Final Report of a Phase <scp>II</scp> Study of Ibrutinib and Venetoclax in Previously Untreated Waldenström Macroglobulinemia

The BTK inhibitor ibrutinib and the BCL-2 antagonist venetoclax are active therapies as single agents in Waldenström macroglobulinemia (WM). In this phase 2 study, we sought to investigate the combination of ibrutinib and venetoclax as a 2-year fixed-duration, oral-based, chemotherapy-free regimen in symptomatic, treatment-naive WM patients. All patients had MYD88 mutations, 17 (38%) had CXCR4 mutations, and 4 (9%) had TP53 alterations. Following enrollment of 45 patients, treatment and enrollment were stopped due to the occurrence of ventricular arrhythmias in 4 (9%), which included two grade 5 events. The median treatment time was 10 cycles, each lasting 28 days. Follow-up continued after protocol treatment was terminated. The very good partial response/complete response (VGPR/CR) rate was 42%, and it was lower in patients with CXCR4 (29% vs. 50%) or TP53 (25% vs. 44%) mutations. With a median follow-up of 49 months, the median progression-free survival (PFS) was 36 months (range 28-42). The median treatment-free survival (TFS) and overall survival (OS) were not reached, and the 4-year TFS and OS rates were 73% and 91%, respectively. The median PFS after end of therapy (PFS-EOT) was 29 months. TP53 mutations were associated with inferior PFS, TFS, and PFS-EOT, while CXCR4 mutations did not adversely impact these outcomes. Given the deep and durable responses seen in this study, concurrent BTK and BCL-2 inhibition warrants further development in WM. TP53 mutations emerged as an adverse factor in WM in this combination study.