The impact of poly ADP ribose polymerase (PARP) inhibitors on clonal hematopoiesis.

1513 Background: Poly (ADP-ribose) polymerase (PARP) inhibitors are an important new class of anti-cancer therapies. Therapy-related myeloid neoplasia (tMN) has been reported following PARPi therapy, and is associated with adverse outcomes. Further insight is required into the risk of tMN conferred by PARPi therapy, independent of germline genetic background and prior therapy. We have shown that oncologic therapy selects for acquired mutations in the blood (clonal hematopoiesis; CH) particularly those in the DNA damage response pathway (DDR) including PPM1D, TP53 and CHEK2 and that CH confers an increased risk of tMN. We hypothesized that characterization of the relationship between CH and PARPi therapy provides insight into its potential for leukemogenesis and may offer opportunities for tMN prevention. Methods: We assessed for CH in the blood of 10,156 cancer patients, including 54 who received PARPi therapy, 5942 who received another systematic therapy or radiation therapy and 4160 untreated prior to blood draw. Results: Patients exposed to PARPi therapy were more likely to have CH (33%) compared to those exposed to other systemic therapies or radiation (18%) or untreated patients (16%). This was particularly pronounced for DDR CH; 25% of PARPi treated patients had DDR CH compared to 2% of untreated patients. In a multivariable model accounting for demographics, exposure to chemotherapeutic agents, radiation therapy and germline BRCA mutation status, exposure to PARPi conferred an increased risk of DDR CH (OR = 3.6, 95% CI 1.5-8.5, p = 0.004). This effect was attenuated after accounting for cumulative exposure to therapy (OR = 2.8, 95% CI 0.97-8.2, p = 0.06) suggesting a multifactorial contribution to the enrichment of CH following PARPi therapy. To characterize this further we performed a prospective collection of patients with CH over a median follow-up time of 58 months. During the follow-up period, 17 patients received PARPi, 360 received cytotoxic therapies or radiation and 232 were untreated or received targeted therapies. The growth rate of DDR CH was significantly higher among those who were exposed to PARPi (median, +2.8% increase in VAF per year) compared to untreated patients (+0.08% per year, p = 0.02) and those exposed to other cytotoxic therapies (+1% per year, p = 0.04). Conclusions: Taken together our data suggests that PARPi therapy promotes the expansion of DDR CH. Future studies should examine the potential of CH to identify individuals at high risk of tMN following PARPi therapy and to develop therapies aimed to prevent tMN in patients with CH.