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.

Diagnosis and management of Waldenström macroglobulinaemia—A British Society for Haematology guideline

“…In a phase I dose‐finding study, venetoclax showed efficacy in four WM patients 89 . Following this report, a phase II study evaluating the safety and efficacy of venetoclax monotherapy in 32 previously treated WM patients was initiated 90 . High levels of response were reported with an ORR of 84% and MRR of 81% with a median PFS of 30 months.…”

Targeted Agents in the Treatment of Indolent B-Cell Non-Hodgkin Lymphomas

“…Early results in MZL and WM are more encouraging. In a phase 2 study of venetoclax monotherapy in 32 patients with WM, an ORR of 84% was observed with a median PFS of 30 months, including significant activity after BTKi failure or in the presence of CXCR4 mutations [69]. Legend: ORR, overall response rate; PFS, progression free survival; FL, follicular lymphoma; MZL, marginal zone lymphoma; DoR, duration of response; BR, bendamustine plus rituximab; PR, partial response; CR, complete response; Ritux, rituximab.…”

“…Early results in MZL and WM are more encouraging. In a phase 2 study of venetoclax monotherapy in 32 patients with WM, an ORR of 84% was observed with a median PFS of 30 months, including significant activity after BTKi failure or in the presence of CXCR4 mutations [ 69 ].…”

Treatment paradigm in Waldenström macroglobulinemia: frontline therapy and beyond

“…After a median follow-up of 33 months, the median PFS was 30 months and ⩾ grade 3 neutropenia was seen in 45% of patients. 75 The role of venetoclax in MYD88 WT genotype remains to be studied. Daratumumab, a CD38 monoclonal antibody, was studied in a phase 2 trial in 13 patients with RRWM.…”