New First-line Combination Treatment Approved for Certain Forms of Leukemia and Lymphoma
The second-generation BTK inhibitor acalabrutinib was approved for use with venetoclax.
The U.S. Food and Drug Administration (FDA) approved acalabrutinib (Calquence) in combination with venetoclax (Venclexta) for adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
Acalabrutinib is a targeted therapy that inhibits Bruton tyrosine kinase (BTK), a protein that enables the growth and spread of malignant B cells. Acalabrutinib stops the cancer-promoting signaling by binding to and inhibiting BTK. Research published in the American Association for Cancer Research (AACR) journal Clinical Cancer Research demonstrated acalabrutinib’s ability to selectively target BTK as well as its efficacy against CLL in preclinical models. Venetoclax is a targeted therapy that kills cells by inhibiting BCL-2, a protein that blocks the processes that lead to cell death.
The newly approved combination of acalabrutinib and venetoclax is the first all-oral, first-line regimen with a fixed treatment duration of 14 months for CLL and SLL. Zanubrutinib (Brukinsa), another BTK inhibitor, was approved for first-line treatment of CLL and SLL in 2023, but the duration of treatment with zanubrutinib is open-ended rather than fixed. Both acalabrutinib and zanubrutinib are second-generation BTK inhibitors that are more selective for BTK than the first-generation inhibitor ibrutinib (Imbruvica).
The approval of acalabrutinib and venetoclax was based on results from the AMPLIFY clinical trial, a randomized, open-label, multicenter phase III trial that enrolled 581 adult patients with previously untreated CLL without deletion of chromosome 17p or mutations in TP53 (genetic alterations that are associated with poor outcomes after chemoimmunotherapy). Patients were randomly assigned (1:1) to receive either acalabrutinib and venetoclax or the investigator’s choice of chemoimmunotherapy—either fludarabine plus cyclophosphamide plus rituximab (Rituxan) or bendamustine plus rituximab.
Following a median follow-up of 42.6 months, patients receiving acalabrutinib and venetoclax were 35% less likely to have experienced disease progression or death than the patients receiving chemotherapy. The median progression-free survival (PFS) in the chemoimmunotherapy arm was 47.6 months, but the median PFS was not estimable in the acalabrutinib and venetoclax arm (meaning that more than 50% of those patients had not experienced disease progression by the time of follow-up).
After a median follow-up of 41 months, 18 deaths had occurred in the acalabrutinib and venetoclax arm, and 42 deaths had occurred in the chemotherapy arm.
The recommended dosage consists of up to 14 28-day cycles of acalabrutinib and 12 28-day cycles of venetoclax. It is recommended that patients receive 100 mg of oral acalabrutinib every 12 hours. Daily oral venetoclax should begin on the first day of the third acalabrutinib cycle, starting at 20 mg and titrating upward over five weeks until a once-daily maintenance dose of 400 mg is reached. Both acalabrutinib and venetoclax should be continued until disease progression, unacceptable toxicity, or the end of the fourteenth acalabrutinib cycle.
CLL and SLL are slow-growing cancers of the blood and bone marrow in which the body overproduces abnormal lymphocytes, a type of white blood cell. CLL and SLL are the same disease, but in CLL, cells accumulate primarily in the blood and bone marrow, whereas SLL cells concentrate in the lymph nodes. According to federal statistics, it was estimated that 22,670 individuals would be diagnosed with CLL and 4,350 patients would die of the disease in the United States in 2025.
The FDA rendered its decision on February 19, 2026. Check this resource for updated information on all therapeutics regulated by the FDA.