Advances in myelodysplastic syndromes: promising novel agents and combination strategies

ABSTRACT

Introduction

Myelodysplastic syndromes (MDS) are heterogeneous group of clonal hematopoietic stem cell neoplasms that have limited approved treatment options. Multiple novel agents are currently being tested in a clinical trial setting. From a therapeutic perspective, MDS is generally divided into lower-risk and higher-risk disease. In this review, we summarize some of the most prominent novel agents currently in development.

Areas covered

This review focuses on select clinical trials in both lower- and higher-risk MDS, elucidating the mechanisms of action and rationale for drug combinations and summarizing early safety and efficacy data using novel agents in MDS.

Expert opinion

Advances in understanding the innate immune system, telomere biology, as well as genomic drivers of the disease have led to the development of multiple novel agents that are currently in late stages of clinical development in MDS. Imetelstat is being tested in lower-risk disease and the phase III clinical trial recently completed accrual. Magrolimab, sabatolimab, and venetoclax in addition to novel oral hypomethylating agents (HMA) are being investigated in higher-risk MDS. These advances will hopefully bring better treatment options to patients and lead to a shift in the treatment paradigm. Post HMA therapy remains an area of dire unmet need.

Plain Language Summary

MDS are rare bone marrow cancers that lead to low blood counts and carry the risk of disease progression to acute myeloid leukemia. The disease risk (lower vs higher) determines the treatment approach. For lower-risk MDS, the focus has been to improve blood counts and patients’ quality of life. Novel treatment strategies are moving earlier in the course of disease to perhaps delay progression. In higher-risk MDS, the goal is to prolong survival and delay progression to acute leukemia. Multiple advanced-phase clinical trials are ongoing to evaluate agents in combination with azacitidine that have shown encouraging results in earlier-phase studies.

KEYWORDS:

• Myelodysplastic syndromes
• targeted therapies
• novel agents
• mechanisms
• MDS biology

Article highlights

• Management of lower-risk MDS and higher-risk MDS has heavily relied on using IPSS and Revised IPSS scoring systems. The development of IPSS-molecular (IPSS-M) scoring system may eventually impact which patients receive treatment in lower- vs. higher-risk MDS trials.

• Novel agents in lower-risk MDS include imetelstat and roxadustat which are in late stages of development, and other agents such as IRAK4 inhibitors, TPO agonists, or moving approved therapies earlier in the course of disease are discussed.

• Several drugs in late stages of development are being investigated in combination with azacitidine in the frontline setting for higher-risk MDS are highlighted here. Post HMA setting and TP53-mutated MDS are areas of unmet need for novel drug development as limited options exist for the vast majority of patients.

Declaration of Interest

YF Madanat has received honoraria/consulting fees from BluePrint Medicines, GERON, and OncLive, has participated in advisory boards and received honoraria from Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, Morphosys, Taiho Oncology, and Novartis, and received travel reimbursement from Blueprint Medicines and Morphosys.

AM Zeidan received research funding (institutional) from Celgene/BMS, AbbVie, Astex, Pfizer, MedImmune/AstraZeneca, Boehringer-Ingelheim, Trovagene/Cardiff oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics; participated in advisory boards and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, and Tyme; served on clinical trial committees for Novartis, AbbVie, Geron, and Celgene/BMS. None of these relationships were related to this work. All figures are created with Biorender.com.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded