Ibrutinib + Rituximab (BTK / CD20) Lifts 48‑mo PFS to 72% in CXCR4‑Mutant Waldenström Macroglobulinemia

Ibrutinib, a covalent BTK inhibitor, plus rituximab (anti-CD20) was compared with ibrutinib alone in a pooled patient‑level analysis of three prospective studies (N=174 MYD88‑mutated WM; 58 I+R, 116 I). Overall VGPR was 38% vs 28% (p = 0.21) and 48‑month PFS 74% vs 61% (p = 0.22), with OS 94% vs 89%. In the CXCR4‑mutated subset (≈40% of cohort) the doublet improved VGPR 27% vs 11% and 48‑month PFS 72% vs 43% (p = 0.03). The 61% 4‑year PFS for single‑agent ibrutinib aligns with its reported 5‑year PFS of 54% and 87% OS, while second‑generation BTK inhibitor zanubrutinib shows higher VGPR+CR (36%) with fewer adverse events in ASPEN. Earlier iNNOVATE demonstrated I+R cut progression risk vs rituximab alone by ~77%, but this analysis indicates limited additive benefit unless CXCR4 is mutated.