Hypomethylating agent combination strategies in myelodysplastic syndromes: hopes and shortcomings

Abstract

The hypomethylating agents (HMA) azacitidine and decitabine are both approved by the FDA for the treatment of myelodysplastic syndromes (MDS). Although heralded as a significant advancement, HMA lead to responses in less than half of patients and for those that respond most will relapse. As such, there is a crucial need to improve frontline therapy approaches. One promising strategy involves combining azacitidine or decitabine with investigational or existing therapies with the goal of achieving synergistic activity and better patient outcomes. The purpose of this paper is to critically review the efficacy and safety of reported HMA-based combination regimens in patients with higher-risk MDS.

Keywords: AML; DNA methyltransferase inhibitor; MDS; combination therapy; epigenetic; hypomethylating agent.

Figure 1. Overview of current therapies used in combination with hypomethylating agents in MDS

A) HDAC inhibitors remove acetyl molecules on histone and non-histone proteins to regulate transcription and multiple physiologic processes. B) Lenalidomide activates the CRBN-CRL4 E3 ubiquitin ligase leading to degradation of casein kinase 1A1 (CSNK1A1) and p53 mediated apoptosis in patients with 5q- haploinsufficiency. The mechanism of lenalidomide in patients without the 5q- deletion is less clear. C) ESAs and TPO mimetics bind to growth factor receptors to promote production of RBCs and platelets, and potentially mitigate treatment associated cytopenias. D) Kinase and multikinase inhibitors target cell signaling pathways essential to leukemogenesis. E) The antibody drug conjugates gemtuzumab ozogamicin and SGN-CD33A target the myeloid marker CD33, and are linked to cytotoxic agents. F) The oral nucleoside analog sapacitabine is incorporated into DNA leading to single-strand breaks and G2/M cell cycle arrest. G) IDH inhibitors decrease conversion of α-ketoglutarate to β-hydroxyglutarate, a metabolite responsible for impairing TET2 mediated hydroxymethylation; H) The inducers of apoptosis, AEG35156 and SMAC degrade the inhibitor of apotosis proteins (IAP) thereby promoting programmed cell death. I) Immune checkpoint proteins (e.g. PD-1, CTLA4, PD-L1, and PD-L2) are upregulated after pretreatment with hypomethylating therapy and are therefore potential targets for checkpoint inhibitor therapies. J) Upregulation of tumor antigens (e.g. PRAME and SSX2) with hypomethylating therapy also has the potential to serve as targets for chimeric antigen receptor (CAR) or T cell receptor (TCR) based adoptive T cell therapies.