Venetoclax in Previously Treated Waldenström Macroglobulinemia

Abstract

Purpose: BCL2 is overexpressed and confers prosurvival signaling in malignant lymphoplasmacytic cells in Waldenström macroglobulinemia (WM). Venetoclax is a potent BCL2 antagonist and triggers in vitro apoptosis of WM cells. The activity of venetoclax in WM remains to be clarified.

Patients and methods: We performed a multicenter, prospective phase II study of venetoclax in patients with previously treated WM (NCT02677324). Venetoclax was dose-escalated from 200 mg to a maximum dose of 800 mg daily for up to 2 years.

Results: Thirty-two patients were evaluable, including 16 previously exposed to Bruton tyrosine kinase inhibitors (BTKis). All patients were MYD88 L265P-mutated, and 17 carried CXCR4 mutations. The median time to minor and major responses was 1.9 and 5.1 months, respectively. Previous exposure to BTKis was associated with a longer time to response (4.5 v 1.4 months; P < .001). The overall, major, and very good partial response rates were 84%, 81%, and 19%, respectively. The major response rate was lower in those with refractory versus relapsed disease (50% v 95%; P = .007). The median follow-up time was 33 months, and the median progression-free survival was 30 months. CXCR4 mutations did not affect treatment response or progression-free survival. The only recurring grade ≥ 3 treatment-related adverse event was neutropenia (n = 14; 45%), including one episode of febrile neutropenia. Laboratory tumor lysis without clinical sequelae occurred in one patient. No deaths have occurred.

Conclusion: Venetoclax is safe and highly active in patients with previously treated WM, including those who previously received BTKis. CXCR4 mutation status did not affect treatment response.

FIG 1.

Flow diagram.

FIG 2.

Categorical response rates to venetoclax for (A) all patients, and according to (B) relapsed or refractory disease, (C) number of previous lines of therapy, (D) prior BTKi exposure, (E) CXCR4 mutational status, and (F) IPSSWM. BTKi, Bruton tyrosine kinase inhibitor; IPSSWM, International Prognostic Scoring System for Waldenström Macroglobulinemia; MR, minor response; MUT, mutated; ORR, overall response rate; PR, partial response; VGFR, very good partial response; WT, wild-type.

FIG 3.

Kaplan-Meier curves for PFS for (A) the entire cohort, and according to (B) relapsed or refractory disease, (C) number of previous lines of therapy, (D) prior BTKi exposure, (E) CXCR4 mutational status, and (F) IPSSWM. BTKi, Bruton tyrosine kinase inhibitor; IPSSWM, International Prognostic Scoring System for Waldenström Macroglobulinemia; MUT, mutated; PFS, progression-free survival; WT, wild-type.

FIG A1.

Response kinetics to venetoclax in patients with previously treated WM. MR, minor response; ORR, overall response rate; PR, partial response; VGFR, very good partial response; WM, Waldenström macroglobulinemia.