CDK4/6 inhibition mitigates chemotherapy-induced expansion of TP53-mutant clonal hematopoiesis

Therapy-related myeloid neoplasm (tMN) is a fatal consequence of exposure to cytotoxic therapy administered in the treatment of cancer. Individuals with pre-existing TP53 clonal hematopoiesis (CH) are at high risk of tMN, with avoidance of therapy being the only strategy to reduce tMN risk. Here, we show in four randomized clinical trials of the CDK4/6 inhibitor, trilaciclib, given in conjunction with a variety of chemotherapeutic regimens and across diverse cancer patient populations that trilaciclib mitigates chemotherapy-related expansion of CH clones with mutations in DNA damage response (DDR) genes including TP53. This finding was also observed in a syngeneic murine model of TP53-mutant CH demonstrating that trilaciclib blocks platinum-induced TP53 competitive repopulation through promoting hematopoietic stem and progenitor quiescence and decreasing the stemness advantage of TP53-mutant clones. This represents a proof-of-concept for a potential pharmacologic strategy to block chemotherapy-induced expansion of pre-leukemic TP53-mutant clones.