Ibrutinib and Venetoclax in Previously Untreated Waldenström Macroglobulinemia

Background: BTK inhibitors and BCL2 antagonists have shown (separately) to be safe and effective in patients with Waldenström macroglobulinemia (WM). We, therefore, designed a prospective study evaluating the combination of the BTK inhibitor ibrutinib and the BCL2 antagonist venetoclax in previously untreated patients with WM.

Aims: To evaluate the safety and efficacy of the combination of ibrutinib and venetoclax in previously untreated patients with WM.

Methods: This was an investigator-initiated, single-arm, multicenter, prospective phase II study. Assuming a null VGPR rate of <25% and an alternative VGPR rate of >45%, a sample size of 50 patients was needed (power 80%, alpha 3%). All patients met diagnostic criteria for WM, met criteria to treat, and provided written consent. Study therapy was given in 4-week cycles. Ibrutinib was started at a dose of 420 mg orally daily starting on cycle 1. On cycle 2, venetoclax was started at 100 mg orally daily for 1 week, then 200 mg orally daily for 1 week, and then 400 mg orally daily for 2 weeks. Both agents were given concurrently starting on cycle 3 to complete 24 cycles. The patients were monitored for tumor lysis syndrome monitoring during cycle 2 (venetoclax ramp up). All patients underwent baseline laboratory studies, a bone marrow biopsy for MYD88 and CXCR4 genotyping, and computed tomography scans to evaluate for extramedullary disease. Responses were assessed using modified criteria by the 6^th International Workshop for WM. Our Institutional Review Board approved the present study, registered under ClinicalTrials.Gov ID NCT04273139.

Results: Between July 2020 and January 2022, a total of 45 patients were enrolled. Baseline characteristics were: median age 67 years (range 40-82), male:female ratio was 2:1 (30:15), MYD88 L265P 45 (100%), CXCR4 mutation 17 (38%), serum IgM 4297 mg/dl (range 572-9211), hemoglobin 10.2 g/dl (range 7.8-15.3), bone marrow involvement 60% (5-90%), lymphadenopathy >1.5 cm 25 (56%), splenomegaly >15 cm 13 (29%), von Willebrand disease 9 (20%), and cryoglobulins 3 (7%). Best categorical responses were VGPR 18 (40%), partial response (PR) 24 (53%), and minor response (MR) 3 (7%), for an ORR of 100% and a major response rate of 93% (Figure A). The median time to MR was 1.9 months, without difference in CXCR4 mutated patients (p=0.27), and the median time to major response was 1.9 months and was longer in CXCR4 mutated patients (2.8 v 1.8; p=0.048). The VGPR rate was lower in CXCR4 mutated patients (24% v 50%; p=0.08). There was improvement in lymphadenopathy in 82% and in splenomegaly in 92% of patients. With a median follow-up of 11 months, 1 patient progressed with transformation to aggressive lymphoma, and 2 patients died of ventricular arrhythmia. The estimated 12-month PFS rate is 92% (Figure B). Grade ≥3 adverse events seen in >1 patient included neutropenia (n=13; 29%), cardiac arrest/ventricular arrhythmia (n=3; 7%), oral mucositis (n=2; 4%), and tumor lysis syndrome (n=2; 4%). On January 19, 2022, a third Grade ≥4 cardiac arrest/ventricular arrhythmia was reported prompting a hold on further accrual given the higher-than-expected rate of events. All participants on active treatment were required to undergo cardiac evaluations including ECGs, echocardiograms, and stress tests. On April 6, 2022, one participant developed a Grade 2 ventricular tachycardia while undergoing a stress test, prompting a full clinical hold on this trial given a rate of ventricular arrhythmia/cardiac arrest of 9% (n=4). All active participants stopped study therapy and are under active follow-up.

Conclusion: The combination of ibrutinib and venetoclax was associated with a major response rate of 93%, and a VGPR rate of 40% in previously untreated WM. However, there was a higher-than-expected rate of ventricular arrhythmia of 9%, which prompted stopping study therapy.

Castillo:TG Therapeutics: Research Funding; Roche: Consultancy; Janssen: Consultancy; Cellectar: Consultancy; Beigene: Consultancy, Research Funding; AstraZeneca: Research Funding; Pharmacyclics: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding. Sarosiek:ADC Therapeutics: Research Funding; BeiGene: Consultancy. Branagan:Janssen/Pharmacyclics: Consultancy; Adaptive Biotechnologies: Consultancy; Genzyme: Consultancy; BeiGene: Consultancy; CSL Behring: Consultancy; Karyopharm Therapeutics: Consultancy. Treon:Abbvie: Consultancy; Janssen/Pharmacyclics: Consultancy, Research Funding; BMS: Research Funding; BeiGene: Consultancy; X4: Consultancy, Research Funding.

Venetoclax is not approved for the frontline treatment of Waldenström macroglobulinemia.