Hypomethylating agents (HMAs) are the current standard of care in high-risk myelodysplastic syndromes (MDS). However, only ∼50% of patients with MDS respond to HMAs and most responding patients eventually progress.1,2 Outcomes after HMA failure are particularly poor, with a median overall survival (OS) of 4 to 6 months.3,4 Venetoclax is an oral selective inhibitor of the anti-apoptotic protein BCL-2 and, in combination with azacitidine, increased responses and prolonged survival when compared with azacitidine alone in a phase 3 study for patients with previously-untreated acute myeloid leukemia (AML), ineligible for intensive chemotherapy.5 Preclinical studies have demonstrated that BCL-2 is overexpressed in high-risk MDS, and BCL-2 inhibition induces apoptosis in MDS progenitor cells.6,7 However, MDS is defined by bone marrow dysplasia and cytopenias, and the addition of venetoclax to HMAs in MDS has potential for cumulative myelosuppression. Phase 1 studies evaluating venetoclax in combination with HMAs in treatment-naïve and relapsed/refractory (R/R) MDS are currently under investigation.8,9 Here, we present real-world evidence supporting the use of venetoclax in combination with HMAs in patients with MDS. We also identify risk factors impacting response and survival after treatment with the combination.
