PARP inhibitors and the rising incidence of secondary myelodysplastic syndrome and acute myeloid leukemia: A comprehensive meta-analysis

Abstract

Abstract Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) have transformed the management of BRCA-mutated ovarian and breast cancers. However, post-marketing surveillance has raised concerns about therapy-related myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) after prolonged PARPi exposure. We conducted a pooled meta-analysis to quantify the incidence of MDS/AML associated with PARPi use and to explore associated demographic and clinical features. Methods: We performed a systematic review and meta-analysis of 17 studies, including 13 real-world observational datasets and 4 published meta-analyses. Studies were included if they reported the total number of patients treated with PARPi and the incidence or number of MDS/AML cases. Extracted variables included sample size, median age, gender distribution, mortality, and latency. A pooled incidence rate with 95% confidence intervals (CI) was calculated using a random-effects model. Results: The combined cohort included 106,793 patients treated with PARPi, including olaparib, niraparib, rucaparib, and talazoparib. A total of 1,579 cases of MDS or AML were reported. The median age across studies was 62 years, and the female-to-male ratio was approximately 53:1, reflecting the predominance of PARPi use in gynecologic malignancies. Most studies originated from high-income countries, including the United States, Japan, and Canada. The mean mortality rate among patients developing MDS/AML was 38.3%. The pooled hazard ratio (HR) for death associated with therapy-related MDS/AML following PARPi exposure was 3.37, indicating a significant increase in mortality risk. Incidence of MDS/AML varied across studies from 0.3% to 3.5%. The pooled incidence was 1.48% (95% CI, 1.41%–1.55%). Among studies reporting latency, the median time from PARPi initiation to MDS/AML diagnosis was 19.5 months. Conclusions: This meta-analysis highlights that while MDS and AML are uncommon complications of PARP inhibitor therapy, their occurrence is clinically meaningful, with an overall incidence of approximately 1.5%. The risk notably increases with extended treatment duration and is associated with substantial mortality. These results underscore the importance of vigilant hematologic monitoring in patients receiving long-term PARP inhibitors and emphasize the need for prospective studies to discover predictive biomarkers and enhance personalized risk stratification.