Myelodysplastic syndrome and acute myeloid leukaemia in patients treated with PARP inhibitors

January 2021 Clinical trials Eline Feenstra

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 leukaemia, for which data are scarce.

In a meta-analysis recently published in The Lancet Haematology, the aim was to estimate the risk of MDS and AML as a result of the use of PARP inhibitors. The study also describes the clinical features of PARP inhibitor-related cases of MDS and AML as reported in the WHO database VigiBase.

The meta-analysis systematically reviewed randomized controlled trials (RCTs) comparing PARP inhibitor therapy versus control treatments. The primary outcome was the summary risk of MDS and AML related to PARP inhibition versus placebo treatment in RCTs. In a separate observational study of VigiBase, the cases of MDS and AML related to PARP inhibitor therapy were extracted and clinical features were summarized with a focus median duration of PARP inhibitor exposure, median latency period between first drug exposure and diagnosis, and proportion of cases resulting in death.

Risk assessment and clinical features

A total of 31 RCTs were were systematically reviewed for eligibility. 28 RCTs with available adverse events were analysed (18 placebo and ten non-placebo RCTs), with 5693 patients in PARP inhibitor groups and 3406 patients in control groups. Based on the 18 placebo RCTs (n = 7,307 patients), PARP inhibitors significantly increased the risk of MDS and AML compared to placebo treatment (OR 2.63 [95% CI 1.13–6.14], p = 0.026) with no heterogeneity between studies. The incidence of MDS and AML in PARP inhibitor groups was 0.73% (95% CI 0.50-1.07) and 0.47% in the placebo groups (95% CI 0.26-0.85).

In VigiBase, 178 cases of myelodysplastic syndrome (n=99) and acute myeloid leukaemia (n=79) related to PARP inhibitor therapy were extracted. The median duration of treatment was 9.8 months (IQR 3.6-17.4; n = 96) and the median latency period since first exposure to a PARP inhibitor was 17.8 months (IQR 8.4-29.2; n = 58). Of the 104 cases reporting outcomes, 47 (45%) resulted in death.

In conclusion, PARP inhibitors increased the risk of myelodysplastic syndrome and acute myeloid leukaemia 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.

Reference

Morice PM, Leary A, Dolladille C et al. Myelodysplastic syndrome and acute myeloid leukaemia in patients treated with PARP inhibitors: a safety meta-analysis of randomised controlled trials and a retrospective study of the WHO pharmacovigilance database. Lancet Haematol. 2020 Dec 18;S2352-3026(20)30360-4.

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