PARP inhibitors increase risk of myelodysplastic syndrome and acute myeloid leukaemia: Lancet study

The study is published in the Journal of Lancet Hematology.

Poly(ADP-ribose) polymerase (PARP) inhibitors have shown efficacy and acceptable safety in a range of neoplasms, particularly in ovarian cancers. However, some concerns have emerged regarding rare and delayed adverse events including cases of myelodysplastic syndrome and acute myeloid leukemia, for which data are scarce.

Therefore, the present study was conducted to estimate the risk of myelodysplastic syndrome and acute myeloid leukemia related to PARP inhibitors, via a systematic review and safety meta-analysis, and to describe clinical features of PARP inhibitor-related myelodysplastic syndrome and acute myeloid leukemia cases reported in WHO's pharmacovigilance database.

By a stepwise method to capture all available adverse events, the authors first extracted data on myelodysplastic syndrome and acute myeloid leukemia cases. A total of 5693 patients in PARP inhibitor groups and 3406 patients in control groups were placed. If cases were not available, then extractions were done from published manuscripts, or subsequently contacted corresponding authors or sponsors to provide data.

The primary outcome was the summary risk of myelodysplastic syndrome and acute myeloid leukemia related to PARP inhibition versus placebo treatment in RCTs. In a separate observational, retrospective, cross-sectional pharmacovigilance study of VigiBase, cases of myelodysplastic syndrome and acute myeloid leukemia related to PARP inhibitor therapy were extracted and clinical features summarized with a focus on a median duration of PARP inhibitor exposure, the median latency period between first drug exposure and diagnosis, and proportion of cases resulting in death.

The following findings were drawn-

a. Based on the 18 placebo RCTs (n=7307 patients), PARP inhibitors significantly increased the risk of myelodysplastic syndrome and acute myeloid leukemia compared with placebo treatment (Peto OR 2·63 [95% CI 1·13–6·14], p=0·026) with no between-study.

b. The incidence of myelodysplastic syndrome and acute myeloid leukemia across PARP inhibitor groups were 0·73% and across placebo groups was 0·47%.

c. All 28 RCTs were rated as having an unclear risk of bias.

d. In VigiBase, 178 cases of myelodysplastic syndrome (n=99) and acute myeloid leukemia (n=79) related to PARP inhibitor therapy was extracted.

e. In cases with available data, median treatment duration was 9·8 months and median latency period since first exposure to a PARP inhibitor was 17·8 months.

f. Of 104 cases that reported outcomes, 47 (45%) resulted in death.

Hence, it was concluded that "PARP inhibitors increased the risk of myelodysplastic syndrome and acute myeloid leukemia versus placebo treatment. These delayed and often lethal adverse events should be studied further to improve clinical understanding, particularly in the front-line maintenance setting."