Abstract
Background:
Bruton tyrosine kinase inhibitors (BTKis) have transformed the treatment landscape for B-cell malignancies. While first-generation BTKis such as ibrutinib have demonstrated efficacy, their use is limited by adverse effects including bleeding and hypertension. Next-generation BTKis including acalabrutinib, zanubrutinib, and pirtobrutinib were developed to improve tolerability while maintaining therapeutic benefit. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the incidence of bleeding and hypertension associated with next-generation BTKis in patients with hematologic malignancies.
Methods:
A comprehensive literature search was conducted following PRISMA guidelines using Cochrane, EMBASE, and MEDLINE databases from inception through July 28, 2025. Phase II/III RCTs utilizing next-generation BTKis (acalabrutinib, pirtobrutinib, or zanubrutinib) in patients with hematologic malignancies reporting bleeding and hypertension as adverse events were included. Trials with ibrutinib, chemotherapy, or standard comparators were included. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Heterogeneity was evaluated using the I² statistic. Risk of bias was assessed using the Cochrane RoB 2.0 tool. A prespecified subgroup analysis excluded trials in which ibrutinib was used as a comparator to better isolate the safety profile of next-generation agents.
Results:
A total of 4,654 patients from nine phase III RCTs (ECHO, ELEVATE-TN, ASCEND, AMPLIFY, NCT02477696, ASPEN, SEQUOIA, ALPINE, and BRUIN CLL-321) and one phase II RCT (ROSEWOOD) were included. AMPLIFY and ELEVATE-TN enrolled treatment-naive patients with chronic lymphocytic leukemia (CLL), while SEQUOIA included patients with either untreated CLL or small lymphocytic leukemia. ALPINE and ASCEND enrolled patients with relapsed or refractory (R/R) CLL, NCT02477696 included previously treated CLL patients, and BRUIN CLL-321 focused on R/R CLL patients with prior exposure to covalent BTK inhibitors. ASPEN studied patients with symptomatic Waldenström macroglobulinemia, ECHO included those with untreated mantle cell lymphoma, and ROSEWOOD enrolled patients with R/R follicular lymphoma.
The incidence of any-grade bleeding was significantly higher in the BTKi arm compared to the control arm (32.38% vs 20.10%, RR 2.20, 95% CI: 1.29-3.74, p=0.004). The incidence of high-grade bleeding was higher in the BTKi arm compared to the control arm, but not statistically significantly different (3.17% vs 2.54%, RR 1.35, 95% CI: 0.78-2.32, p=0.28). The incidence of high-grade HTN was not statistically significantly different between the BTKi arm versus the control arm (6.04% vs 6.70%, RR 1.00, 95% CI: 0.61-1.63, p=0.99). Similarly, the incidence of any-grade HTN was not significantly different between the two groups (9.13% vs 10.96%, RR 1.01, 95% CI: 0.69-1.50, p=0.94).
A subgroup analysis excluding trials with ibrutinib as a comparator (ALPINE, ASPEN, and NCT02477696) included 3,278 patients across seven studies. In this cohort, the incidence of any-grade bleeding was significantly higher in the BTKi arm compared to the control arm (32.06% vs 9.73%; RR 3.47, 95% CI: 2.14-5.62, p<0.00001). High-grade bleeding was also more frequent in the BTKi group (2.76% vs 1.25%) and approached statistical significance (RR 2.69, 95% CI: 1.00-7.26, p=0.05). The incidence of high-grade hypertension was similar between groups (3.36% vs 3.42%; RR 1.16, 95% CI: 0.67-2.00, p=0.61), as was the incidence of any-grade hypertension (6.67% vs 7.00%; RR 1.09, 95% CI: 0.82-1.45, p=0.55).
Conclusion:
This meta-analysis demonstrated a significantly increased risk of any-grade bleeding in patients with hematologic malignancies treated with BTK inhibitors compared to chemotherapy, both in analyses that included and excluded trials with ibrutinib comparators. No significant difference in hypertension risk was observed between treatment arms. These findings emphasize the bleeding risk associated with BTKi-based regimens, particularly with next-generation agents, and support the need for vigilant monitoring and proactive management to reduce bleeding-related complications.
