Long-term outcomes with continuous venetoclax for relapsed chronic lymphocytic leukemia

McKeague, S; Lau, L; Lew, TE; Lowe, A; Thompson, PA; Whitechurch, A; Carney, D; Wolf, M; Reynolds, G; Blombery, P; Seymour, JF; Roberts, AW; Anderson, MA

Author(s): McKeague, S; Lau, L; Lew, TE; Lowe, A; Thompson, PA; Whitechurch, A; Carney, D; Wolf, M; Reynolds, G; Blombery, P; Seymour, JF; Roberts, AW; Anderson, MA;
Details: Publication Year 2026-10-13,Volume 10,Issue #19,Page 6459-6467
Journal Title: Blood Advances
Abstract: Venetoclax was first approved for continuous use in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), but the efficacy and consequences of very long-term BCL2 inhibition are unknown. We describe the frequency, characteristics, and outcomes of patients with R/R CLL treated with >5 years of continuous venetoclax. Long-term responders (>5 years of continuous therapy without progressive disease [PD]) were identified from a cohort of 86 patients with R/R CLL treated with continuous venetoclax with or without rituximab. Landmark analyses at 2 and 5 years assessed association between undetectable measurable residual disease (uMRD; 10-4 peripheral blood flow cytometry) and progression-free survival (PFS). Next-generation sequencing was performed at PD for BCL2 and TP53 mutations. Twenty-nine patients (33%) were long-term responders. Compared to those with PD within 5 years, they were more likely to have mutated immunoglobulin heavy chain variable region (44% vs 14%; P = .029), noncomplex karyotype (89 vs 50%; P = .043), and uMRD (79 vs 30%; P< .001). At a median follow-up of 11.1 years, 76% had discontinued venetoclax, mostly due to PD. In a landmark analysis of patients continuing venetoclax beyond 2 years, 5-year PFS was 87% for those with uMRD vs 45% without (hazard ratio, 1.30; 95% confidence interval, 1.12-1.52; P = .001). BCL2 mutations were detected in 4 of 8 patients at PD. Grade >/=3 toxicities, including infection (51%), neutropenia (20%), and thrombocytopenia (10%), occurred at consistent frequency throughout treatment. Long-term responses to continuous venetoclax occur in approximately one-third of patients with R/R CLL. Sustained uMRD confers the most favorable outcomes, although all patients show a continuous risk of relapse, infection, and cytopenias.
Publisher: ASH
Keywords: Humans; *Bridged Bicyclo Compounds, Heterocyclic/therapeutic use/administration &; dosage/adverse effects; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/mortality/genetics; *Sulfonamides/therapeutic use/administration & dosage/adverse effects; Female; Male; Aged; Recurrence; Mutation; *Antineoplastic Agents/therapeutic use/adverse effects; Treatment Outcome; Aged, 80 and over; Proto-Oncogene Proteins c-bcl-2/genetics
Research Division(s): Blood Cells and Blood Cancer
PubMed ID: 42498281
Publisher's Version: https://doi.org/10.1182/bloodadvances.2026020789
Open Access at Publisher's Site: https://doi.org/10.1182/bloodadvances.2026020789
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-07-30 09:25:12

Last Modified: 2026-10-02 08:19:42