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Table.  Characteristics of Patients With Cancer Treated With a PARPi and Diagnosed With Pancytopenia, Using Pharmacovigilance Data From the World Health Organization VigiBasea
Characteristics of Patients With Cancer Treated With a PARPi and Diagnosed With Pancytopenia, Using Pharmacovigilance Data From the World Health Organization VigiBasea
1.
European Medicines Agency. Niraparib. September 17, 2018. Accessed February 24, 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/zejula
2.
European Medicines Agency. Olaparib. September 17, 2018. Accessed April 8, 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/lynparza
3.
Salem  J-E, Manouchehri  A, Moey  M,  et al.  Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study.   Lancet Oncol. 2018;19(12):1579-1589. doi:10.1016/S1470-2045(18)30608-9 PubMedGoogle ScholarCrossref
4.
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. 2021;8(2):e122-e134. doi:10.1016/S2352-3026(20)30360-4PubMedGoogle ScholarCrossref
5.
Friedlander  M, Matulonis  U, Gourley  C,  et al.  Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy.   Br J Cancer. 2018;119(9):1075-1085. doi:10.1038/s41416-018-0271-y PubMedGoogle ScholarCrossref
6.
Ledermann  J, Harter  P, Gourley  C,  et al.  Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.   N Engl J Med. 2012;366(15):1382-1392. doi:10.1056/NEJMoa1105535 PubMedGoogle ScholarCrossref
Research Letter
October 14, 2021

Occurrence of Pancytopenia Among Patients With Cancer Treated With Poly(Adenosine Diphosphate–Ribose) Polymerase Inhibitors: A Pharmacoepidemiologic Study

Author Affiliations
  • 1French National Institute of Health and Medical Research (INSERM) U1086 Interdisciplinary Research Unit for Cancers Prevention and Treatment (ANTICIPE), François Baclesse Comprehensive Cancer Center, Normandie University, University of Caen Normandy (UNICAEN), Unicancer, Caen, France
  • 2Pharmacoepidemiology Unit, Department of Pharmacology, Pharmacovigilance Regional Center, Caen University Hospital, France
  • 3Breast Cancer Unit, François Baclesse Comprehensive Cancer Center, Caen, France
  • 4Department of Pharmacology, Caen University Hospital, INSERM U1086 ANTICIPE, Normandie University, UNICAEN, Caen, France
JAMA Oncol. 2021;7(12):1899-1900. doi:10.1001/jamaoncol.2021.4672

Pre- and postmarketing reports on 2 poly(adenosine diphosphate–ribose) inhibitors (PARPis), niraparib and olaparib, indicate that these drugs induce pancytopenia adverse events (AEs).1,2 We used World Health Organization (WHO) pharmacovigilance data (1) to investigate the association between PARPi class and the occurrence of pancytopenia among patients with cancer and (2) to determine the clinical features of PARPi-related pancytopenia.

Methods

For this cross-sectional study (ClinicalTrials.gov identifier: NCT04774627), we used VigiBase, the WHO global pharmacovigilance database of individual case safety reports. We used search dates from the first report of a PARPi-related AE in 2009 to March 24, 2021. First, we performed a case-noncase study using the reporting odds ratio (ROR) to compare observed and expected drug-AE associations when using the full database as the comparator.3 In our study, reports of PARPi-related pancytopenia were considered cases and all other reports were considered noncases. The PARPis studied were olaparib, rucaparib, niraparib, talazoparib, and veliparib. Demographic characteristics and data on pancytopenia features (eg, seriousness, latency period, and outcomes) and coreported AEs were also collected.4 The median latency period (in months) was considered the interval between a patient with cancer starting PARPi treatment and then being diagnosed with pancytopenia. The proportion of fatalities was calculated as the number of reported deaths divided by the number of total available reports. A significant signal was detected if the lower limit of the Bonferroni-corrected 95% CI of the ROR (ROR025) exceeded 1. Sensitivity analyses were performed by recalculating the ROR025 value using the protein kinase inhibitor group (L01E) as the comparator.

This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. The use of confidential, electronically processed patient data was approved by the Caen University Hospital Research Ethics Committee. No informed consent was required because this was an anonymized retrospective analysis of data from the WHO pharmacovigilance database.

Results

Overall, 23 305 AEs were reported in VigiBase for the 5 PARPis, and the total number of AEs with any drug(s) was 20 269 537. Pancytopenia was significantly associated with PARPi class, with 201 reports (ROR, 5.5; 95% CI, 4.6-6.7) in the database. Moreover, this association remained significant for each PARPi studied, with 16 reports for talazoparib (ROR, 17.4; 95% CI, 8.9-34.0), 102 for niraparib (ROR, 6.8; 95% CI, 5.3-8.9), 57 for olaparib (ROR, 5.3; 95% CI, 3.7-7.6), 5 for veliparib (ROR, 8.2; 95% CI, 2.5-27.1), and 21 for rucaparib (ROR, 2.2; 95% CI, 1.2-4.0). All ROR025 values were subjected to Bonferroni correction (α = .05 for 6 analyses), and the results of the sensitivity analyses were consistent with the primary finding. There were 194 reports (97%) of serious pancytopenia, and the median latency period was 1.6 months (IQR, 0.7-11.0 months) from the first PARPi exposure (Table). Among frequently coreported AEs, 18 of 146 patients (12%) were diagnosed with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Finally, there were 117 reports with known outcomes: 69 patients (59%) had recovered or were recovering, 30 (26%) had not recovered, and 18 (15%) died.

Discussion

To our knowledge, this work is the first to highlight a substantial association between PARPi class and an increased risk of reported pancytopenia. Our results indicate that half of the patients in this study had an early onset of pancytopenia within the first 2 months after the initiation of PARPi treatment for cancer, suggesting the need for enhanced blood surveillance. In placebo-controlled Study 19, 2 of 136 patients in the olaparib-only arm experienced pancytopenia and subsequently developed MDS or AML.5,6 In line with our previous cohort,4 8 of 30 patients in the current study who had not recovered from pancytopenia also subsequently developed MDS or AML, suggesting that pancytopenia could be a relevant safety signal for the early detection of potential PARPi-related MDS or AML. Moreover, the product information for niraparib and olaparib advises temporarily interrupting PARPi treatment in the case of severe hematologic toxicities, including pancytopenia.1,2

We acknowledge limitations to this study. Although VigiBase provides a significant ROR025 value, a causal association could not be formally ascertained on a case-by-case basis. Moreover, we could not compute the incidence of PARPi-related pancytopenia, because the exact number of patients exposed to PARPi was unknown and drug-induced pancytopenia AEs are not systematically reported to pharmacovigilance systems.

Clinicians should consider careful monthly blood monitoring for patients with PARPi-treated cancer to check for early pancytopenia onset. This surveillance should be followed by a dose interruption as soon as possible to avoid the permanent discontinuation of these drugs, which could lead to a cancer relapse.

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Article Information

Accepted for Publication: July 29, 2021.

Published Online: October 14, 2021. doi:10.1001/jamaoncol.2021.4672

Corresponding Author: Joachim Alexandre, MD, PhD, Department of Pharmacology, Caen University Hospital, INSERM U1086 ANTICIPE, Normandie University, UNICAEN, Avenue de la Côte de Nacre, F-14000 Caen, France (alexandre-j@chu-caen.fr).

Author Contributions: Dr Morice had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Morice, Alexandre.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Morice, Alexandre.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Dolladille.

Administrative, technical, or material support: Chrétien.

Supervision: Morice, Alexandre.

Conflict of Interest Disclosures: Dr Alexandre reported receiving personal fees from Bayer and Bioserenity. No other disclosures were reported.

Disclaimer: The information presented in this study does not represent the opinion of the Uppsala Monitoring Centre or the World Health Organization.

Additional Contributions: We thank the custom searches team of the Uppsala Monitoring Centre research section for providing data from VigiBase, without whom this study would not have been possible.

Additional Information: At this time, data from VigiBase, the World Health Organization global pharmacovigilance database of individual case safety reports, are only available for national pharmacovigilance centers and the Uppsala Monitoring Centre. Public access to overview statistics from VigiBase can be gained via the VigiAccess website (http://www.vigiaccess.org).

References
1.
European Medicines Agency. Niraparib. September 17, 2018. Accessed February 24, 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/zejula
2.
European Medicines Agency. Olaparib. September 17, 2018. Accessed April 8, 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/lynparza
3.
Salem  J-E, Manouchehri  A, Moey  M,  et al.  Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study.   Lancet Oncol. 2018;19(12):1579-1589. doi:10.1016/S1470-2045(18)30608-9 PubMedGoogle ScholarCrossref
4.
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. 2021;8(2):e122-e134. doi:10.1016/S2352-3026(20)30360-4PubMedGoogle ScholarCrossref
5.
Friedlander  M, Matulonis  U, Gourley  C,  et al.  Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy.   Br J Cancer. 2018;119(9):1075-1085. doi:10.1038/s41416-018-0271-y PubMedGoogle ScholarCrossref
6.
Ledermann  J, Harter  P, Gourley  C,  et al.  Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.   N Engl J Med. 2012;366(15):1382-1392. doi:10.1056/NEJMoa1105535 PubMedGoogle ScholarCrossref
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