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Incidence of myelodysplastic syndrome and acute myeloid leukemia in patients receiving poly-ADP ribose polymerase inhibitors for the treatment of solid tumors: A meta-analysis of randomized trials

  • Author Footnotes
    1 Co-first authors (contributed equally).
    Roni Nitecki
    Footnotes
    1 Co-first authors (contributed equally).
    Affiliations
    Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
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  • Author Footnotes
    1 Co-first authors (contributed equally).
    Alexander Melamed
    Footnotes
    1 Co-first authors (contributed equally).
    Affiliations
    Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, United States of America
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  • Allison A. Gockley
    Affiliations
    Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, United States of America
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  • Jessica Floyd
    Affiliations
    Department of Obstetrics and Gynecology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, United States of America
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  • Kate J. Krause
    Affiliations
    Research Medical Library, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
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  • Robert L. Coleman
    Affiliations
    US Oncology Research, The Woodlands, TX, United States of America
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  • Ursula A. Matulonis
    Affiliations
    Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States of America
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  • Sharon H. Giordano
    Affiliations
    Departments of Health Services Research and Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
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  • Karen H. Lu
    Affiliations
    Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
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  • J. Alejandro Rauh-Hain
    Correspondence
    Corresponding author at: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler, Houston, TX 77030-1362, United States of America.
    Affiliations
    Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
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  • Author Footnotes
    1 Co-first authors (contributed equally).

      Highlights

      • The overall risk of MDS/AML was similar in patients who were randomly assigned to receive PARPi compared to controls.
      • PARPi use was associated with an increase in risk of MDS/AML in the front-line setting, but not in the recurrent setting.
      • PARPi use was associated with an increase in risk of MDS/AML in studies with a low proportion of heavily pretreated patients.
      • Among studies that included a high proportion of heavily pretreated patients, PARPi use was not associated with MDS/AML.

      Abstract

      Background

      Clinical trials demonstrated that PARPi (poly [adenosine diphosphate–ribose]-ADP polymerase inhibitor) therapy is effective in solid tumors. However, long term effects such as therapy-related myelodysplastic syndrome or acute myeloid leukemia (MDS/AML) are poorly described. We sought to quantify whether PARPi therapy is associated with the development of MDS/AML.

      Methods

      Medline, Embase, and Cochrane databases were searched (inception to January 6, 2020) and phase 2 and 3 clinical trials that randomized patients with solid tumors to a PARPi or control therapy were included. The PRISMA guidelines were used to extract data independently by multiple authors. We extracted person-time and number of cases of MDS/AML in the PARPi and control arms of each study and pooled results with a random-effects Poisson regression model. The pooled incidence rate ratio (IRR) for MDS/AML among patients randomized to PARPi therapy was compared to those randomized to a control.

      Results

      We identified 14 studies that included 5739 patients. Accounting for intra-study clustering, the risk of MDS/AML was similar in patients who were randomly assigned to receive PARPi compared to controls (IRR 1.32, 95% confidence interval [CI] 0.78–2.26). In the front-line setting, PARPi therapy was associated with developing MDS/AML (IRR 5.43, 95% CI 1.51–19.60). Among patients treated for recurrence, however, the risk of MDS/AML appeared to be similar among patients randomized to PARPi or control treatment. Among studies that included only patients with a BRCA mutation, the risk of MDS/AML was similar in both treatment groups (IRR 0.83, 95% CI 0.45–1.53), but PARPi therapy was associated with MDS/AML in studies with an unrestricted population (IRR 2.43, 95% CI 1.17–5.06).

      Conclusion

      The pooled overall effect was not statistically significant. However, treatment with PARPi was associated with a statistically significant increase in the incidence of MDS/AML among patients receiving front-line cancer therapy and those with limited prior exposure to chemotherapy.
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