Natural history of Waldenström macroglobulinemia following acquired resistance to ibrutinib monotherapy
Joshua N. Gustine,
Shayna Sarosiek,
Catherine A. Flynn,
Kirsten Meid,
Carly Leventoff,
Timothy White,
Maria Luisa Guerrera,
Lian Xu,
Amanda Kofides,
Nicholas Tsakmaklis,
Manit Munshi,
Maria Demos,
Christopher J. Patterson,
Xia Liu,
Guang Yang,
Zachary R. Hunter,
Andrew R. Branagan,
Steven P. Treon,
Jorge J. Castillo
Affiliations
Joshua N. Gustine
Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA, USA; Boston University School of Medicine
Shayna Sarosiek
Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston MA
Catherine A. Flynn
Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Kirsten Meid
Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Carly Leventoff
Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Timothy White
Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Maria Luisa Guerrera
Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Lian Xu
Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Amanda Kofides
Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Nicholas Tsakmaklis
Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Manit Munshi
Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Maria Demos
Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Christopher J. Patterson
Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Xia Liu
Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA
Guang Yang
Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston MA
Zachary R. Hunter
Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston MA
Andrew R. Branagan
Department of Medicine, Harvard Medical School, Boston MA, USA; Division of Medical Oncology, Massachusetts General Hospital, Boston MA
Steven P. Treon
Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston MA
Jorge J. Castillo
Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston MA
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 years). Following discontinuation of ibrutinib, a rapid increase in serum immunoglobulin M level was observed in 60% (29/48) of evaluable patients, of whom ten 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% confidence interval [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 (odds ratio [OR] 0.20, 95% CI: 0.05-0.73) and salvage therapy ≤7 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 (hazard ratio 0.08, 95% CI: 0.02-0.38). TP53 mutations were associated with shorter OS, while acquired BTK C481S mutations had no impact. Our findings reveal that continuation of ibrutinib until subsequent treatment is associated with improved disease control and clinical outcomes.