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. Overall design: Following 4 weeks of treatment with either vehicle, carboplatin, trilaciclib, or a combination of carboplatin with trilaciclib, bone marrow cells from competitive transplanted Vav-cre Tp53 WT or Vav-cre Tp53 R172H/WT mice were washed twice with cold PBS before labeling with unique TotalSeqA-compatible HashTags. Subsequently, samples were incubated with mouse Fc receptor-blocking agent and labeled with DAPI for live cell sorting by flow cytometry. After sorting equal numbers of cells were pooled and submitted for scRNA-sequencing