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

Venetoclax in Previously Treated Waldenström Macroglobulinemia

Jorge J Castillo  1   2 , John N Allan  3 , Tanya Siddiqi  4 , Ranjana H Advani  5 , Kirsten Meid  1 , Carly Leventoff  1 , Timothy P White  1 , Catherine A Flynn  1 , Shayna Sarosiek  1   2 , Andrew R Branagan  2   6 , Maria G Demos  1 , Maria L Guerrera  1 , Amanda Kofides  1 , Xia Liu  1 , Manit Munshi  1 , Nicholas Tsakmaklis  1 , Lian Xu  1 , Guang Yang  1 , Christopher J Patterson  1 , Zachary R Hunter  1   2 , Matthew S Davids  2   7 , Richard R Furman  3 , Steven P Treon  1   2
Affiliations
Clinical Trial

Venetoclax in Previously Treated Waldenström Macroglobulinemia

Jorge J Castillo et al. J Clin Oncol. .

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.

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Conflict of interest statement

Jorge J. CastilloConsulting or Advisory Role: Janssen, Roche/Genentech, Beigene, AbbVie/PharmacyclicsResearch Funding: Pharmacyclics (Inst), AbbVie (Inst), Janssen (Inst), BeiGene (Inst), TG Therapeutics (Inst) John N. AllanHonoraria: AstraZeneca, AbbVie, Pharmacyclics/Janssen, BeiGeneConsulting or Advisory Role: AbbVie/Genentech, Pharmacyclics, Ascentage Pharma, BeiGene, Janssen Oncology, Epizyme, AstraZeneca, TG Therapeutics, ADC TherapeuticsResearch Funding: Genentech, Janssen, Celgene, TG Therapeutics Tanya SiddiqiConsulting or Advisory Role: Juno Therapeutics, AstraZeneca, BeiGene, Celgene, Pharmacyclics, Bristol Myers Squibb/CelgeneSpeakers' Bureau: Pharmacyclics/Janssen, AstraZeneca, BeiGene, Bristol Myers Squibb/CelgeneResearch Funding: Juno Therapeutics (Inst), Kite, a Gilead company (Inst), Acerta Pharma (Inst), TG Therapeutics (Inst), BeiGene (Inst), Pharmacyclics (Inst), Celgene (Inst), Oncternal Therapeutics (Inst), Bristol-Myers Squibb/Sanofi (Inst) Ranjana H. AdvaniConsulting or Advisory Role: Genentech/Roche, Seattle Genetics, Takeda, Portola Pharmaceuticals, Celgene, Sanofi, Kura Oncology, Merck, Karyopharm Therapeutics, ADC Therapeutics, Daiichi Sankyo, Bristol Myers Squibb/Celgene, Epizyme, IncyteResearch Funding: Millennium (Inst), Seattle Genetics (Inst), Genentech/Roche (Inst), Pharmacyclics (Inst), Janssen (Inst), Merck (Inst), Kura Oncology (Inst), Forty Seven (Inst), Cyteir (Inst) Catherine A. FlynnConsulting or Advisory Role: Pharmacyclics, Karyopharm Therapeutics Shayna SarosiekResearch Funding: Acrotech Biopharma (Inst) Andrew R. BranaganConsulting or Advisory Role: Pharmacyclics/Janssen, Genzyme, Adaptive Biotechnologies, BeiGene, Karyopharm Therapeutics, CSL Behring Xia LiuEmployment: Merck (I) Guang YangEmployment: AbbVie (I), Blueprint MedicinesStock and Other Ownership Interests: Blueprint MedicinesHonoraria: Janssen Matthew S. DavidsHonoraria: Research to PracticeConsulting or Advisory Role: Genentech, Janssen, Pharmacyclics, TG Therapeutics, AbbVie, AstraZeneca, Celgene, MEI Pharma, Adaptive Biotechnologies, Verastem, Ascentage Pharma, BeiGene, Lilly, Novartis, Takeda, Bristol Myers SquibbResearch Funding: Genentech (Inst), TG Therapeutics (Inst), Pharmacyclics (Inst), Surface Oncology (Inst), MEI Pharma (Inst), Verastem (Inst), Ascentage Pharma (Inst), AstraZeneca (Inst), Novartis (Inst)Travel, Accommodations, Expenses: TG Therapeutics, Janssen, AbbVie, BeiGene, Genentech Richard R. FurmanHonoraria: Janssen, AstraZeneca, Pharmacyclics, Janssen Biotech, Genentech/Roche, Loxo, TG Therapeutics, Verastem, Acerta Pharma, AstraZeneca, Beigene, Incyte, OncoTracker, AbbVie, MorphoSys, SanofiResearch Funding: Acerta Pharma, TG TherapeuticsExpert Testimony: AbbVie, Janssen OncologyTravel, Accommodations, Expenses: TG Therapeutics, Janssen OncologyOther Relationship: Incyte, Janssen Biotech Steven P. TreonHonoraria: Abbvie/Pharmacyclics, Janssen Oncology, BeiGeneConsulting or Advisory Role: Janssen, Pharmacyclics, Beigene, X4 Pharmaceuticals, Bristol Myers SquibbResearch Funding: Pharmacyclics, Bristol Myers Squibb (Inst), X4 Pharmaceuticals (Inst), Lilly (Inst), Beigene (Inst), AbbVie (Inst)Patents, Royalties, Other Intellectual Property: My institution holds patents related to use of MYD88 and CXCR4 testing for which a predetermined financial distribution to the laboratory and individuals is provided. I have not received any income to this date related to these patents (Inst)Travel, Accommodations, Expenses: Janssen OncologyOther Relationship: Janssen, Pharmacyclics, BeigeneNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Flow diagram.
FIG 2.
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.
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.
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.
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