Venetoclax plus azacitidine in higher-risk myelodysplastic syndromes: a treatment-purpose framework for interpreting...

Venetoclax plus azacitidine has demonstrated substantial clinical activity in treatment-naïve higher-risk myelodysplastic syndromes (HR-MDS), including high rates of complete remission, marrow complete remission, and overall response. However, recent phase 3 experience indicates that greater response depth does not necessarily translate into improved overall survival. We propose a treatment-purpose framework for interpreting the clinical value of venetoclax plus azacitidine in HR-MDS. This framework first distinguishes its potential use as a bridge to allogeneic haematopoietic stem cell transplantation from its use for non-transplant disease control. For patients treated with transplant intent, rapid blast reduction, preservation of transplant readiness, the proportion proceeding to transplantation, and post-transplant outcomes should be prioritised. For patients without transplant intent, durable haematological improvement, transfusion independence, symptom control, infection burden, hospitalization, treatment interruption, and quality of survival may be more clinically meaningful. Molecular and cytogenetic variables, including TP53 status, complex karyotype, and IPSS-M risk, should currently support stratified evaluation rather than direct treatment selection. Future studies should align response assessment and clinical endpoints with treatment intent, molecular risk, tolerability, and long-term outcomes.