Zanubrutinib plus Venetoclax for Frontline CLL / SLL

Authored by Brian Koffman, MDCM )retired), MSEd

Bottom Line:

Combining zanubrutinib with venetoclax results in nearly a 100% response rate. Nine of ten frontline CLL patients, regardless of their del(17p) status, do not progress at two years.

Who Performed the Research and Where Was it Presented:

Dr. Mazyar Shadman of Fred Hutch andhis international colleagues presented the results of one cohort of the SEQUOIA trial at the American Society of Clinical Oncology (ASCO) Annual Meeting in 2025.

Background:

Zanubrutinib is a next-generation Bruton’s Tyrosine Kinase Inhibitor or BTKi approved for chronic lymphocytic leukemia / small lymphocytic lymphoma or CLL / SLL. Initial results in the SEQUOIA trial demonstrated superior improved progression-free survival(PFS) at 26.2 months in treatment-naive (TN) CLL / SLL patients without del(17p) and improved PFS at five years compared to those who received bendamustine plus rituximab (BR). Combining a B-cell lymphoma 2 (BCL-2) inhibitor and a BTKi has shown promising synergy. Still, there is little data on patients with poor prognostic markers of del(17p) and/or TP53 mutation. This abstract presents results in the SEQUOIA cohort treated with a combination of zanubrutinib with venetoclax in patients with or without del(17p) and/or TP53mutation.

Methods: 

This was a nonrandomized cohort of the SEQUOIA study of patients 65 or older or 18 through 64 years with comorbidities. Patients received zanubrutinib for three months and then started standard venetoclax (the only approved BCL-2 inhibitor) ramp-up in cycle four for another two years, followed by continuous zanubrutinib monotherapy until progressive disease (PD), unacceptable toxicity, or reaching undetectable measurable or minimal residual disease (uMRD) on two consecutive tests at least 12 weeks apart.

Results: 

• Patient characteristics:
  • Between November 2019 and July 2022, 114 patients were enrolled:
    • 66 (58%) with del(17p) and/or TP53 mutation, 47 (41%) without del(17p) and TP53mutation, and one with missing TP53 results.
    • In all patients, the median age was 67 years
    • 64 (56%) were male
    • 86 (75%) had unmutated IGHV
    • 47 (41%) had complex karyotypes (≥3 abnormalities).
• Outcomes:
  • As of September 16, 2024, 85 (75%) remained on treatment.
  • The most common reasons for early discontinuation were:
    • Meeting uMRD-guided early stopping rules (zanubrutinib: 7%; venetoclax: 7%)
    • Adverse events (AEs) (zanubrutinib: 8%; venetoclax 6%)
    • Progressive disease (zanubrutinib: 5%; venetoclax: 4%)
  • Six patients died (5 due to non–non-treatment-related AEs and 1 due to PD).
  • Patients without or with del(17p) / TP53mutation achieved similar efficacy responses.
  • At two years, for patients without versus with del(17p) / TP53mutation was respectively:
    • PFS was 89% versus 94%,
    • The overall response rate (ORR) was 98% versus 100%
    • uMRD in the peripheral blood was 60% versus 59%
• Adverse Events (AEs): The most common were:
  • COVID-19 (54%),
  • diarrhea (41%),
  • contusion (32%),
  • nausea (30%).
• The most common serious or grade ≥3 AEs were
  • neutropenia or low count of neutrophils, a type of white blood cells (17%),
  • hypertension (10%),
  • diarrhea (6%),

Conclusions: 

The combination of venetoclax plus zanubrutinib proved to be a very effective therapy with no new toxicities signal and remarkably high and similar outcomes in those with or without del(17p) / TP53mutation. The first combination of a BCL2 plus a BTKi approved by the FDA in the USA is likely to be acalabrutinib plus venetoclax. Ibrutinib plus venetoclax has already been approved in Canada and most of Western Europe but not the USA, and approval is not anticipated. Other combinations are promising, including this combination of zanubrutinib plus venetoclax and the combination of zanubrutinib with the experimental BCL-2 inhibitor, sonrotoclax. Time-limited oral therapies such as this promise to transform CLL / SLL care for all patients, including those with high-risk markers.

Links:

To read the source ASCO abstract, click on Combination of zanubrutinib (zanu) + venetoclax (ven) for treatment-naive (TN) CLL / SLL: Results in SEQUOIA arm D.