The Rising Era of Immune Checkpoint Inhibitors in Myelodysplastic Syndromes

Abstract

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases characterized by ineffective hematopoiesis and a wide spectrum of manifestations ranging from indolent and asymptomatic cytopenias to acute myeloid leukemia (AML). MDS result from genetic and epigenetic derangements in clonal cells and their surrounding microenvironments. Studies have shown associations between MDS and other autoimmune diseases. Several immune mechanisms have been identified in MDS, suggesting that immune dysregulation might be at least partially implicated in its pathogenesis. This has led to rigorous investigations on the role of immunomodulatory drugs as potential treatment options. Epigenetic modification via immune check point inhibition, while well established as a treatment method for advanced solid tumors, is a new approach being considered in hematologic malignancies including high risk MDS. Several trials are looking at the efficacy of these agents in MDS, as frontline therapy and in relapse, both as monotherapy and in combination with other drugs. In this review, we explore the utility of immune checkpoint inhibitors in MDS and current research evaluating their efficacy.

Clinical performance and utility of a comprehensive next-generation sequencing DNA panel for the simultaneous analysis of variants, TMB and MSI for myeloid neoplasms

“…Unlike solid tumors where TMB and/or programmed death ligand 1 (PD-L1) expression have been validated as biomarkers to identify patients who may benefit from ICI, their utility in AML and MDS is yet to be established [ 24 ]. Nevertheless, several studies have reported benefit of ICI in combination with standard therapies including hypomethylating agents in AML and MDS, though the mechanism appears to be enhancement of graft-versus-tumor effect and is independent of TMB [ 25 , 26 ]. Cut-off values for TMB vary considerably across histological types of malignancies.…”

Immune checkpoint-based therapy in myeloid malignancies: a promise yet to be fulfilled

“…Lastly, immune regulation within the bone marrow is a complex interplay between T-cells, mesenchymal stromal cells, myeloid-derived suppressor cells, and various soluble factors. These interactions are highly complex and have been reviewed in detail elsewhere 18,41,42 .…”

Molecular Targeted Therapy in Myelodysplastic Syndromes: New Options for Tailored Treatments

“…Aberrant immune function and dysregulation of immune checkpoint (IC) molecules represent a known pathophysiological aspect of MDS, providing the rationale for studying the role of IC inhibitors (ICI) in those patients, especially after HMA failure [ 122 , 123 , 124 ].…”