Ibrutinib Monotherapy in Symptomatic, Treatment-Naive Patients With Waldenstrom Macroglobulinemia

PurposeIbrutinib is active in previously treated Waldenstrom macroglobulinemia (WM). MYD88 mutations (MYD88(MUT)) and CXCR4 mutations (CXCR4(MUT)) affect ibrutinib response. We report on a prospective study of ibrutinib monotherapy in symptomatic, untreated patients with WM, and the effect of CXCR4(MUT) status on outcome.Patients and MethodsSymptomatic, treatment-naive patients with WM were eligible. Ibrutinib (420 mg) was administered daily until progression or unacceptable toxicity. All tumors were genotyped for MYD88(MUT) and CXCR4(MUT).ResultsA total of 30 patients with WM received ibrutinib. All carried MYD88(MUT), and 14 (47%) carried a CXCR4(MUT). After ibrutinib treatment, median serum IgM levels declined from 4,370 to 1,513 mg/dL, bone marrow involvement declined from 65% to 20%, and hemoglobin level rose from 10.3 to 13.9 g/dL (P < .001 for all comparisons). Overall (minor or more than minor) and major (partial or greater than partial) responses for all patients were 100% and 83%, respectively. Rates of major (94% v 71%) and very good partial (31 v 7%) responses were higher and time to major responses more rapid (1.8 v 7.3 months; P = 0.01) in patients with wild-type CXCR4 versus those with CXCR4(MUT), respectively. With a median follow-up of 14.6 months, disease in two patients (both with CXCR4(MUT)) progressed. The 18-month, estimated progression-free survival is 92% (95% CI, 73% to 98%). All patients are alive. Grade 2/3 treatment-related toxicities in > 5% of patients included arthralgia (7%), bruising (7%), neutropenia (7%), upper respiratory tract infection (7%), urinary tract infection (7%), atrial fibrillation (10%), and hypertension (13%). There were no grade 4 or unexpected toxicities.ConclusionIbrutinib is highly active, produces durable responses, and is safe as primary therapy in patients with symptomatic WM. CXCR4(MUT) status affects responses to ibrutinib.