Ibrutinib and venetoclax as primary therapy in symptomatic, treatment-naïve Waldenström macroglobulinemia

Author(s): Jorge J. Castillo1,2; Andrew R. Branagan2,3; David Sermer2,4; Catherine A. Flynn1; Kirsten Meid1; Megan Little1; Katherine Stockman1; Timothy White1; Alexa Canning1; Maria L. Guerrera1; Amanda Kofides1; Shirong Liu1; Xia Liu1; Kris Richardson1; Nicholas Tsakmaklis1; Christopher J. Patterson1; Zachary R. Hunter1; Steven P. Treon1,2; Shayna Sarosiek1,2
Source: Blood (2024) 143 (7): 582–591.
Maem Hussein MD

Dr. Maen Hussein's Thoughts

This combination had impressive results but led to a high rate of ventricular arrythmias (9%), hence the combination is not recommended. Another study with the combination and rituximab was also suspended, the etiology of the higher rate of Vent arrhythmias is not known. This combination in another lymphoid malignancies did not lead to that rate of toxicity.


Concurrent Bruton tyrosine kinase and BCL2 inhibition has not yet been investigated in Waldenström macroglobulinemia (WM). We performed an investigator-initiated trial of ibrutinib and venetoclax in symptomatic treatment-naïve patients with MYD88-mutated WM. Patients received ibrutinib 420 mg once daily (cycle 1), followed by a ramp-up of venetoclax to 400 mg daily (cycle 2). The combination was then administered for 22 additional 4-week cycles. The attainment of very good partial response (VGPR) was the primary end point. Forty-five patients were enrolled in this study. The median baseline characteristics were as follows: age 67 years, serum IgM 43 g/L, and hemoglobin 102 g/L. Seventeen patients (38%) carried CXCR4 mutations. Nineteen patients (42%) achieved VGPR. Grade 3 or higher adverse events included neutropenia (38%), mucositis (9%), and tumor lysis syndrome (7%). Atrial fibrillation occurred in 3 (9%), and ventricular arrhythmia in 4 (9%) patients that included 2 grade 5 events. With a median follow-up of 24.4 months, the 24-month progression-free survival (PFS) and overall survival (OS) rates were 76% and 96%, respectively, and were not impacted by CXCR4 mutations. The median time on therapy was 10.2 months, and the median time after the end of therapy (EOT) was 13.3 months. Eleven of the 12 progression events occurred after EOT, and the 12-month PFS rates after EOT were 79%; 93% if VGPR was attained, and 69% for other patients (P = .12). Ibrutinib and venetoclax induced high VGPR rates and durable responses after EOT, although they were associated with a higher-than-expected rate of ventricular arrhythmia in patients with WM, leading to early study treatment termination. This trial was registered at www.clinicaltrials.gov as #NCT04273139.

Author Affiliations

1Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA; 2Department of Medicine, Harvard Medical School, Boston, MA; 3Center for Multiple Myeloma, Massachusetts General Hospital, Boston, MA; 4Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, MA

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