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Tumor Lysis Syndrome with CD20 Monoclonal Antibodies for Chronic Lymphocytic Leukemia: Signals from the FDA Adverse Event Reporting System

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Abstract

Background and Objective

Although tumor lysis syndrome was reported with obinutuzumab and rituximab, the association with CD20 monoclonal antibodies for chronic lymphocytic leukemia is unclear.

Methods

A disproportionality analysis was conducted to investigate the link between CD20 monoclonal antibodies and tumor lysis syndrome by accounting for known confounders and comparing with other anticancer drugs, using data from the US Food and Drug Administration Adverse Event Reporting System. Reporting odds ratios and the information component were calculated as disproportionality measures. A stepwise sensitivity analysis was conducted to test the robustness of disproportionality signals. Bradford Hill criteria were adopted to globally assess the potential causal relationship.

Results

From 2004 to 2022, 197, 368, 41, and 14 tumor lysis syndrome reports were detected for obinutuzumab, rituximab, ofatumumab, and alemtuzumab (CD52 monoclonal antibody), respectively. Disproportionality signals were found for the above four monoclonal antibodies when compared with other anticancer drugs. Sensitivity analyses confirmed robust disproportionality signals for obinutuzumab, rituximab, and ofatumumab. The median onset time was 4.5, 1.5, and 2.5 days for rituximab, obinutuzumab, and ofatumumab, respectively. A potential causal relationship was fulfilled by assessing Bradford Hill criteria.

Conclusions

This pharmacovigilance study on the FDA Adverse Event Reporting System detected a plausible association between CD20 monoclonal antibodies (but not CD52) and tumor lysis syndrome by assessing the adapted Bradford Hill criteria. Urgent clarification of drug- and patient-related risk factors is needed through large comparative population-based studies.

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Acknowledgements

We appreciate the help of Dr. Mohammad Ali Khaleel in extracting raw data from a cleaned FAERS dataset.

Author information

Authors and Affiliations

  1. Department of Pharmacy, The Second Xiangya Hospital, Central South University, 139# Renmin Middle Road, Furong District, Changsha, 410011, China

    Shuang Xia, Jia-ting Ma, Rui Ma, Bi-kui Zhang, Hui Gong & Miao Yan

  2. International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, 410011, China

    Shuang Xia, Jia-ting Ma, Rui Ma, Bi-kui Zhang, Hui Gong & Miao Yan

  3. Toxicology Counseling Center of Hunan Province, Changsha, China

    Shuang Xia, Jia-ting Ma, Rui Ma, Bi-kui Zhang, Hui Gong & Miao Yan

  4. Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China

    Linna Guo

  5. Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Via Irnerio 48, 40126, Bologna, Italy

    Emanuel Raschi

  6. Laboratory of Clinical Pharmacy, Gifu Pharmaceutical University, Gifu, 501-1196, Japan

    Yoshihiro Noguchi

  7. Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA

    Mayur Sarangdhar

  8. Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA

    Mayur Sarangdhar

  9. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA

    Mayur Sarangdhar

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  1. Shuang Xia
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Corresponding authors

Correspondence to Hui Gong or Miao Yan.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 81974532), the Hunan Natural Science Funds for Distinguished Young Scholars (No. 2022JJ10097), and the Research Foundation of Education Bureau of Hunan Province for Young Scholars (No. 21B0014).

Conflict of Interest

Shuang Xia, Jia-ting Ma, Emanuel Raschi, Rui Ma, Bi-kui Zhang, Linna Guo, Yoshihiro Noguchi, Mayur Sarangdhar, Hui Gong, and Miao Yan have no conflicts of interest that are directly relevant to the content of this study.

Ethics Approval

No institutional ethics approval was required because this study utilized anonymized data from an open-access database.

Consent to Participate

Because all data in FAERS are anonymized, patient informed consent is not required.

Consent for Publication

Not applicable.

Data Availability

All data are publicly available on the website of AERSMine, a curated FAERS database: https://research.cchmc.org/aers/.

Code Availability

Not applicable.

Author Contributions

Conceptualization: MY, HG, SX; methodology: NY, ER, SX; formal analysis and investigation: SX, JTM; writing, original draft preparation: SX, JTM, ER; writing, review, and editing: SX, ER, NY, HG, MY; funding acquisition: MY; resources: MS, LG, BKZ; supervision: MY, HG.

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Xia, S., Ma, Jt., Raschi, E. et al. Tumor Lysis Syndrome with CD20 Monoclonal Antibodies for Chronic Lymphocytic Leukemia: Signals from the FDA Adverse Event Reporting System. Clin Drug Investig 43, 773–783 (2023). https://doi.org/10.1007/s40261-023-01308-0

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