FDA Approves Acalabrutinib Plus Venetoclax for Chronic Lymphocytic Leukemia
The FDA approved the combination of acalabrutinib and venetoclax as the first all-oral, fixed-duration regimen for adults with previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma, based on Phase 3 AMPLIFY trial results.
On February 19, 2026, the Food and Drug Administration approved acalabrutinib (Calquence, AstraZeneca) tablets and capsules in combination with venetoclax (Venclexta, AbbVie Inc. and Genentech Inc.) for adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The approval establishes the regimen as the first all-oral, fixed-duration combination therapy approved in the first-line setting for CLL.
The approval was based on positive results from the AMPLIFY Phase III trial, which were presented at the American Society of Hematology 2024 Annual Meeting and published in The New England Journal of Medicine. The global, multi-center Phase III trial evaluated acalabrutinib plus venetoclax, with or without obinutuzumab, compared with investigator-selected chemoimmunotherapy regimens — fludarabine, cyclophosphamide and rituximab (FCR) or bendamustine and rituximab (BR) — in patients without del(17p) or TP53 mutation.
Trial results showed that the fixed-duration combination reduced the risk of disease progression or death by 35% compared with chemoimmunotherapy (hazard ratio 0.65; 95% CI: 0.49–0.87; p=0.0038). Median progression-free survival was not reached in the combination arm, compared with 47.6 months for chemoimmunotherapy. Results showed 77% of patients treated with acalabrutinib plus venetoclax were progression free at three years, versus 67% of patients treated with standard-of-care chemotherapy. The median duration of PFS follow-up was 42.6 months. With a median follow-up of 41.0 months, there were 18 (6%) deaths in the acalabrutinib-venetoclax arm and 42 (14%) in the FCR/BR arm.
The recommended regimen for acalabrutinib in combination with venetoclax consists of up to 14 cycles of acalabrutinib and 12 cycles of venetoclax starting at cycle 3. Each cycle is 28 days. The recommended acalabrutinib dose is 100 mg taken orally approximately every 12 hours until disease progression, unacceptable toxicity, or completion of 14 cycles of treatment. Start venetoclax at 20mg according to the 5-week ramp-up dosing schedule in the prescribing information. Following the ramp-up, the recommended venetoclax dose is 400 mg orally once daily until disease progression, unacceptable toxicity, or until the last day of Cycle 14.
The safety profile of the combination was consistent with the known safety profiles of the individual agents. The most common adverse reactions occurring in at least 20% of patients included neutropenia, headache, diarrhea, musculoskeletal pain and COVID-19. The most common serious adverse events included COVID-19, second primary malignancies and neutropenia. In AMPLIFY, serious adverse reactions occurred in 25% of patients receiving acalabrutinib-venetoclax, and serious or Grade 3 or higher infections in 14%. The incidence of tumor lysis syndrome was 0.3%, and no new safety signals were reported.
The acalabrutinib prescribing information includes warnings and precautions for serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrythmias, and hepatotoxicity. The venetoclax prescribing information includes warnings and precautions for tumor lysis syndrome, neutropenia, infections, and embryo-fetal toxicity.
CLL is the most common type of leukemia in adults and originates in the bone marrow, affecting a subset of white blood cells known as lymphocytes. An estimated 18,500 people were treated for CLL in the 1st-line setting in the US in 2024. Although treatment outcomes have improved in recent years, many patients require prolonged therapy and ongoing disease management. The treatment is designed to provide a time-limited alternative to continuous therapy, offering patients the potential for treatment-free intervals.
Venetoclax is a B-cell lymphoma-2 (BCL-2) inhibitor that promotes cancer cell apoptosis by targeting a protein that helps malignant cells survive. The drug is jointly developed by AbbVie and Roche and is approved in more than 80 countries for various hematologic malignancies.
Acalabrutinib plus venetoclax is approved in the European Union, Canada, UK and several other countries, and regulatory applications for the regimen based on the AMPLIFY results are currently under review in additional countries. The applications were granted orphan drug designation.