Two-Year Follow-up after Ibrutinib and Venetoclax in Symptomatic, Treatment-Naive Patients with Waldenström Macroglobulinemia
Authors: Castillo Jorge J. , Sarosiek Shayna R , Branagan Andrew R. , von Keudell Gottfried , Flynn Catherine A. , Ramirez-Gamero Andres , Budano Nina S , Eurell Alexandra N. , Meid Kirsten , Guerrera Maria Luisa , Kofides Amanda , Liu Shirong , Liu Xia , Richardson Kris , Tsakmaklis Nickolas , Patterson Christopher J , Hunter Zachary R , Treon Steven P. 
Published: December 2024

Background: BTK inhibitors and BCL2 antagonists as monotherapy are highly active and well tolerated in Waldenström macroglobulinemia (WM). We initiated a prospective study evaluating ibrutinib and venetoclax in treatment-naive WM. Study therapy was stopped on March 31, 2022, after four ventricular arrhythmia events, including two grade 5 events as previously reported. Herein, we present follow-up data 2 years after stopping therapy to assess the response durability of the combination in WM.
Methods: This was an investigator-initiated, multicenter, prospective phase II study in symptomatic treatment-naïve WM patients (ClinicalTrials.gov ID NCT04273139). Study therapy was given in 4-week cycles. Intended therapy consisted of ibrutinib at 420 mg/day on cycle 1. Venetoclax was added on cycle 2 at 100 mg/day for one week, 200 mg/day for one week, and 400 mg/day for two weeks, followed by ibrutinib 420 mg/day and venetoclax 400 mg/day given together for cycles 3-24. All patients underwent baseline laboratory studies, a bone marrow aspiration and biopsy with MYD88 and CXCR4 genotyping, and CT scans of the chest, abdomen, and pelvis with intravenous contrast to evaluate extramedullary disease. Responses were assessed using modified IWWM6 criteria.
Results: Between July 2020 and January 2022, 45 (30 males and 15 females) patients were enrolled. Baseline characteristics were median age 67 (range 40-82 years), median serum IgM 4297 (range 572-9211 mg/dL), median hemoglobin 10.2 (range 7.8-15.3 g/dL), median bone marrow involvement 60% (5-90%), lymphadenopathy (&gt;1.5 cm) 25 (56%), and splenomegaly (&gt;15 cm) 13 (29%). MYD88 L265P was detected in all patients, and CXCR4 mutations were detected in 17 patients (38%; 10 nonsense, and 7 frameshift). The median time on treatment was 10.2 months (range 1.9-20.8) before treatment was halted. No patient completed the 24 planned treatment cycles. Three patients discontinued therapy before study therapy was stopped: one because of grade 4 ventricular arrhythmia, one because of an intracranial bleed possibly related to study therapy in a patient with a previously unknown benign brain lesion, and one because of transformation to DLBCL. Very good partial response (VGPR) was attained in 19 patients (42%), partial response in 24 (53%), and minor response in 2 (4%), for an overall response rate of 100%. CXCR4 mutations were associated with numerically lower VGPR rates (29% v 50%; p=0.18).
The median study follow-up was 36 months (range 34-39). There were 23 (51%) progression events, two treatment-emergent deaths three and four months into study therapy, and one death of unknown cause two years after stopping study therapy. Six patients (13%) started a new treatment. At 36 months, the progression-free survival (PFS) rate was 51% (95% CI 35-65), the therapy-free survival (TFS) rate was 88% (95% CI 74-95), and the overall survival (OS) rate was 93% (95% CI 79-98). CXCR4 mutations did not impact PFS (p=0.86), TFS (p=0.49), or OS (p=0.20). The median time after end of therapy (EOT) was 26 months (95% CI 25-27). There were 20 progression events after EOT, and the 24-month PFS rate after EOT was 56% (95% CI 40-69). CXCR4 mutations (p=0.70), time on therapy ≥12 months (p=0.47), and VGPR attainment at EOT (p=0.62) did not impact PFS after EOT. No treatment-emergent events, especially arrhythmia, were observed after treatment stopped. Twenty-two patients (49%) underwent a bone marrow biopsy two years after EOT. No emergent mutations in BTK were detected. Mutations in BCL2 will be assessed at a later time.
Conclusion: Despite early treatment truncation due to unexpected ventricular arrhythmia, the combination of ibrutinib and venetoclax was active in symptomatic, treatment-naive WM patients and is associated with durable responses after stopping therapy. CXCR4 mutations, time on study treatment, or VGPR attainment did not impact PFS after EOT. No treatment-emergent toxicities occurred after EOT, including arrhythmia or the emergence of BTK mutations.