Ibrutinib is highly active and produces long-term responses in patients with Waldenström macroglobulinemia (WM), but acquired resistance can occur with prolonged treatment. We therefore evaluated the natural history and treatment outcomes in 51 WM patients with acquired resistance to ibrutinib monotherapy. The median time between ibrutinib initiation and discontinuation was 2 years (range, 0.4-6.5). Following discontinuation of ibrutinib, a rapid increase in serum IgM level was observed in 60% (29/48) of evaluable patients, of whom 10 acutely developed symptomatic hyperviscosity. Forty-eight patients (94%) received salvage therapy after ibrutinib. The median time to salvage therapy after ibrutinib cessation was 18 days (95% CI 13-27). The overall and major response rates to salvage therapy were 56% and 44%, respectively, and the median duration of response was 48 months (95% CI 34-not reached). Quadruple-class (rituximab, alkylator, proteasome inhibitor, ibrutinib) exposed disease (OR 0.20, 95% CI 0.05-0.73) and salvage therapy 07 days after discontinuing ibrutinib (OR 4.12, 95% CI 1.07-18.9) were identified as independent predictors of a response to salvage therapy. The 5-year overall survival (OS) following discontinuation of ibrutinib was 44% (95% CI 26-75%). Response to salvage therapy was associated with better OS after ibrutinib (HR 0.08, 95% CI 0.02-0.38). TP53 mutations were associated with shorter OS, while acquired BTKC481S mutations had no impact. Our findings reveal that continuation of ibrutinib until subsequent treatment is associated with improved disease control and clinical outcomes.
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