Risk of secondary hematological malignancies and hematological toxicities in recurrent ovarian cancer patients treated with poly adenosine diphosphate ribose polymerase (PARP) inhibitors maintenance

Background: Most patients with advanced ovarian cancer, the eighth most common cause of cancer death in women worldwide, recur after they receive initial platinum-based chemotherapy. PARP inhibitors showed a synthetic lethality in cancer cells via specific DNA repair defects. Yet, the risk of secondary hematological malignancies (SHM) and hematological toxicities, remains substantial. We undertook a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of SHM and hematological toxicities. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through March 2018 were queried. Phase III RCTs that mention any hematological malignancies and toxicities as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) and absolute risk difference (RD) with 95% confidence interval (CI). Fixed effects model was applied. Results: Three phase III RCTs with 1401 patients were eligible. The study arms used olaparib or niraparib or rucaparib while the control arms utilized placebo. The I2 statistic for heterogeneity was 16.86, and the heterogeneity X2 (Cochran's Q) was 2 (P = 0.30), suggesting homogeneity. The SHM incidence was 12 (1.28%) in PARP inhibitors group vs 5 (1.07%) in control group. The RR for SHM was 1.14 (95% CI: 0.42 – 3.08, P = 0.79) and RD was 0.002 (95% CI: - 0.01 – 0.014, P = 0.72). The RR of all-grade side effects were as follows: anemia, 6.57 (95% CI: 4.64 – 9.30, p < 0.001); thrombocytopenia, 9.80 (95% CI: 6.19 – 15.50, p < 0.001); and neutropenia, 4.13 (95% CI: 2.79 – 6.12, p < 0.001). The RR of high-grade adverse effects were as follows: anemia, 28.85 (95% CI: 10.06 – 82.72, p < 0.001); thrombocytopenia, 28.74 (95% CI: 8.24 – 100.24, p < 0.001); and neutropenia, 5.90 (95% CI: 3.01 – 11.57, p < 0.001). Conclusions: Patients on PARP inhibitors experienced a notable increase in the risk of all grades of hematological toxicities. However, there was no significant increase in the risk of secondary hematological malignancies in PARP inhibitors group. Long-term follow-up of these patients is required to determine the actual relation. Legal entity responsible for the study: Kyaw Zin Thein/ Texas Tech University Health Sciences Center. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.