Dysregulated apoptosis contributes to the pathogenesis of many hematologic malignancies. BH3-mimetics, antagonists of antiapoptotic BCL-2 proteins, represent novel, and promising cancer drugs. While the acute myelosuppressive effects of Venetoclax, the first Food and Drug Administration approved BCL-2 inhibitor, are fairly well described, little is known about side effects of novel BH3-mimetics and effects of chronic Venetoclax treatment.

Highly relevant publications focused on the effects of acute and chronic Venetoclax therapy, with focus on cell-type specific adaptive mechanisms, the emergence of clonal hematopoiesis, and the selection of BAX-mutated hematopoietic cells in patients treated with Venetoclax for a long period. Important advances were made in understanding primary and secondary Venetoclax resistance and prediction of Venetoclax response. Combination therapies of BH3-mimetics targeting different BCL-2 proteins are highly anticipated. However, human stem and progenitors require both MCL-1 and BCL-XL for survival, and serious myelosuppressive effects of combined MCL-1/BCL-XL inhibition can be expected.

Long-term studies are indispensable to profile the chronic side effects of Venetoclax and novel BH3-mimetics and better balance their risk vs. benefit in cancer therapy. Combination therapies will be powerful, but potentially limited by severe myelosuppression. For precision medicine, a better knowledge of BCL-2 proteins in the healthy and diseased hematopoietic system is required.