Signal detection and analysis of hematologic and lymphatic adverse events associated with Axicabtagene ciloleucel based on the FDA adverse event reporting system_Chinese Journal of Evidence-Based Medicine

Authors：

ZHANG Zhenpo ¹ , ZHENG Jingping ¹ , LIANG Yankun ¹ ,  MA Lin ² ,  SU Ling ¹

1. Department of Pharmacy, Jinan University, Guangzhou 511443, P. R. China;
2. Organ Transplantation Administration Office, Guangdong Hospital of Traditional Chinese Medicine, Guangzhou 510120, P. R. China;

Corresponding author：

MA Lin, Email: bluemalin@qq.com; SU Ling, Email: 38105596@163.com

Keywords：

Axicabtagene ciloleuce; Adverse drug event; Hemic and lymphatic diseases; Data mining

DOI：

10.7507/1672-2531.202411144

Video：

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Objective To conduct a comprehensive analysis of hematologic and lymphatic adverse events associated with Axicabtagene ciloleucel using the FDA adverse event reporting system (FAERS) database, providing valuable references for clinical safety in medication. Methods We retrieved reports of adverse reactions related to Axicabtagene ciloleucel from the FAERS database covering the period from October 2017 to December 2023. A disproportionality analysis was performed using the reporting odds ratio (ROR) and information component (IC) to identify hematologic and lymphatic adverse events associated with Axicabtagene ciloleucel. Results A total of 790 reports of hematologic and lymphatic adverse events related to Axicabtagene ciloleucel were identified, leading to the detection of 16 signals. Six of these adverse events were not included in the product labeling. Neutropenia was the most frequently reported hematologic adverse event associated with Axicabtagene ciloleucel. The strongest signal identified was cytopenia. Notably, 13.9% of cases resulted in death, with pancytopenia being the most common adverse event among the fatal outcomes. Conclusion Adverse events such as disseminated intravascular coagulation, coagulopathy, and bone marrow dysfunction are rarely reported in clinical practice and are not included in the product labeling, yet they are highly associated with mortality.

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16.	Rejeski K, Perez A, Sesques P, et al. CAR-HEMATOTOX: a model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood, 2021, 138(24): 2499-2513.
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18.	邵宗鸿. 骨髓衰竭性疾病研究进展. 中华医学信息导报, 2017, 32(5): 21.
19.	Qasrawi A, Arora R, Ramlal R, et al. Allogenic hematopoietic stem cell transplantation for prolonged bone marrow aplasia after chimeric antigen receptor (CAR) T-cell therapy for relapsed diffuse large B-cell lymphoma. Am J Hematol, 2020, 95(4): 89-91.
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21.	Cutini I, Puccini B, Fabbri A, et al. Late haemophagocytic lymphohistiocytosis in a patient treated with Axicabtagene ciloleucel. Transpl Immunol, 2022, 75: 101719.
22.	Wang Y, Qi K, Cheng H, et al. Coagulation disorders after chimeric antigen receptor T cell therapy: analysis of 100 patients with relapsed and refractory hematologic malignancies. Biol Blood Marrow Transplant, 2020, 26(5): 865-875.
23.	Rejeski K, Kunz WG, Rudelius M, et al. Severe Candida glabrata pancolitis and fatal Aspergillus fumigatus pulmonary infection in the setting of bone marrow aplasia after CD19-directed CAR T-cell therapy - a case report. BMC Infect Dis, 2021, 21(1): 121.
24.	Jain T, Olson TS, Locke FL. How I treat cytopenias after CAR T-cell therapy. Blood, 2023, 141(20): 2460-2469.
25.	Liu R, Lv Y, Hong F, et al. A comprehensive analysis of coagulopathy during anti-B cell maturation antigen chimeric antigen receptor-T therapy in multiple myeloma, a retrospective study based on LEGEND-2. Hematol Oncol, 2023, 41(4): 704-717.

1. 国家卫生健康委员会. 弥漫性大B细胞淋巴瘤诊疗指南. 2022.
2. Zahid U, Akbar F, Amaraneni A, et al. A review of autologous stem cell transplantation in lymphoma. Curr Hematol Malig Rep, 2017, 12(3): 217-226.
3. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol, 2019, 20(1): 31-42.
4. 国家药监局批准阿基仑赛注射液上市. 上海医药, 2021, 42(13): 54.
5. Papadouli I, Mueller-Berghaus J, Beuneu C, et al. EMA review of axicabtagene ciloleucel (Yescarta) for the treatment of diffuse large B-cell lymphoma. Oncologist, 2020, 25(10): 894-902.
6. Fried S, Avigdor A, Bielorai B, et al. Early and late hematologic toxicity following CD19 CAR-T cells. Bone Marrow Transplant, 2019, 54(10): 1643-1650.
7. 国家药品监督管理局. 阿基仑赛注射液说明书(国药准字S20210019). 2021.
8. Raschi E, Fusaroli M, Ardizzoni A, et al. Thromboembolic events with cyclin-dependent kinase 4/6 inhibitors in the FDA adverse event reporting system. Cancers (Basel), 2021, 13(8): 1758.
9. U. S. Food and Drug Administration. FDA adverse event reporting system (FAERS) quarterly data extract files. 2022.
10. Caster O, Aoki Y, Gattepaille LM, et al. Disproportionality analysis for pharmacovigilance signal detection in small databases or subsets: recommendations for limiting false-positive associations. Drug Saf, 2020, 43(5): 479-487.
11. Ang PS, Chen Z, Chan CL, et al. Data mining spontaneous adverse drug event reports for safety signals in Singapore - a comparison of three different disproportionality measures. Expert Opin Drug Saf, 2016, 15(5): 583-590.
12. Hou Y, Ye X, Wu G, et al. A comparison of disproportionality analysis methods in national adverse drug reaction databases of China. Expert Opin Drug Saf, 2014, 13(7): 853-857.
13. Maus MV, Alexander S, Bishop MR, et al. Society for immunotherapy of cancer (SITC) clinical practice guideline on immune effector cell-related adverse events. J Immunother Cancer, 2020, 8(2): e001511.
14. Luo W, Li C, Zhang Y, et al. Adverse effects in hematologic malignancies treated with chimeric antigen receptor (CAR) T cell therapy: a systematic review and Meta-analysis. BMC Cancer, 2022, 22(1): 98.
15. Song Z, Tu D, Tang G, et al. Hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation are underestimated, but fatal adverse events in chimeric antigen receptor T-cell therapy. Haematologica, 2023, 108(8): 2067-2079.
16. Rejeski K, Perez A, Sesques P, et al. CAR-HEMATOTOX: a model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood, 2021, 138(24): 2499-2513.
17. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-Cell therapy in refractory large B-cell lymphoma. N Engl J Med, 2017, 377(26): 2531-2544.
18. 邵宗鸿. 骨髓衰竭性疾病研究进展. 中华医学信息导报, 2017, 32(5): 21.
19. Qasrawi A, Arora R, Ramlal R, et al. Allogenic hematopoietic stem cell transplantation for prolonged bone marrow aplasia after chimeric antigen receptor (CAR) T-cell therapy for relapsed diffuse large B-cell lymphoma. Am J Hematol, 2020, 95(4): 89-91.
20. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood, 2016, 127(26): 3321-3330.
21. Cutini I, Puccini B, Fabbri A, et al. Late haemophagocytic lymphohistiocytosis in a patient treated with Axicabtagene ciloleucel. Transpl Immunol, 2022, 75: 101719.
22. Wang Y, Qi K, Cheng H, et al. Coagulation disorders after chimeric antigen receptor T cell therapy: analysis of 100 patients with relapsed and refractory hematologic malignancies. Biol Blood Marrow Transplant, 2020, 26(5): 865-875.
23. Rejeski K, Kunz WG, Rudelius M, et al. Severe Candida glabrata pancolitis and fatal Aspergillus fumigatus pulmonary infection in the setting of bone marrow aplasia after CD19-directed CAR T-cell therapy - a case report. BMC Infect Dis, 2021, 21(1): 121.
24. Jain T, Olson TS, Locke FL. How I treat cytopenias after CAR T-cell therapy. Blood, 2023, 141(20): 2460-2469.
25. Liu R, Lv Y, Hong F, et al. A comprehensive analysis of coagulopathy during anti-B cell maturation antigen chimeric antigen receptor-T therapy in multiple myeloma, a retrospective study based on LEGEND-2. Hematol Oncol, 2023, 41(4): 704-717.

Chinese Journal of Evidence-Based Medicine

Latest ArticlesSignal detection and analysis of hematologic and lymphatic adverse events associated with Axicabtagene ciloleucel based on the FDA adverse event reporting system

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