Page 155 - Haematologica May 2022

Plasma Cell Disorders
Natural history of Waldenström macroglobulinemia following acquired resistance to ibrutinib monotherapy
Joshua N. Gustine,1,2 Shayna Sarosiek,1,3 Catherine A. Flynn,1 Kirsten Meid,1 Carly Leventoff,1 Timothy White,1 Maria Luisa Guerrera,1 Lian Xu,1
Amanda Kofides,1 Nicholas Tsakmaklis,1 Manit Munshi,1 Maria Demos,1 Christopher J. Patterson,1 Xia Liu,1 Guang Yang,1,3 Zachary R. Hunter,1,3 Andrew R. Branagan,3,4 Steven P. Treon1,3 and Jorge J. Castillo1,3
1Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute; 2Boston University School of Medicine; 3Department of Medicine, Harvard Medical School and 4Division of Medical Oncology, Massachusetts General Hospital, Boston, MA, USA
ABSTRACT
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 nat- ural 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 medi- an 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.
Introduction
Waldenström macroglobulinemia (WM) is an immunglobulin M (IgM)-secreting lymphoplasmacytic lymphoma.1 Whole-genome sequencing has identified highly recurrent somatic mutations in MYD88 (95-97%) and CXCR4 (30-40%) in WM patients.2,3 Mutated MYD88 triggers NF-kB pro-survival signaling via Bruton’s tyro- sine kinase (BTK) and interleukin-1 receptor-associated kinase 1 (IRAK1)/IRAK4, and transactivates hematopoietic cell kinase (HCK).4,5 Both BTK and HCK are tar- geted by ibrutinib.4,5 Mutations in the C-terminal domain of CXCR4 are typically subclonal and support intrinsic ibrutinib resistance through upregulation of AKT and ERK1/2 signaling.6-9
In 2015, ibrutinib became the first approved agent by the United States Food and Drug Administration and European Medicines Agency for the treatment of symp- tomatic WM patients. The regulatory approval of ibrutinib was based on the results from a multi-center, single-arm, phase II trial of 63 previously treated WM patients.10 Ibrutinib monotherapy was highly active with an overall response rate
Ferrata Storti Foundation
Haematologica 2022 Volume 107(5):1163-1171
Correspondence:
JORGE J. CASTILLO
jorgej_castillo@dfci.harvard.edu
Received: April 28, 2021. Accepted: June 16, 2021. Pre-published: June 24, 2021.
https://doi.org/10.3324/haematol.2021.279112 ©2022 Ferrata Storti Foundation
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