Incidence of second primary malignancies in patients with hematologic malignancies treated with next-generation bruton tyrosine kinase (BTK) inhibitors: A meta-analysis of randomized controlled trials

Abstract Background: Second primary malignancies (SPMs) have emerged as a clinically relevant concern in patients with hematologic malignancies receiving prolonged targeted therapy. Although next-generation Bruton tyrosine kinase inhibitors (BTKis), including acalabrutinib, zanubrutinib, and pirtobrutinib, demonstrate improved safety profiles relative to first-generation agents such as ibrutinib, their long-term oncologic risks remain incompletely characterized. To address this, a meta-analysis of randomized controlled trials (RCTs) was conducted to assess the incidence of SPMs in patients treated with next-generation BTKis compared with control regimens, including ibrutinib and conventional chemotherapy. Methods: A systematic literature search of MEDLINE, EMBASE, and Cochrane was conducted from inception through July 22, 2025, following PRISMA guidelines. Eligible studies included phase II/III RCTs enrolling adults with hematologic malignancies and reporting SPMs associated with next-generation BTKis (acalabrutinib, zanubrutinib, or pirtobrutinib). Trials with ibrutinib, chemotherapy, or standard comparators were included. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Heterogeneity was assessed with the I² statistic, and bias risk was evaluated using the Cochrane RoB 2.0 tool. Pre-specified subgroup analyses excluded ibrutinib comparators and examined individual BTKis. Results: Ten phase II/III RCTs comprising 4,654 patients with reported SPM outcomes were included. Trials evaluated acalabrutinib (ECHO, ELEVATE-TN, ASCEND, AMPLIFY, NCT02477696), zanubrutinib (ASPEN, SEQUOIA, ALPINE, ROSEWOOD), and pirtobrutinib (BRUIN CLL-321). Treatment with next generation BTKis was associated with a statistically significant increased risk of SPMs compared with control therapies (RR 1.45; 95% CI: 1.06-1.99; p=0.02; I²=60%). A total of 280 SPMs occurred in BTKi arms vs 159 in control arms (10.4% vs 8.1%; number needed to harm ≈43). In a sensitivity analysis limited to seven studies that excluded ibrutinib as a comparator, including the acalabrutinib trials (ECHO, ELEVATE TN, ASCEND, and AMPLIFY), the zanubrutinib trials (SEQUOIA and ROSEWOOD), and the pirtobrutinib trial (BRUIN CLL-321), the risk of SPMs remained elevated but did not reach statistical significance (RR 1.65; 95% CI: 0.95-2.86; p=0.08; I²=73%). Subgroup analyses demonstrated that acalabrutinib was significantly associated with a higher risk of SPMs (RR 1.53; 95% CI: 1.19-1.95; p=0.0008; I²=72%), based on five studies: ECHO, ELEVATE TN, ASCEND, AMPLIFY, and NCT02477696. In contrast, zanubrutinib was not associated with a statistically significant increase in SPM risk (RR 1.29; 95% CI: 0.91-1.83; p=0.15; I²=31%), based on four studies: ASPEN, SEQUOIA, ALPINE, and ROSEWOOD. Conclusion: Next-generation BTK inhibitors were associated with a modest but statistically significant increase in the risk of second primary malignancies, particularly with acalabrutinib. These findings underscore the importance of incorporating long-term carcinogenic risk into BTKi treatment decisions and post-treatment surveillance strategies. Prospective studies and registries are warranted to elucidate underlying biological mechanisms and inform risk-adapted management approaches.