FDA Alert

FDA Approves Acalabrutinib Plus Venetoclax for First-Line Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Edited by:
Ashton L. Stahl

Key Highlights

  • Acalabrutinib plus venetoclax has been approved for adults with previously untreated CLL or SLL without del(17p) or TP53 mutation.
  • Approval was based on improved progression-free survival vs FCR or BR in the phase 3 AMPLIFY trial.

On February 19, 2026, the FDA approved Calquence (acalabrutinib) tablets and capsules in combination with Venclexta (venetoclax) for adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The approval applies to patients with previously untreated CLL who do not have del(17p) or a TP53 mutation.

The approval was supported by results from AMPLIFY (NCT03836261), a randomized, multicenter trial comparing acalabrutinib plus venetoclax (AV) with the investigator’s choice of chemotherapy—fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine plus rituximab (BR). The primary endpoint was progression-free survival (PFS) assessed by an independent review committee. At a median PFS follow-up of 42.6 months, median PFS was not estimable (95% CI, 51.1 months to not estimable) in the AV arm vs 47.6 months (95% CI, 43.3 months to not estimable) with FCR/BR (hazard ratio, 0.65; 95% CI, 0.49–0.87; P = .0038). At a median follow-up of 41.0 months, there were 18 deaths (6%) in the AV arm and 42 deaths (14%) in the chemotherapy arm.

The FDA noted that serious adverse reactions occurred in 25% of patients receiving acalabrutinib plus venetoclax, and serious or Grade 3 or higher infections occurred in 14%. Prescribing information for acalabrutinib includes warnings for serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrhythmias, and hepatotoxicity. Venetoclax carries warnings for tumor lysis syndrome, neutropenia, infections, and embryo-fetal toxicity.

The recommended regimen consists of up to 14 cycles of acalabrutinib and 12 cycles of venetoclax, beginning at cycle 3; each cycle is 28 days. Acalabrutinib is administered at 100 mg orally approximately every 12 hours until disease progression, unacceptable toxicity, or the completion of 14 cycles. Venetoclax is initiated at 20 mg with a 5-week ramp-up schedule, followed by 400 mg orally once daily until disease progression, unacceptable toxicity, or the last day of cycle 14.

Reference

US Food and Drug Administration. FDA approves acalabrutinib with venetoclax for chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. Published February 19, 2026. Accessed February 20, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-acalabrutinib-venetoclax-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphom