PARP Inhibitor Use Linked To ‘Rare’ Risk Of MDS, AML

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Patients given poly(ADP-ribose) polymerase (PARP) inhibitors have an increased risk of developing secondary myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML), report the authors of a meta-analysis published in The Lancet Haematology. 

“These delayed adverse events need further research to improve understanding, and clinicians should be aware of these potentially fatal haematological toxicities, particularly in the front-line maintenance setting”, emphasize Joachim Alexandre, from Caen University Hospital in France, and co-workers. 

The team collated information from 28 randomised controlled trials (RCTs) of the PARP inhibitors olaparib, veliparib, niraparib, talazoparib or rucaparib in patients with ovarian, gastric, colorectal, prostate, breast or pancreatic cancer, small-cell or non-small-cell lung cancer, or melanoma. 

Data for 7307 cancer patients who participated in one of 18 placebo-controlled randomised trials revealed that PARP inhibitor use was significantly associated with an increased risk of MDS or AML compared with placebo, with a Peto odds ratio of 2.63 and no significant heterogeneity between the trials. 

Overall, 21 out of 4533 PARP inhibitor-treated patients developed MDS or AML, at a rate of 0.73%, compared with three out of 2774 placebo-treated patients, giving a rate of 0.47%. 

However, the investigators say that all 28 of the trials in the study “were rated as having unclear risk of bias.” 

All MDS and AML cases in the meta-analysis occurred in ovarian cancer trials assessing PARP inhibitors as maintenance therapy in the platinum-sensitive or front-line setting. 

“This exclusivity for ovarian cancer might be explained by the difference in median follow-up across studies, with ovarian cancer RCTs having the longest follow-up in completed trials (around 2–6 years), thus increasing the likelihood of detecting these rare and delayed adverse events”, the authors say. 

The team adds that the “occurrence of these adverse events in first-line maintenance RCTs suggest that these events might be a toxicity specific to PARP inhibitors”. 

However, noting that the SOLO2 trial indicated an improvement in overall survival with olaparib use, the researchers say they are unable to rule out that the two adverse events “could have a stronger association with previous lines of chemotherapy than with PARP inhibition.” 

The team also conducted a cross-sectional study of the WHO’s pharmacovigilance database VigiBase, identifying 99 cases of MDS and 79 cases of AML that were deemed related to PARP inhibitor therapy.  

The available VigiBase information indicated that 96 of these affected patients received PARP inhibitors for a median 9.8 months and the median latency from first use of a PARP inhibitor to diagnosis of MDS or AML in 58 patients was 17.8 months. 

Patients were followed-up for a median of 5.6 months after MDS or AML diagnosis; of the 104 patients with reported outcomes, 9% were described as recovered or recovering, 46% as having ongoing disease, and 45% as having died, the team says. 

Discussing the meta-analysis findings in a linked comment, Anna Tinker, from the University of British Columbia in Vancouver, Canada, notes that subgroup analysis did not find any specific risk factors for MDS and AML, such as specific PARP inhibitor used, duration of treatment or the presence of deleterious BRCA1/2 germline alterations. 

“Given the common use of PARP inhibitors in BRCA1/2 mutation carriers, the finding that these patients do not appear to have elevated risk is reassuring”, she writes. 

Nevertheless, the commentator says that despite being considered “a late toxicity”, clinicians should “remain aware that the onset of myelodysplastic syndrome and acute myeloid leukaemia can occur soon after PARP inhibitor initiation even after brief drug exposure.” 

Anna Tinker concludes: “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 haematological changes. 

“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.” 

References 

Morice P-M, 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; Advance online publication 18 December 2020. Doi: 10.1016/S2352-3026(20)30360-4 

Tinker AV. PARP inhibitors–understanding the risk of myelodysplastic syndrome and acute myeloid leukaemia. Lancet Haematol; Advance online publication 18 December 2020. Doi: 10.1016/S2352-3026(20)30375-6