Long-term follow-up of ibrutinib monotherapy in treatment-naive patients with Waldenstrom macroglobulinemia

Jorge J Castillo,Andrew J Yee,Christopher J Patterson,Elizabeth O’Donnell,Joshua Gustine ,Catherine Flynn ,Amanda Kofides,Guang Yang,Andrew R Branagan,Noopur Raje,Shayna Sarosiek,Zachary Hunter ,Xia Liu,Timothy P White ,Maria Demos ,Manit Munshi,Xu Liu ,Kirsten Meid,Nicholas Tsakmaklis,Maria Luisa Guerrera ,Carly Leventoff,Steven P Treon

doi:10.1038/s41375-021-01417-9

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

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

METHODS

RESULTS

DISCUSSION