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

PURPOSE We report the long-term findings and final analysis of a pivotal multicenter trial of ibrutinib monotherapy in previously treated patients with Waldenstrom macroglobulinemia (WM). PATIENTS AND METHODS 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. RESULTS 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 (P < .001 for all comparisons). Responses were impacted by mutated (Mut) MYD88 and CXCR4 status. Patients with MYD88(Mut), wild-type (WT) CXCR4 showed higher major (97.2% v 68.2%; P < .0001) and very good partial (47.2% v 9.1%; P < .01) response rates and a shorter time to major response (1.8 v 4.7 months; P = .02) versus patients with MYD88(Mut)CXCR4(Mut). Conversely, four patients who had MYD88(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 MYD88(Mut)CXCR4(WT) and MYD88(Mut)CXCR4(Mut) WM, respectively (P = .02). In patients with MYD88(WT), the median PFS was 0.4 years (P < .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. CONCLUSION 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 MYD88 and CXCR4 mutation status. (C) 2020 by American Society of Clinical Oncology