Long-Term Follow-Up of Ibrutinib Monotherapy in Symptomatic, Previously Treated Patients With Waldenström Macroglobulinemia.

Abstract

We report the long-term findings and final analysis of a pivotal multicenter trial of ibrutinib monotherapy in previously treated patients with Waldenström macroglobulinemia (WM). Sixty-three symptomatic patients with median prior therapies of two (range, one to nine therapies), of whom 40% were refractory to their previous therapy, received ibrutinib at 420 mg/d. Dose reduction was permitted for toxicity. The median follow-up was 59 months, and overall and major response rates were 90.5% and 79.4%, respectively. At best response, median serum immunoglobulin M declined from 3,520 to 821 mg/dL, bone marrow disease involvement declined from 60% to 20%, and hemoglobin rose from 10.3 to 14.2 g/dL (<i>P</i> < .001 for all comparisons). Responses were impacted by mutated (Mut) <i>MYD88</i> and <i>CXCR4</i> status. Patients with <i>MYD88</i>^Mut, wild-type (WT) <i>CXCR4</i> showed higher major (97.2% <i>v</i> 68.2%; <i>P</i> < .0001) and very good partial (47.2% <i>v</i> 9.1%; <i>P</i> < .01) response rates and a shorter time to major response (1.8 <i>v</i> 4.7 months; <i>P</i> = .02) versus patients with <i>MYD88</i>^Mut<i>CXCR4</i>^Mut. Conversely, four patients who had <i>MYD88</i>^WT disease showed no major responses. The median 5-year progression-free survival (PFS) rate for all patients was not reached, and was 70% and 38% for those with <i>MYD88</i>^Mut<i>CXCR4</i>^WT and <i>MYD88</i>^Mut<i>CXCR4</i>^Mut WM, respectively (<i>P</i> = .02). In patients with <i>MYD88</i>^WT, the median PFS was 0.4 years (<i>P</i> < .01 for three-way comparisons). The 5-year overall survival rate for all patients was 87%. Grade ≥ 3 adverse events in more than one patient at least possibly related included neutropenia (15.9%), thrombocytopenia (11.1%), and pneumonia (3.2%). Eight patients (12.7%) experienced atrial arrhythmia, and seven of the eight continued therapy with medical management. Ibrutinib is highly active and produces long-term disease control in previously treated patients with WM. Treatment is tolerable. Response depth, time to major response, and PFS are impacted by <i>MYD88</i> and <i>CXCR4</i> mutation status.