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

Summary

Background

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. The aim of this study was to estimate the risk of myelodysplastic syndrome and acute myeloid leukaemia 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 leukaemia cases reported in WHO's pharmacovigilance database (VigiBase).

Methods

We systematically reviewed randomised controlled trials (RCTs) comparing PARP inhibitor therapy versus control treatments (placebo and non-placebo) in adults (age ≥18 years) treated for cancer in MEDLINE, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov registry with ongoing surveillance up to May 31, 2020. The date range for included studies was not restricted. By a stepwise method to capture all available adverse events, we first extracted data on myelodysplastic syndrome and acute myeloid leukaemia cases from ClinicalTrials.gov. If cases were not available, we extracted them from published manuscripts, or subsequently contacted corresponding authors or sponsors to provide data. RCTs without available data from ClinicalTrials.gov, publications, or corresponding authors or sponsors were excluded. The primary outcome was the summary risk of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibition versus placebo treatment in RCTs. We used a fixed-effects meta-analysis to obtain Peto odds ratios (ORs) with 95% CIs. In a separate observational, retrospective, cross-sectional pharmacovigilance study of VigiBase, cases of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibitor therapy were extracted on May 3, 2020, and clinical features summarised with a focus on median duration of PARP inhibitor exposure, median latency period between first drug exposure and diagnosis, and proportion of cases resulting in death. Our systematic review and safety meta-analysis were registered with PROSPERO, CRD42020175050. Our retrospective pharmacovigilance study was registered on ClinicalTrials.gov, NCT04326023.

Findings

For our safety meta-analysis, initial searches identified 1617 citations, and 31 RCTs 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=7307 patients), PARP inhibitors significantly increased the risk of myelodysplastic syndrome and acute myeloid leukaemia compared with placebo treatment (Peto OR 2·63 [95% CI 1·13–6·14], p=0·026) with no between-study heterogeneity (I²=0%, χ² p=0·91). The incidence of myelodysplastic syndrome and acute myeloid leukaemia across PARP inhibitor groups was 0·73% (95% CI 0·50–1·07; I²=0%, χ² p=0·87; 21 events out of 4533 patients) and across placebo groups was 0·47% (0·26–0·85; I²=0%, χ² p=1·00; three events out of 2774 patients). All 28 RCTs were rated as having unclear risk of bias. In VigiBase, 178 cases of myelodysplastic syndrome (n=99) and acute myeloid leukaemia (n=79) related to PARP inhibitor therapy were extracted. In cases with available data, median treatment duration was 9·8 months (IQR 3·6–17·4; n=96) and median latency period since first exposure to a PARP inhibitor was 17·8 months (8·4–29·2; n=58). Of 104 cases that reported outcomes, 47 (45%) resulted in death.

Interpretation

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.

Funding

None.

Introduction

Oral poly(ADP-ribose) polymerase (PARP) inhibitors provide clinical benefit in a range of cancers with or without deleterious mutations in homologous recombination genes involved in DNA repair (eg, BRCA1/BRCA2). PARP inhibitors have mainly shown clinically significant improvements in progression-free survival in both recurrent and primary ovarian cancers.1, 2 The ability of the drugs to provide such benefit led to the approval of four PARP inhibitors by both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) between 2014 and 2018 in various clinical indications for patients with ovarian, breast, pancreatic, or prostate cancers. In randomised controlled trials (RCTs), the most common adverse events of PARP inhibitors were fatigue and haematological and gastrointestinal toxicities.³ Adverse events with PARP inhibitors generally occurred during the first 3 months of treatment. A potential risk of developing myelodysplastic syndrome or acute myeloid leukaemia has not yet been confirmed, but the few reported cases from RCTs found that myelodysplastic syndrome and acute myeloid leukaemia could be a delayed adverse event following treatment initiation.4, 5, 6, 7 In these conditions, isolated RCTs might be underpowered to assess the association of PARP inhibitor treatment with the development of myelodysplastic syndrome and acute myeloid leukaemia. Additionally, the clinical features of myelodysplastic syndrome and acute myeloid leukaemia associated with PARP inhibitors and their incidence remain unknown. In this study, we did a systematic review and safety meta-analysis of placebo RCTs to estimate the risk of developing myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibitors. Subsequently, we assessed the incidence and risk of PARP inhibitor-related myelodysplastic syndrome and acute myeloid leukaemia in placebo and non-placebo RCTs. Furthermore, we describe clinical features of myelodysplastic syndrome and acute myeloid leukaemia cases related to PARP inhibitors reported in VigiBase, the WHO pharmacovigilance database.