FDA Approves Acalabrutinib Plus Venetoclax for Previously Untreated Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma
Clinical Summary:
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Based on results from the phase 3 AMPLIFY trial, the FDA approved acalabrutinib plus venetoclax for adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
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In the phase 3 AMPLIFY trial, previously untreated patients with CLL or SLL without del(17p) or TP53 mutations were randomized to receive acalabrutinib plus venetoclax or investigator's choice of chemoimmunotherapy.
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This approval introduces a time-limited, chemotherapy-free treatment option for previously untreated patients with CLL or SLL without del(17p) or TP53 abnormalities, expanding first-line treatment options.
On February 19, 2026, the US Food and Drug Administration (FDA) approved acalabrutinib in combination with venetoclax for adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The approval was supported by findings from the phase 3 AMPLIFY trial.
In this multicenter trial, previously untreated patients with CLL or SLL without del(17p) or TP53 mutations were randomized to receive acalabrutinib plus venetoclax or investigator's choice of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab or bendamustine plus rituximab. The primary end point was progression-free survival (PFS), as assessed by an independent review committee.
After a median follow-up of 42.6 months, median PFS was not reached in the acalabrutinib plus venetoclax arm compared with 47.6 months in the chemoimmunotherapy arm (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49 to 0.87; P = .0038).
Serious adverse reactions occurred in 25% of patients receiving acalabrutinib plus venetoclax, and serious or grade ≥3 infections were reported in 14% of patients. Eighteen deaths occurred in the acalabrutinib plus venetoclax arm compared with 42 deaths in the chemoimmunotherapy arm.
The prescribing information for acalabrutinib includes warnings and precautions for serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrhythmias, and hepatotoxicity. Venetoclax includes warnings and precautions for tumor lysis syndrome, neutropenia, infections, and embryo-fetal toxicity.
The recommended dose of acalabrutinib is 100 mg orally every 12 hours. Venetoclax should be initiated using the recommended 5-week dose ramp-up schedule before continuing at 400 mg orally once daily. Treatment consists of up to 14 28-day cycles of acalabrutinib, with venetoclax administered for 12 cycles beginning in cycle 3, or until disease progression or unacceptable toxicity.
Source:
US Food and Drug Administration. FDA approves acalabrutinib with venetoclax for chronic lymphocytic leukemia or small lymphocytic lymphoma. Accessed on February 20, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-acalabrutinib-venetoclax-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma
