Hematological disorders after salvage PARPi treatment for ovarian cancer: Cytogenetic and molecular defects and clinical outcomes

Abstract

Inhibitors of poly(ADP‐ribose) polymerase (PARPi) are increasingly employed as salvage therapy in epithelial ovarian cancer (EOC), but cytotoxic drug exposure along with PARP inhibition may favor development of hematological disorders. In our study, 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 acute myeloid leukemia. All experienced persistent cytopenia after PARPi discontinuation. Seven patients had del(5q)/−5 and/or del(7q)/−7, nine had a complex karyotype and TP53 mutations, recently reported as risk factor for t‐MNs in EOC post‐PARPi, were found 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 allogeneic hematopoietic cell transplantation in seven. Three of these 11 patients experienced refractory 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 patient free of both solid and hematological tumors. Ten patients died because of leukemia, two because of transplant‐related events, one from heart failure. Five more patients experienced persistent cell blood count abnormalities following PARPi discontinuation, without reaching MDS diagnostic criteria. A customized Myelo‐panel showed clonal hematopoiesis in all five patients. These findings confirm the actual risk of t‐MNs in EOC patients after chemotherapy and prolonged PARPi therapy. The management of these patients is complex and outcomes are extremely poor. Careful diagnostic procedures are strongly recommended whenever unusual cytopenias develop in patients receiving PARPi therapy.

Myeloid neoplasms post PARP inhibitors for ovarian cancer

“…The median PARPi exposure and time to onset of myeloid neoplasms were 17 months and 2 years, respectively. The European Institute of Oncology studied 182 patients with ovarian cancer treated with various PARPi, of whom 16 (8.7%) developed secondary hematological malignancies (12 myelodysplastic syndrome and 4 acute myeloid leukemia) 22 23. This incidence of 8.7% was the first from a real-life setting and is in line with the 8% rate retrieved from the final analysis of the SOLO2 trial.…”

“…Since ovarian cancer and myeloid neoplasms represent two completely different cancers, finding a therapeutic strategy that fits both cancer types without serious toxicity is challenging. One attempt might be to control ovarian cancer with radiotherapy while treating myeloid malignancy, but for the moment this is only anectodal 23. The optimal management remains an unmet clinical need and should be discussed in referral centers with expertise and experience in this field.…”

Outcomes of patients with therapy‐related myeloid neoplasms after treatment with poly(ADP‐ribose) polymerase proteins inhibitors for solid tumours

“…These mutations carry an intrinsic resistance to apoptotic mechanisms. 4,9,10 Of interest, we did not find clinical benefit in patients who received venetoclax. In a subgroup analysis, we found no difference in response for patients with wild-type TP53 (TP53wt) compared to TP53 mutated (80% vs. 57% [p = 0.41]).…”

Differences in Durability of PARP Inhibition by Clinically Approved PARP Inhibitors: Implications for Combinations and Scheduling

“…Indeed, our earlier xenograft studies would suggest that this is plausible [ 19 ]. Introducing a more tolerable schedule could also be beneficial in reducing the risk of haematological disorders arising from long-term PARPi use [ 29 ]. Further clinical evaluation of intermittent scheduling of PARPi is warranted.…”