PARP inhibitors may increase risk for myelodysplastic syndrome, AML
Poly(ADP-ribose) polymerase, or PARP, inhibitors appeared associated with increased risk for secondary myelodysplastic syndrome and acute myeloid leukemia compared with placebo among patients with cancer, according to study results.
“These delayed and often lethal adverse events should be studied further to improve clinical understanding, particularly in the front-line maintenance setting,” Pierre-Marie Morice, PhD, researcher in the interdisciplinary research unit for cancer prevention and treatment at Normandie University in France, and colleagues wrote in the study, published in The Lancet Haematology.
Although PARP inhibitors have been shown to be safe and effective for various neoplasms — with approvals for ovarian, breast, pancreatic and prostate cancers — concerns have emerged regarding rare and delayed adverse events, such as myelodysplastic syndrome and AML.
Morice and colleagues conducted a systematic review and safety meta-analysis to assess the risk for myelodysplastic syndrome and AML associated with PARP inhibitor use. Researchers also aimed to describe the clinical features of PARP inhibitor-related cases of these diseases reported in VigiBase, WHO’s pharmacovigilance database.
The summary risk for myelodysplastic syndrome and AML associated with PARP inhibition compared with placebo in randomized controlled trials of patients with cancer served as the primary outcome.
The safety meta-analysis included 28 randomized controlled trials rated as having unclear risk for bias, of which 18 were placebo-controlled and included 7,307 patients. PARP inhibitors studied in the trials included olaparib (Lynparza, AstraZeneca; = 8), veliparib (ABT-888, AbbVie; n = 7), niraparib (Zejula, GlaxoSmithKline; n = 2) and rucaparib (Rubraca, Clovis Oncology; n = 1).
According to results of the analysis, use of PARP inhibitors significantly increased risk for myelodysplastic syndrome and AML compared with placebo (OR = 2.63; 95% CI, 1.13-6.14).
The analysis of data from VigiBase showed 99 cases of myelodysplastic syndrome and 79 cases of AML associated with PARP inhibitor use.
Among 96 patients with available data, median treatment duration was 9.8 months (interquartile range [IQR], 3.6-17.4), and among 58 patients with available data, median latency period since first exposure to a PARP inhibitor was 17.8 months (IQR, 8.4-29.2). Researchers observed a high rate of mortality (45%) among 104 patients with reported outcomes. Cytopenia was co-reported in 71 (40%) of the 178 cases of myelodysplastic syndrome or AML, of which anemia was most frequent type (34%).
“Clinical features recorded in WHO’s real-world pharmacovigilance database highlighted that myelodysplastic syndrome and AML occurred several months after PARP inhibitor administration, with a high frequency of death and co-reported cytopenia in confirmed cases,” Morice and colleagues wrote.
The researchers acknowledged that myelodysplastic syndrome and AML incidence may be underestimated in the study, and that long-term prospective cohorts of patients who receive PARP inhibitors are needed to improve accuracy.
Future studies also should examine whether risk differs with PARP inhibitor use in combination with other drugs, such as VEGF inhibitors and immune checkpoint inhibitors, according to an accompanying editorial by Anna V. Tinker, MD, FRCPC, clinical assistant professor in the division of medical oncology at The University of British Columbia.
“The imperative remains to properly counsel patients on the rare but life-threatening toxicities of PARP inhibitors and to offer appropriate monitoring and investigations of hematological changes,” Tinker wrote. “This practice is particularly important as PARP inhibitor indications broaden, including use in first-line therapy — for instance in ovarian cancer, when cure from the primary cancer might remain a possibility.”