Ibrutinib plus rituximab vs ibrutinib monotherapy in patients with Waldenström macroglobulinemia: a pooled analysis

Ibrutinib (I) and ibrutinib plus rituximab (I+R) are highly efficacious in treating Waldenström macroglobulinemia (WM). However, the benefit of adding rituximab remains unclear, and a prospective trial to compare these two regimens has not been undertaken. Therefore, we performed a pooled analysis of prospective studies to compare their effectiveness. Patient-level demographic, response, and survival data were pooled from three prospective studies (ClinicalTrials.gov identifiers: NCT01614821, NCT02604511, NCT02165397). We included patients treated with I+R or I, excluding those without MYD88 mutations. Among 174 patients (58 I+R, 116 I), very good partial response (VGPR) rates were comparable across treatment groups (38% I+R vs 28% I; P = .21). The 48-month progression-free survival (PFS) rate was 74% with I+R vs 61% with I (P = .22). The 48-month overall survival rate was 94% vs 89% (P = .45). In patients with CXCR4 mutations, I+R trended toward higher VGPR (27% vs 11%; P = .10), and had a superior 48-month PFS rate (72% vs 43%; P = .03). CXCR4 mutations were associated with inferior VGPR (42% vs 17%; P = .001) and 48-month PFS in the I arm (43% vs 72%; P = .002). In the I+R arm, CXCR4 mutations were associated with numerically inferior VGPR (47% vs 27%; P = .12), but the 48-month PFS rate was not impacted (74% vs 72%; P = .96). I+R significantly improved PFS over I in patients with CXCR4-mutated WM, along with a nonsignificant increase in VGPR in this subgroup. These results support routine CXCR4 testing in patients with WM, and clinical trials of rituximab with covalent or noncovalent Bruton tyrosine kinase inhibitors.