FDA Approves Acalabrutinib Plus Venetoclax for First-Line CLL and SLL Treatment

The FDA has approved the combination of acalabrutinib (Calquence) and venetoclax (Venclexta) for the treatment of adult patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). The approval establishes acalabrutinib-venetoclax as a chemotherapy-free, 14-month, fixed-duration first-line option for adult CLL/SLL and the first time-limited BTK inhibitor-based regimen in the United States.

The approval covers adult patients with CLL and SLL, the most common adult leukemia. In the United States, an estimated 18,500 patients were treated in the first-line CLL setting in 2024. While some individuals remain asymptomatic at diagnosis, others experience fatigue, infections, lymph node enlargement and other systemic symptoms as abnormal B lymphocytes accumulate in blood, bone marrow and lymphatic tissue.

The approval is based on results from the Phase III AMPLIFY trial, presented at the American Society of Hematology 2024 Annual Meeting and published in The New England Journal of Medicine. At a median follow-up of 40.8 months, acalabrutinib plus venetoclax elicited an estimated 3-year progression-free survival rate of 76.5% compared with 66.5% with standard-of-care chemoimmunotherapy, which was investigator's choice of fludarabine plus cyclophosphamide and rituximab, or bendamustine plus rituximab.

The median progression-free survival was not reached in the combination arm versus 47.6 months in the chemotherapy group. The regimen reduced the risk of disease progression or death by 35% compared with chemoimmunotherapy.

The estimated 36-month overall survival rate was 94.1% with acalabrutinib plus venetoclax versus 85.9% with standard-of-care treatment.

The rates of undetectable minimal residual disease levels in peripheral blood by flow cytometry at a sensitivity of 10–4 in the intention-to-treat population were 51.0% with acalabrutinib plus venetoclax versus 26.8% with standard-of-care treatment. However, among evaluable patients, the rates of undetectable minimal residual disease levels at end of treatment and 3 months after end of treatment were 45.0% and 38.0%, respectively, in the acalabrutinib/venetoclax arm versus 72.9% and 77.9%, respectively, in the standard-of-care arm.

The trial enrolled patients without del(17p) or TP53 mutation across 27 countries between 2019 and 2021, continuing through the COVID-19 pandemic. Patients were randomized to receive fixed-duration acalabrutinib plus venetoclax, the same combination with obinutuzumab, or standard chemoimmunotherapy. The primary endpoint was progression-free survival assessed by independent review. Acalabrutinib was administered for a fixed duration of 14 28-day cycles. Patients in the standard-of-care arm received treatment for 6 cycles.

The most common grade 3 or higher adverse events of clinical interest in the acalabrutinib/venetoclax arm were cardiac events (1.7%), atrial fibrillation or flutter (0.3%), hypertension (2.7%), hemorrhage (1.0%), neutropenia (32.3%), infection (12.4%), second primary cancer (1.7%), and tumor lysis syndrome (0.3%).

Safety findings were consistent with the known profile of acalabrutinib, and no new safety signals were identified.

Acalabrutinib plus venetoclax is already approved in the European Union, Canada and the United Kingdom, with additional regulatory reviews ongoing. Beyond CLL and SLL, acalabrutinib is approved in multiple markets for mantle cell lymphoma and is being studied across a broader development program in B-cell malignancies, including diffuse large B-cell lymphoma.