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

Therapy-related myeloid neoplasms (tMN) represent 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 for development of tMN but currently avoidance of therapy is 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 expansion of chemotherapy-related CH clones with mutations in DNA damage response genes (including TP53, PPM1D, and CHEK2 mutations). 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 TP53 mutant stemness advantage. This represents the first demonstration of a pharmacologic strategy to block chemotherapy-induced expansion of pre-leukemic TP53-mutant clones.