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.

• Authors: Jorge J Castillo, John N Allan, Tanya Siddiqi, Ranjana H Advani, Kirsten Meid, Carly Leventoff, Timothy P White, Catherine A Flynn, Shayna Sarosiek, Andrew R Branagan, Maria G Demos, Maria L Guerrera, Amanda Kofides, Xia Liu, Manit Munshi, Nicholas Tsakmaklis, Lian Xu, Guang Yang, Christopher J Patterson, Zachary R Hunter, Matthew S Davids, Richard R Furman, Steven P Treon
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 40 Issue 1 Pg. 63-71 (01 01 2022) ISSN: 1527-7755 [Electronic] United States
• PMID: 34793256 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• BCL2 protein, human
• Biomarkers, Tumor
• Bridged Bicyclo Compounds, Heterocyclic
• CXCR4 protein, human
• MYD88 protein, human
• Myeloid Differentiation Factor 88
• Proto-Oncogene Proteins c-bcl-2
• Receptors, CXCR4
• Sulfonamides
• venetoclax

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (adverse effects, therapeutic use)
• Biomarkers, Tumor (genetics)
• Bridged Bicyclo Compounds, Heterocyclic (adverse effects, therapeutic use)
• Disease Progression
• Female
• Humans
• Male
• Middle Aged
• Mutation
• Myeloid Differentiation Factor 88 (genetics)
• Progression-Free Survival
• Prospective Studies
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Receptors, CXCR4 (genetics)
• Sulfonamides (adverse effects, therapeutic use)
• Time Factors
• United States
• Waldenstrom Macroglobulinemia (diagnosis, drug therapy, genetics, mortality)