Advances and challenges in the treatment of myelodysplastic syndromes

Abstract

Myelodysplastic syndromes (MDS) is a heterogeneous group of pre-leukemic diseases characterized by peripheral blood cytopenia, morphologic dysplasia, and an increased risk of transformation to leukemia. MDS develop from genetically mutant clonal hematopoietic stem and progenitor cells (HSPCs) which have defects in generating mature functional blood cells due to impaired differentiation and/or survival activities. In addition, mutant HSPCs also inhibit the generation of new blood cells from remaining healthy HSPCs. Thus, the complete elimination of mutant HSPCs is the optimal goal for MDS treatment. However, most current therapies for MDS are little more than palliative, primarily addressing cytopenia-related symptoms and improving the quality of life. Only the hypomethylating agents (HMA) lenalidomide and imetelstat reduced the mutational burden, and then only in a small subset of cases. Many HMA-based combination therapies failed to show benefits superior to single-agent HMA treatment in clinical trials. At the present time, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still the only cure for the minority of qualified patients who have HLA-matched donors. Novel effective treatments are urgently needed. Here we summarize the current standard therapeutic approaches for MDS patients and discuss major advances in MDS research and treatments. We also discuss major challenges and potential solutions to overcome these challenges for future MDS research and drug development.

Keywords: Challenges; Innate immunity; MDS; Treatments.

Fig. 1

Current treatments for MDS patients. Patients are classified based on LPSS diagnostic criteria. Based on the classification into (A) LR or (B) HR in addition to other factors, different treatment strategies are employed. LR: low-risk; HR: high-risk; TD: transfusion dependency; RARS: refractory anemia with ring sideroblasts; LEN: lenalidomide; IST: immune-suppressive therapies; ESAs: erythropoietic stimulating agents; allo-HSCT: allogeneic HSC transplantation; HMA: hypomethylating agents

Fig. 2

Diagram of MDS treatments and mechanisms. Based on patients’ clinical symptoms and IPSS-R scores, the treatment strategies for MDS patients include: A Improving blood cell counts to reduce cytopenia-related symptoms and morbidity by stimulating erythropoiesis and thrombopoiesis. B Targeting disease clones to delay AML transformation and prolong survival. C Targeting the innate immune system for MDS patients with overactive TLR signaling, targeting autoimmune signaling for MDS patients with hypocellular BM, and inhibiting RIPK1 for MDS with RIPK1-dependent cell death. The agents shown in green font are FDA-approved medications. The agents in black font are still in clinical trial evaluations, whereas the clinical trials for the agents in red font were terminated due to failure to meet their primary endpoints. The agents in blue font are still in pre-clinical evaluation