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

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.

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“…4 , should be recommended, given that the patient’s genomic profile can affect the clinical outcome [ 83 ]. Although several treatment options are presently available for WM patients, including alkylators, NAs, proteasome inhibitors, and monoclonal antibodies, the first-in-class oral Bruton tyrosine kinase (BTK) inhibitor ibrutinib, as monotherapy, has been employed in patients with MYD88 and without CXCR4 mutations, both in frontline and relapse settings [ 84 , 85 ]. For patients with MYD88 and CXCR4 mutations or without MYD88 or CXCR4 mutations, chemoimmunotherapy or proteasome-inhibitor-based regimens are preferred [ 86 ].…”

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“…46 In a recent update, there was also a trend towards a lower 4-year PFS rate in patients with CXCR4 mutations (59% versus 92%). 36 These findings were further confirmed in the phase III iNNOVATE trial where patients with CXCR4 MUT required longer time to major response (2.8 months) compared with patients with CXCR4 WT (1.9 months), though 30-month PFS was similar in both groups. 37 In a substudy of this trial where 31 patients with rituximab-refractory disease received open-label IR, the overall responses were similar for CXCR4 WT and CXCR4 MUT patients, although the magnitude of IgM reduction was greater and response was earlier in those with CXCR4 WT .…”

“…A recent update of this trial reported a 4-year PFS of 76%. 36 The iNNOVATE trial, a phase III randomized trial of 150 TN or R/R patients, compared ibrutinib/rituximab (IR) with placebo/rituximab (R), using rituximab 375 mg/m 2 given intravenously for eight weekly doses on weeks 1-4 and weeks 17-20 in both treatment groups. 37 Although singleagent rituximab was generally regarded as a poor control regimen, it was at that time a commonly used real-world regimen for WM in countries such as the USA.…”

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“…However, this study does not answer the question whether rituximab adds value to ibrutinib alone since it lacks an ibrutinib monotherapy arm. The updated long-term data of these pivotal studies of ibrutinib in the relapse and front-line setting and of the iNNOVATE trial have been recently published, further confirming the efficacy and safety profiles (56)(57)(58).…”