Ibrutinib and Venetoclax as Primary Therapy in Symptomatic Patients With Treatment-Naïve MYD88-Mutated Waldenström Macroglobulinemia
abstract
This abstract is available on the publisher's site.
Access this abstract nowConcurrent BTK and BCL2 inhibition has not been investigated in Waldenström macroglobulinemia. We performed an investigator-initiated trial of ibrutinib and venetoclax in symptomatic, treatment-naive 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 four-week cycles. Attainment of VGPR was the primary endpoint. Forty-five patients were enrolled. Median baseline characteristics were 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 two grade 5 events. With median follow-up of 24.4 months, the 24-month progression-free (PFS) and overall survival (OS) rates were 76% and 96%, not impacted by CXCR4 mutations. Median time on therapy was 10.2 months, and median time after end of therapy (EOT) was 13.3 months. Eleven of the 12 progression events occurred after EOT, and the 12-month PFS rate after EOT was 79%; 93% if VGPR was attained, and 69% for other patients (p=0.12). Ibrutinib and venetoclax induced high VGPR rate and durable responses after EOT, though associated with a higher-than-expected rate of ventricular arrhythmia in WM patients leading to early study treatment termination. The trial was funded by Abbvie and Pharmacyclics (NCT04273139).
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Ibrutinib and venetoclax as primary therapy in symptomatic treatment naïve Waldenström macroglobulinemia
Blood 2023 Oct 27;[EPub Ahead of Print], JJ Castillo, AR Branagan, D Sermer, C Flynn, KE Meid, M Little, K Stockman, TP White, AG Canning, ML Guerrera, A Kofides, S Liu, X Liu, K Richardson, N Tsakmaklis, CJ Patterson, ZR Hunter, SP Treon, S SarosiekFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
In an important observation, Castillo and colleagues report the outcomes of patients with Waldenström macroglobulinemia (WM) treated with the combination of ibrutinib and venetoclax. While the combination is active, 2 patients experienced sudden death. The study was terminated, and another study also using rituximab with this combination has been halted.
Why did this occur? Beyond the obvious knowledge of BTK inhibitors causing cardiac arrhythmias, here is no immediate logical explanation for the high rate of fatal events. Similar combinations have been extensively used in CLL without known rates of high ventricular arrythmias (mostly atrial). Is there something unique about patients with WM (eg, light chain amyloidosis), or was this merely a spurious finding?
Until we know better, caution is warranted and the combination should be avoided in WM. Clinicians tempted to use this combination because of its use in CLL should be cautious. While venetoclax is active in WM, and the arrhythmias are more likely linked to the BTK inhibitor, other combinations could be of greater interest (eg, venetoclax with rituximab alone or even obinutuzumab). The role of venetoclax as treatment for WM needs to be studied further, but perhaps not in combination with covalent BTK inhibitors.