FDA Approves Acalabrutinib Plus Venetoclax for Previously Untreated CLL

The FDA approved acalabrutinib (Calquence) plus venetoclax (Venclexta) for previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma as the first all-oral, fixed-duration regimen in the frontline setting. The approval was granted on February 20, 2026.

Approval was based on results from the phase III AMPLIFY trial, which showed that the combination regimen reduced the risk of disease progression or death by 35% versus chemoimmunotherapy. The international AMPLIFY trial enrolled 867 treatment-naive CLL patients. They were randomized to 14 cycles of oral acalabrutinib-venetoclax with or without obinutuzumab (Gazyva) or six cycles of fludarabine, cyclophosphamide, and rituximab, or bendamustine plus rituximab, according to investigator's choice.

At 3 years, the progression-free survival (PFS) rate reached 76.5% in the acalabrutinib/venetoclax arm compared with 66.5% in the chemoimmunotherapy arm (P=0.0038). Median PFS was not reached with the combination versus 47.6 months with chemoimmunotherapy. At a median follow-up of 42.6 months, median progression-free survival was not reached in patients receiving venetoclax plus acalabrutinib (95% CI, 51.1 months–not reached) versus 47.6 months in patients receiving chemoimmunotherapy (95% CI, 43.3 months–not reached).

With 41 months of median follow-up, 6% of patients in the acalabrutinib/venetoclax arm died, as compared with 14% of those assigned to chemoimmunotherapy.

The most common adverse reactions (≥20%) in patients receiving acalabrutinib/venetoclax were neutropenia, headache, diarrhea, musculoskeletal pain, and COVID-19. The most common serious adverse reactions (≥2%) were COVID-19, including COVID-19 pneumonia (9%), second primary malignancies (2.7%), and neutropenia (2.1%). The incidence of tumor lysis syndrome was 0.3%. The safety profile of venetoclax plus acalabrutinib was consistent with the known safety profile of each therapy alone.

The drugs include warnings and precautions for "serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrhythmias, and hepatotoxicity," and for "tumor lysis syndrome, neutropenia, infections, and embryo-fetal toxicity," the FDA noted.

Venetoclax is already approved for adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), and in combination regimens for newly diagnosed AML patients aged 75 or older, or those ineligible for standard chemotherapy. Venetoclax is developed by AbbVie and Genentech, and is jointly commercialized in the United States and marketed by AbbVie outside the U.S.