/refractory AML and MDS, © 2019 by The American Society of Hematology, Copyright ©2020 by American Society of Hematology, Diagnostics in MDS: the first step toward an individual prognostication and treatment, Current standard of care in treating patients with MDS, Novel concepts in the treatment of HR-MDS, https://doi.org/10.1182/blood-2018-10-844696, Introduction to a review series on myelodysplastic syndromes, The central role of inflammatory signaling in the pathogenesis of myelodysplastic syndromes, MDS overlap disorders and diagnostic boundaries, Proposals for revised IWG 2018 hematological response criteria in patients with MDS included in clinical trials, Genetic predisposition to MDS: clinical features and clonal evolution. There is a particularly urgent medical need in patients failing current first-line therapies, such as with erythropoiesis-stimulating or hypomethylating agents. 2020 Aug 12;12(8):2255. doi: 10.3390/cancers12082255. Prognostic tools, including performance status (eg, Karnofsky score) and HSCT-specific CI (HSCT-CI),14  show a strong prognostic impact on outcome, independently of disease characteristics. Thrombocytopenia and neutropenia are less frequent than anemia in LR-MDS, and their treatment has proven more difficult. The impact of MRD on outcome was significantly different between patients who received RI regimens and patients who received a MA regimen. The ELN and the National Comprehensive Cancer Network (NCCN) formulated the general recommendation for HSCT at diagnosis based on the International Prognostic Scoring System (IPSS).7,8  The panel recognized the disease risk scored according to the revised IPSS (IPSS-R) and Comorbidity Index (CI), graded according to the Hematopoietic Cell Transplantation–Comorbidity Index (HCT-CI), as the most relevant clinical variables for patients for HSCT eligibility.

The new cytogenetic risk classification19,28  has prognostic significance following HSCT. Contribution: All authors contributed to the literature review, drafted specific sections of the manuscript, contributed to the preliminary versions and the final version of the manuscript, and approved the final version of the manuscript.
The scope of this review, describing the current therapeutic landscape in MDS, is to highlight the new frontiers that have recently been opened up through a better understanding of the molecular pathophysiology and through clinical and translational research.

Roxadustat promotes erythropoiesis by increasing endogenous EPO levels and improves iron regulation by modulating hepcidin levels. Other potentially available approaches include the use of targeted molecular therapies (eg, with IDH or FLT3-inhibitors).80,81,94  IDH181  or IDH2 inhibitors80  have shown meaningful clinical activity in relapsed AML including a small subset of MDS patients.80  FLT-3 inhibitors have already been approved in the United States for second-line treatment of patients with AML and may thus offer a therapeutic option in rare FLT-3 mutated cases with disease progression (Figure 4).

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