Hematological disorders after salvage PARPi treatmentfor ovarian cancer: Cytogenetic and molecular defectsand clinical outcomes

Inhibitors of poly(ADP-ribose) polymerase (PARPi) are increasingly employed as sal-vage therapy in epithelial ovarian cancer (EOC), but cytotoxic drug exposure alongwith PARP inhibition may favor development of hematological disorders. In ourstudy, of 182 women with EOC treated with PARPi, 16 (8.7%) developed therapy-related myeloid neoplasms (t-MNs), with 12 cases of myelodysplasia and 4 of acutemyeloid leukemia. All experienced persistent cytopenia after PARPi discontinuation.Seven patients had del(5q)/5 and/or del(7q)/7, nine had a complex karyotype andTP53 mutations, recently reported as risk factor for t-MNs in EOC post-PARPi, werefound in 12 out of 13 tested patients. Four patients had a rapid and fatal outcome,one had stable disease, eleven underwent induction therapy, followed by allogeneichematopoietic cell transplantation in seven. Three of these 11 patients experiencedrefractory disease, and 8 had complete remission. During a 6.8 months (range 2.3-49)median observation time, 3 out of 16 patients were alive, with one surviving patientfree of both solid and hematological tumors. Ten patients died because of leukemia,two because of transplant-related events, one from heart failure. Five more patientsexperienced persistent cell blood count abnormalities following PARPi discontinua-tion, without reaching MDS diagnostic criteria. A customized Myelo-panel showedclonal hematopoiesis in all five patients. These findings confirm the actual risk of t-MNs in EOC patients after chemotherapy and prolonged PARPi therapy. The man-agement of these patients is complex and outcomes are extremely poor. Careful diag-nostic procedures are strongly recommended whenever unusual cytopenias developin patients receiving PARPi therapy.