FDA Approves Acalabrutinib Plus Venetoclax for Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Key Clinical Summary:

• Based on results from the phase 3 AMPLIFY trial, the FDA has approved acalabrutinib plus venetoclax for adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. 
• In this trial, patients without del(17p) or TP53 mutations were randomized to receive acalabrutinib plus venetoclax or investigator’s choice of chemotherapy. At a median follow-up of 42.6 months, median PFS was not estimable with acalabrutinib plus venetoclax and  47.6 months with chemotherapy (HR 0.65; 95% CI, 0.49 to 0.87; P = 0.0038). Serious AEs occurred in 25%, and grade ≥3 infections in 14% of patients receiving the combination. Deaths occurred in 6% and 14% of patients, respectively. 
• Acalabrutinib plus venetoclax provides a chemotherapy-free, fixed-duration regimen (14 cycles) with superior PFS and lower mortality versus standard chemoimmunotherapy in front-line chronic lymphocytic leukemia or small lymphocytic lymphoma, supporting its adoption as a new first-line option for patients without high-risk TP53 abnormalities.

On February 19, 2026, the US Food and Drug Administration (FDA) approved acalabrutinib plus  venetoclax for adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). This approval was based on results from the phase 3 AMPLIFY trial. 

In this multicenter trial, previously untreated patients with CLL without del(17p) or TP53 mutations were randomized to receive acalabrutinib plus venetoclax or investigator’s choice of chemotherapy (fludarabine, cyclophosphamide, and rituximab or bendamustine plus rituximab). The primary end point was progression-free survival (PFS), assessed via independent review committee. 

At a median follow-up of 42.6 months, median PFS was not estimable in the acalabrutinib plus venetoclax arm and was 47.6 months in the chemotherapy arm (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49 to 0.87; P  = 0.0038). 

Serious adverse reactions were reported in 25% of patients and serious or grade ≥3 infections occurred in 14% of patients receiving acalabrutinib plus venetoclax. Eighteen deaths were reported in the acalabrutinib plus venetoclax arm compared with 42 deaths in the chemotherapy arm. 

The prescribing information for acalabrutinib includes warnings and precautions for serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrhythmias, and hepatotoxicity. Additionally, the venetoclax prescribing information includes warnings and precautions for tumor lysis syndrome, neutropenia, infections, and embryo-fetal toxicity. 

The recommended dose of oral acalabrutinib is 100 mg approximately every 12 hours until disease progression, unacceptable toxicity, or completion of 14 cycles. Venetoclax should be initiated at 20 mg according to the 5-week ramp-up schedule in the prescribing information, followed by 400 mg orally once daily until disease progression, unacceptable toxicity, or completion of cycle 14. Patients may receive up to 14 cycles of acalabrutinib and 12 cycles of venetoclax beginning at cycle 3, with each cycle defined as 28 days. 

Source:

US Food and Drug Administration. FDA approves acalabrutinib with venetoclax for chronic lymphocytic leukemia or small lymphocytic lymphoma. Accessed February 20, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-acalabrutinib-venetoclax-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma