Abstract

Herein, we present the final report of a single-center, prospective phase II study evaluating ibrutinib 420 mg once daily in 30 treatment-naive patients with Waldenstrom macroglobulinemia (WM). The present study is registered with ClinicalTrials.Gov (NCT02604511). With a median follow-up of 50 months, the overall, major, and VGPR response rates were 100%, 87%, and 30%. The VGPR rate was numerically but not significantly lower in patients with than without CXCR4 mutations (14% vs. 44%; p = 0.09). The median time to a minor response was 0.9 months, and to a major response was 1.9 months, though were longer in those with mutated CXCR4 at 1.7 months (p = 0.07) and 7.3 months (p = 0.01). Six patients had disease progression. The median progression-free survival (PFS) was not reached, and the 4-year PFS rate was 76%. There was also a non-significant lower 4-year PFS rate in patients with than without CXCR4 mutations (59% vs. 92%; p = 0.06). The most common treatment-related adverse events were fatigue, upper respiratory infection, and hematoma. Atrial fibrillation occurred in 20% of patients. Ibrutinib monotherapy induced durable responses in treatment-naive patients with WM. CXCR4 mutations impacted VGPR attainment, time to major response, and 4-year PFS rate.

Highlights

  • The genomic landscape of Waldenstrom macroglobulinemia (WM) is composed of recurrent mutations in the MYD88 and CXCR4 genes, which can be detected in 90–95% and 30–40% of patients with WM, respectively [1, 2]

  • DISCUSSION we present the final report from an investigator-initiated, prospective phase II study evaluating ibrutinib monotherapy in 30 treatment-naive patients with WM with a median follow-up time of 50 months

  • Our data show that ibrutinib monotherapy, as primary therapy for WM, induced a high rate of durable responses and further affirms ibrutinib as a standard of care in treatmentnaive patients with WM

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Summary

INTRODUCTION

The genomic landscape of Waldenstrom macroglobulinemia (WM) is composed of recurrent mutations in the MYD88 and CXCR4 genes, which can be detected in 90–95% and 30–40% of patients with WM, respectively [1, 2]. In 2015, the United States Food & Drug Administration approved the oral BTK inhibitor ibrutinib for the treatment of patients with symptomatic WM, based on the results of an investigator-initiated multicenter phase II study in 63 previously treated patients in which ibrutinib monotherapy induced an overall response rate (ORR) of 91% and a major response rate of 71% [5]. The long-term data from this study were recently published and reported a 5-year progression-free survival (PFS) rate of 54% [6]. We previously reported early data on ibrutinib as primary therapy in patients with WM [7]. This report presents the long-term follow-up from this investigator-initiated, single-center, phase II study evaluating ibrutinib monotherapy in treatment-naive patients with WM

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