Second Primary Malignancies in Patients With B-Cell Lymphomas Treated With Bruton's Tyrosine Kinase Inhibitors: A Systematic Review and Meta-Analysis.

Cuiping Ma; Yuexia Lu; Jiahang Li; Wenjing Liu; Jie Liu

doi:10.1111/ejh.70235

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Second Primary Malignancies in Patients With B-Cell Lymphomas Treated With Bruton's Tyrosine Kinase Inhibitors: A Systematic Review and Meta-Analysis.

Cuiping Ma·Yuexia Lu·Jiahang Li·Wenjing Liu·Jie Liu

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Abstract

OBJECTIVE: To evaluate the overall second primary malignancy (SPM) burden in patients with B-cell lymphomas treated with Bruton's tyrosine kinase (BTK) inhibitors and compare SPM risk versus non-BTK inhibitor or placebo controls. METHODS: We searched major databases from inception to September 30, 2025. The primary outcome was SPM incidence. Consistent treatment backgrounds were defined as comparable baseline clinical and treatment characteristics, with BTK inhibitor exposure as the main between-arm difference. RESULTS: Fifty-two studies involving 9337 patients were included, mainly CLL/SLL; MCL was the largest non-CLL/SLL subtype. Pooled SPM incidence was 8% (95% CI: 6%-11%) with a median follow-up of 31.5 months. Multivariable meta-regression identified follow-up duration as the only independent predictor, whereas disease subtype, inhibitor generation, prior therapy lines, study design, and age were not significant. Furthermore, SPM patterns were comparable between CLL/SLL and non-CLL/SLL cohorts. Compared with controls, BTK inhibitors did not significantly increase SPM risk (RR = 1.30, 95% CI: 0.95-1.78), a finding confirmed in analyses with consistent treatment backgrounds (RR = 1.03, 95% CI: 0.85-1.25). CONCLUSIONS: SPMs occur across disease backgrounds and are mainly influenced by follow-up duration. Current evidence does not establish a direct carcinogenic effect of BTK inhibitors.

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Humans Agammaglobulinaemia Tyrosine Kinase Protein Kinase Inhibitors Neoplasms, Second Primary Lymphoma, B-Cell Incidence Bruton's tyrosine kinase inhibitors B‐cell lymphoma chronic lymphocytic leukemia meta‐analysis second primary malignancies Journal Article Systematic Review Meta-Analysis

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Cuiping Ma, Yuexia Lu, Jiahang Li, Wenjing Liu, Jie Liu. 2026-06-14. Second Primary Malignancies in Patients With B-Cell Lymphomas Treated With Bruton's Tyrosine Kinase Inhibitors: A Systematic Review and Meta-Analysis.. https://doi.org/10.1111/ejh.70235

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