Immune and cellular determinants of response to HMA‐venetoclax regimens in acute myeloid leukemia

Abstract Hypomethylating agents (HMAs) combined with Venetoclax have reshaped the therapeutic landscape of acute myeloid leukemia (AML), yet the biological determinants of response remain unclear. We integrated clinical and genomic profiling in 132 newly diagnosed or relapsed/refractory AML patients treated with HMA‐Venetoclax and performed single‐cell RNA sequencing and T cell receptor (TCR) profiling in 10 newly diagnosed cases to define cellular and immune correlates of response. Response rates and survival aligned with published data. DNA Sequencing confirmed the favorable impact of IDH2 and the poor prognosis of TP53 mutations. scRNA‐seq and TCR analysis showed that responders exhibited expansion of cytotoxic CD8 + T cells, increased TCR clonal diversity, and activation of antigen‐presentation pathways. Nonresponders displayed baseline inflammatory signaling, impaired myeloid maturation, and a suppressive microenvironment enriched in IDO1 + dendritic cells. Resistant AMLs showed stem‐like dedifferentiation and sustained EMT. LAG‐3 expression marked dysfunctional T cell states and emerged as a potential biomarker and therapeutic target.