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TOPLINE:

Venetoclax re-exposure — usually in combination with an anti-CD20 antibody or a Bruton tyrosine kinase (BTK) inhibitor — was associated with high overall response rates and promising progression-free survival (PFS) in selected patients with relapsed chronic lymphocytic leukemia (CLL), according to a review of clinical evidence. Across several studies, the overall response rates ranged from 72% to 100%, with rates of undetectable minimal residual disease in peripheral blood ranging from 32% to 92%. Median PFS ranged from approximately 23 to 58 months.

METHODOLOGY:

• Fixed-duration venetoclax combinations are widely used in both frontline and relapsed or refractory CLL. These regimens can produce deep remissions and frequent undetectable minimal residual disease, but relapse after time-limited therapy remains a clinical challenge with distinct resistance patterns. This review assessed the rationale, efficacy, and molecular outcomes of venetoclax-based retreatment strategies.
• Researchers reviewed results from 10 abstracts or published articles reporting venetoclax retreatment in patients with CLL, including key trials and cohorts such as MURANO, ReVenG, M13-365, and CAPTIVATE, as well as several institutional series; treatment approaches included continuous monotherapy or fixed-duration or minimal residual disease-guided combinations with anti-CD20 monoclonal antibodies (rituximab and obinutuzumab) or covalent BTK inhibitors (ibrutinib and acalabrutinib).
• Patient cohorts across studies were heterogeneous and frequently had high-risk disease features, including IGHV-unmutated status or del17p or TP53 mutations. The median time off venetoclax following initial therapy before retreatment initiation ranged from 9 to 90 months across the different cohorts.
• Extracted outcomes included overall response, complete response, undetectable minimal residual disease in peripheral blood and bone marrow, and PFS following venetoclax retreatment.

TAKEAWAY:

• Across several series, overall response rates to venetoclax retreatment were high (72%-100%), though complete response rates were lower (20%-36%) than those typically seen after frontline fixed-duration therapy.
• Peripheral blood rates of undetectable minimal residual disease at the end of retreatment showed heterogeneity between cohorts (32%-92%), likely reflecting differences in combination regimens and minimal residual disease testing methods.
• Median PFS after retreatment, when reported, varied across cohorts (23-58 months). A longer interval off venetoclax before retreatment was associated with longer PFS on retreatment. For instance, in MURANO, median PFS was 24.3 months among participants with 2 years or more off therapy compared with 14.3 months among those with less than 2 years off therapy (hazard ratio, 0.28; P = .0107).
• Although BCL2 resistance mutations were uncommon, the lack of large-scale systemic data made it difficult to assess the impact of BCL2-mutated oligoclonal progression following fixed-duration venetoclax therapy. The review noted lower reported rates of BTK resistance mutations with venetoclax or BTK inhibitor combinations.

IN PRACTICE:

“Venetoclax-based combinations, whether as [fixed-duration] or MRD-guided, may provide high and durable responses in patients with and without high-risk features in CLL,” the authors of the study wrote, adding that the “[duration of response] after the first venetoclax-based therapy may serve as a predictor of rechallenge efficacy.”

However, although efficacy has been reported for combination treatment with both anti-CD20 monoclonal antibodies and covalent BTK inhibitors, the ideal venetoclax partner remains unclear, they noted.

SOURCE:

The study, led by Mathias Castonguay, Department of Clinical Haematology, Peter MacCallum Cancer Centre, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia, was published online in Blood Advances.

LIMITATIONS:

Evidence for venetoclax retreatment remains preliminary and was mainly reported in abstracts or meeting presentations rather than full publications. The patient populations across studies were heterogeneous with varying disease characteristics, prior treatment regimens, and treatment-free intervals, making direct comparisons difficult. Optimal patient selection criteria remain to be defined because the depth of the initial venetoclax response and time to progression are inconsistently reported across studies.

DISCLOSURES:

The authors did not disclose any funding information. Castonguay disclosed receiving honoraria from Bristol Myers Squibb. Several other authors disclosed receiving honoraria or research funding and having other ties with various sources, including AbbVie, Janssen, AstraZeneca, BeiGene, Sobi, and others. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.