It is time to shift the treatment paradigm in myelodysplastic syndromes: A focus on novel developments and current investigational approaches exploring combinatorial therapy in high-risk MDS. Issue 4 (December 2021)

• Record Type: Journal Article
• Authors: Aguirre, Luis E.; Komrokji, Rami; Padron, Eric
• Is Part Of: Baillière's best practice and research in clinical haematology. Volume 34:Issue 4(2021)
• Publication Date: 2021-12
• Subjects: Myelodysplastic syndromes -- Novel therapies -- TP53 -- NEDD8-activating enzyme -- TIM-3 -- Anti-CD47; Hematology -- Periodicals; Blood -- Periodicals; Hematologic Diseases -- Periodicals; Electronic journals; 616
• DOI: 10.1016/j.beha.2021.101325
• Languages: English
• ISSNs: 1521-6926

Abstract

Abstract: Higher risk myelodysplastic syndromes are defined as a subset of disease with higher risk of AML transformation and poor overall survival. For decades, therapeutic options for high-risk MDS have been limited to allogeneic stem cell transplant (the only option for cure but limited to only a handful of patients) or hypomethylating agents, with the goal to alter the natural history of disease, delay progression and improve survival, while addressing cytopenias, transfusion requirements and improving quality of life. Recent developments in DNA sequencing and other technologies have shed significant light into the pathogenesis of MDS and led to rational and targeted drug development across a variety of therapeutic vulnerabilities, including disruption of protein ubiquitination through NAE inhibition, selective modulation of macrophage activity and immune checkpoint inhibition through blockade of TIM-3. This review highlights some of the most promising agents in recent drug development and their therapeutic efficacy in the management of high-risk MDS, and further explores the rationale behind potential combinatorial approaches using an HMA backbone to synergistically improve treatment outcomes. Highlights: Novel approaches for HR MDS aim to improve duration of response/efficacy via synergistic combinations using HMA backbones. Pevonedistat, a NAE inhibitor, has shown promise in preclinical models via disruption of ubiquitination and HMA synergism. Eprenetapopt, a reactivator of mutant TP53, showed a 53% higher CR when combined with azacitidine in TP53 MT HMA-naïve MDS. Magrolimab, a monoclonal antibody that acts as a macrophage ICI, showed a 6-month CR of 56% when combined with azacitidine. Azacitidine/venetoclax combos can achieve higher ORR and deeper MRD status at the expense of profound myelosuppression. A phase 1b study of satolimab (TIM-3 inhibitor) in combination with HMAs showed an ORR of 64.1% among patients with HR MDS.