Venetoclax in Previously Treated Waldenström Macroglobulinemia

J Clin Oncol. 2022 Jan 1;40(1):63-71. doi: 10.1200/JCO.21.01194. Epub 2021 Nov 18.


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.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers, Tumor / genetics
  • Bridged Bicyclo Compounds, Heterocyclic / adverse effects
  • Bridged Bicyclo Compounds, Heterocyclic / 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
  • Sulfonamides / therapeutic use*
  • Time Factors
  • United States
  • Waldenstrom Macroglobulinemia / diagnosis
  • Waldenstrom Macroglobulinemia / drug therapy*
  • Waldenstrom Macroglobulinemia / genetics
  • Waldenstrom Macroglobulinemia / mortality


  • 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

Associated data