Cytogenetic and molecular associations with outcomes of HMAs plus venetoclax for higher-risk myelodysplastic syndromea: pooled analysis

Hypomethylating agents (HMAs) combined with venetoclax are an emerging therapeutic strategy for higher-risk myelodysplastic syndromes (HR-MDS). The cytogenetic and molecular factors associated with outcomes with this combination for HR-MDS are incompletely understood. Pooled analysis of 3 prospective trials included 80 patients (52 HMA-naïve, 28 HMA-failure). The ORR was 90% in HMA naïve and 57% in HMA-failure, while median OS was 28.2 and 8.3 months, respectively, and median EFS was 17.9 and 5.5 months, respectively. Forty-six percent of the HMA naïve and 11% of the HMA-failure patients proceeded to allogeneic stem cell transplantation. Factors associated with inferior outcomes were prior HMA failure, complex cytogenetics, trisomy 8, TP53 mutation, and RAS pathway mutations. Mutations in RNA splicing, DNA methylation, and ASXL1 appeared favorable. Blast percentage was not predictive of outcomes. The authors conclude that knowledge of cytogenetic and molecular alterations may help identify which patients with HR-MDS benefit the most from HMA plus venetoclax.