Risk of bleeding associated with BTK inhibitor monotherapy: a systematic review and meta-analysis of randomized controlled trials

ABSTRACT

Background

The bleeding risk associated with Bruton’s tyrosine kinase inhibitor (BTKi) monotherapy remains to be understood. This systematic review aims to evaluate BTKi monotherapy related bleeding risk.

Research design and methods

PubMed, Embase, and CENTRAL were searched up to 5 December 2021. We included randomized controlled trials (RCTs) comparing BTKi monotherapy with control drugs, or comparing different BTKi monotherapies.

Results

10 studies with 3139 patients were included. Ibrutinib (vs. control drugs) significantly increased the risk of overall bleeding and major bleeding (RR = 2.22, 95% CI 1.80–2.75, P < 0.00001; RR = 1.80, 95% CI 1.02–3.18, P = 0.04, respectively). Acalabrutinib (vs. control drugs) had a significantly increased overall bleeding risk (RR = 3.45, 95% CI 2.39–4.99, p < 0.00001). A significant difference was found in overall bleeding between ibrutinib and acalabrutinib (RR = 1.35, 95% CI 1.11–1.64, P = 0.002). Compared to zanubrutinib, ibrutinib tended to increase the risk of major bleeding (RR = 1.55, 95% CI 0.57–4.18, P = 0.39).

Conclusions

Ibrutinib and acalabrutinib (vs. control drugs) have a higher risk of bleeding and overall bleeding, respectively. Limited evidence suggests that ibrutinib (vs. acalabrutinib) significantly increases overall bleeding risk, but the differences are not observed in other comparisons.

KEYWORDS:

• Bleeding
• ibrutinib
• acalabrutinib
• zanubrutinib
• randomized controlled trials
• systematic review

Acknowledgments

The authors thank the anonymous peer reviewers for constructive criticism and suggested additions, which have all been addressed and have significantly improved this article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that their institution has received payments for clinical research using zanubrutib, acalabrutinib and ibrutinib. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Author contributions

R Zhao and Z Song conceived and designed the study. D Jiang and Z Song collected, and analyzed the data, and performed the statistical analysis. D Jiang and Z Song wrote the article. D Jiang, Z Song, and Y Hu prepared the pictures and tables. Y Hu, F Dong and R Zhao provided suggestions and participated in the revision of the article. All authors read and approved the final manuscript.

Supplementary material

Supplemental data for this article can be accessed here

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (NSFC) (72074005).