Novel Therapies for Unmet Clinical Needs in Myelodysplastic Syndromes

Abstract

Myelodysplastic syndromes (MDS) are a very heterogeneous disease, with extremely variable clinical features and outcomes. Current management relies on risk stratification based on IPSS and IPSS-R, which categorizes patients into low (LR-) and high-risk (HR-) MDS. Therapeutic strategies in LR-MDS patients mainly consist of erythropoiesis stimulating agents (ESAs), transfusion support, and luspatercept or lenalidomide for selected patients. Current unmet needs include the limited options available after treatment failure, and the consequent transfusion burden with several hospital admissions and poor quality of life. Therapeutic approaches in HR-MDS patients are aimed at changing the natural course of the disease and hypometylating agents (HMA) are the first choice. The only potentially curative treatment is allogeneic stem cell transplant (allo-HCT), restricted to a minority of young and fit candidates. Patients unfit for or those that relapse after the abovementioned options harbor an adverse prognosis, with limited overall survival and frequent leukemic evolution. Recent advances in genetic mutations and intracellular pathways that are relevant for MDS pathogenesis are improving disease risk stratification and highlighting therapeutic targets addressed by novel agents. Several drugs are under evaluation for LR and HR patients, which differ by their mechanism of action, reported efficacy, and phase of development. This review analyzes the current unmet clinical needs for MDS patients and provides a critical overview of the novel agents under development in this setting.

Keywords: immunotherapy; myelodysplastic syndromes; somatic mutations; target therapy; unmet needs.

Figure 1

Novel therapies for myelodysplastic syndromes: immunologic, epigenetic and molecular targets. The physiopathology of myelodysplasia implies several pathogenic mechanisms, including epigenetic alterations, the disruption of intracellular molecular pathways, and the derangement of immunosurveillance that favors leukemic immune escape. All these pathogenic mechanisms may represent a target for novel drugs. For instance, immune checkpoint inhibitors, such as nivolumab, atezolizumab, durvalumab, ipilimumab, magrolimab, are able to restore T cells and adaptive and innate immunity to target dysplastic hematopoietic stem cells. Other immunotherapies include bispecific antibodies, such as flotetuzumab, and in the future, CART cells. Drugs that target intracellular pathways include luspatercept, galunisertib, sabatolimab, pevonedistat, imetelstat, pexmetinib, venetoclax, tomaralimab, roxadustat, and rigosertib and these act on various levels in cell maturation, survival/apoptosis, ineffective erythropoiesis, response to hypoxia, and telomeres elongation. Targeting epigenetic alteration by hypomethylating agents such as azacytidine, decitabine and novel agents (guadecitabine, decitabine/cedazuridine) restores MDS maturation. Finally, specific mutation inhibitors include H3B-8800, ivosidenib, enasidenib and eprenetapopt, which restore hematopoietic differentiation. Novel drugs for low-risk MDS are represented in blue boxes, drugs for high-risk MDS in green boxes and drugs for low-risk and high-risk MDS in red boxes.