Frontline treatment options for higher-risk MDS: can we move past azacitidine?

Although remarkable international efforts have been ongoing for over 17 years to improve upon azacitidine, representing the standard of care therapy for higher-risk myelodysplastic neoplasms (MDS), there still has not been a positive randomized trial in comparison to azacitidine. Real-world data from numerous trials have shown similar results with a median overall survival of 14-18 months, a 40%-50% overall response rate, and a complete remission rate close to 20%. Despite these outcomes, 6 randomized controlled trials have failed to improve outcomes in this patient population, although relevant issues in some of these studies included improper dose adjustments of the hypomethylating agent, lack of placebo- controlled studies, and lack of overall survival (OS) as a primary endpoint, among others. Critical updates in MDS management include the development of molecular prognostication models (eg, the molecular international prognostic scoring system), updates in classification systems highlighting significant overlap in patients with MDS-increased blasts and acute myeloid leukemia (most relevant to TP53 mutations), and refinement of response criteria. Although these paradigm-shifting studies have had great impact in MDS management, the current ongoing randomized phase 3 trials were initiated prior, and prognostic stratification remains via the revised international prognostic scoring system) and with bone marrow blast counts of <20%. Notably, azacitidine + venetoclax, azacitidine + sabatolimab, and azacitidine + magrolimab have shown exciting results in large, single-arm studies and have completed accrual in placebo-controlled, double-blind studies with OS as a primary endpoint. We all eagerly await the results of these studies.
(Copyright © 2023 by The American Society of Hematology.)