Treon SP, et al. - Given that, ibrutinib has shown activity in previously treated Waldenström macroglobulinemia (WM) and MYD88 mutations (MYD88^MUT) and CXCR4 mutations (CXCR4^MUT) influence ibrutinib response, researchers present the findings of a prospective study of ibrutinib monotherapy in symptomatic, untreated patients with WM, and the prognostic impact of CXCR4^MUT status. Eligible subjects were symptomatic, treatment-naïve patients with WM who were administered ibrutinib (420 mg) daily until progression or unacceptable toxicity. All tumors were genotyped for MYD88^MUT and CXCR4^MUT. Findings demonstrated high activity of ibrutinib in patients with symptomatic WM. Furthermore, it induced durable responses and was as safe as primary therapy in these patients. An impact of CXCR4^MUT status on responses to ibrutinib was evident. Higher rates of major and very good partial responses and more rapid time to major responses were observed in patients with wild-type CXCR4 vs those with CXCR4^MUT, respectively.