Real-World Comparative Effectiveness and Safety of BTK Inhibitors Versus Chemoimmunotherapy for Frontline Waldenstrom Macroglobulinemia

No randomized trial has compared Bruton tyrosine kinase inhibitor (BTKi)-based therapy with chemoimmunotherapy (CIT) in frontline Waldenström macroglobulinemia (WM); the RAINBOW trial (NCT04061512) is ongoing. Real-world data are therefore the only current evidence, particularly for older adults, who make up most patients and are underrepresented in trials.

We conducted a retrospective TriNetX study of adults with WM initiating approved first-line BTKi (ibrutinib or zanubrutinib) or CIT (bendamustine-rituximab or dexamethasone-rituximab-cyclophosphamide). Propensity-score matching used eight prespecified covariates spanning age, sex, race, and hematologic, cardiovascular, and renal comorbidities. The primary outcome was three-year overall survival (OS), and a subgroup analysis of patients aged ≥ 75. One-year safety outcomes are shown in Table 1.

After matching (555/arm), three-year OS was 82.3% with BTKi versus 84.6% with CIT (hazard ratio [HR], 1.08; 95% CI, 0.78-1.50; log-rank P=.637). Among patients ≥75 years (167/arm), OS was 79.2% versus 76.0% (HR, 0.83; 95% CI, 0.49-1.41; P=.49), favoring BTKi but not statistically significant. BTKi was associated with significantly lower (all P<.05) serious infection (3.6% vs 7.0%; RR, 0.52), cytopenias (13.5% vs 31.2%; RR, 0.43), hospitalization (25.4% vs 40.4%; RR, 0.63), and transfusion (4.3% vs 12.5%; RR, 0.35; n=554/arm), and significantly more atrial fibrillation/flutter (8.1% vs 3.6%; RR, 2.23; P=.003). Pretreatment hemoglobin was lower among CIT initiators than BTKi initiators (10.4 vs 11.1 g/dL).

BTKi and CIT produced similar three-year OS overall and among patients ≥75 years, a novel comparison given the absence of randomized data. BTKi was associated with significantly fewer infections, cytopenias, hospitalizations, and transfusions, while the higher rate of atrial fibrillation/flutter with BTKi and cytopenias with CIT reflect established toxicities of each regimen. Higher baseline hemoglobin among BTKi initiators may partly explain the hematologic-toxicity gap. Both arms pooled agents with differing toxicity profiles (ibrutinib/zanubrutinib; bendamustine-rituximab/DRC); agent-level data are needed to confirm these findings prospectively.