Venetoclax treatment in cancer patients has limited impact on circulating T and NK cells.

Venetoclax is an effective treatment for certain blood cancers, such as chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, most patients relapse while on venetoclax and further treatment options become limited. Combining venetoclax with immunotherapies is an attractive approach; however, a detailed understanding of how venetoclax treatment impacts normal immune cells in patients is lacking. In this study, we performed deep profiling of peripheral blood cells from CLL and AML patients before and after short-term treatment with venetoclax using mass cytometry (CyTOF) and found no impact on the concentrations of key T cell subsets nor their expression of checkpoint molecules. We also analyzed peripheral blood from breast cancer patients receiving venetoclax long-term using a single-cell multi-omics approach (CITE-seq) and functional assays. We found significant depletion of B cell populations with low expression of MCL-1 relative to other immune cells, attended by extensive transcriptomic changes. By contrast, there was less impact on circulating T cells and natural killer (NK) cells, with no changes in their subset composition, transcriptome or function following venetoclax treatment. Our data indicate that venetoclax has minimal impact on circulating T or NK cells, supporting the rationale of combining this BH3 mimetic drug with cancer immunotherapies for more durable anti-tumour responses.