Efficacy and safety of zanubrutinib in Waldenström macroglobulinemia: A systematic review and meta-analysis of clinical trials.

e19569 Background: Bruton tyrosine kinase (BTK) inhibition has transformed the management of Waldenström macroglobulinemia (WM). Zanubrutinib, a second-generation BTK inhibitor (BTKi), has shown improved selectivity and tolerability in patients with WM, particularly with relapsed/refractory (RR) disease. However, the rarity of WM and limited availability of head-to-head trials restrict the feasibility of comparative meta-analyses of longer-term clinical outcomes. As such, a systematic review and single-arm meta-analysis represents the next best level of evidence to quantitatively assess the clinical performance of zanubrutinib across disease settings while avoiding exclusion of key data from single-arm trials. Methods: We conducted a systematic review and single-arm meta-analysis of prospective clinical trials evaluating zanubrutinib in treatment-naïve (TN) and RR WM. Random-effects models were used to pool response, survival, and adverse event outcomes. Fixed-time survival estimates were extracted directly or reconstructed from Kaplan-Meier curves when not explicitly reported. Results: Five trials comprising six cohorts and 322 WM patients were included, of whom 304 were efficacy evaluable. The pooled ORR was 89.7% (95% CI 82.1–95.6), with a MRR of 76.8% (95% CI 70.2–82.9) and a VGPR rate of 38.0% (95% CI 31.8–44.3). Pooled 12-month PFS and OS were 85.1% and 95.8%, respectively, with corresponding 24-month estimates of 77.8% and 92.1%. Efficacy outcomes were consistent across TN and RR cohorts. Any-grade AEs occurred in 94.8% of patients and grade ≥3 AEs in 64.6%; however, atrial fibrillation (3.5%) and major hemorrhage (3.0%) were infrequent. AE-associated treatment interruption rate was 10.2%. Conclusions: This systematic meta-analysis provides the most comprehensive synthesis of zanubrutinib outcomes in WM to date, demonstrating high response rates, meaningful depth of response, durable survival, and a favorable safety profile. These pooled estimates establish clinically relevant benchmarks that inform treatment selection and contextualize emerging comparative data in WM. Pooled clinical outcomes of zanubrutinib in Waldenström macroglobulinemia stratified by disease subtype. Outcome Pooled Estimate, % [95% CI] TN RR Efficacy Very good partial response rate`Major response rateOverall response rateStable diseaseProgressive disease 31.1 [18.1–45.6]79.0 [61.7–92.5]92.9 [71.2–100]2.2 [0–17.0]3.0 [0–14.4] 44.2 [31.1–57.7]76.6 [68.0–84.4]90.1 [79.4–97.6]2.0 [0–7.0]4.5 [0–15.6] Survival* 12-month PFS12-month OS24-month PFS24-month OS ---- 83.8 [62.9–97.7]93.1 [82.9–99.4]77.8 [51.7–95.8]91.2 [87.8–95.7] CI=Confidence interval, OS=Overall survival, PFS=Progression-free survival, RR=Relapsed/Refractory, TN=Treatment naïve. *Survival outcomes not quantitatively synthesized for TN subgroups due to insufficient data.