FDA OKs Acalabrutinib/Venetoclax in CLL/SLL

The FDA has approved the use of acalabrutinib (Calquence) tablets and capsules and venetoclax (Venclexta) for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).¹

The approval is supported by findings from the randomized, multicenter phase 3 AMPLIFY trial (NCT03836261), which explored the efficacy of the combination in patients with acalabrutinib and venetoclax (AV) or investigator’s choice of chemotherapy, consisting of either fludarabine plus cyclophosphamide plus rituximab (FCR) or bendamustine plus rituximab (BR).

Progression-free survival (PFS), as assessed by independent review committee for the AV arm vs the investigator’s choice arm, was the primary efficacy end point of the trial. Patients receiving AV had a median PFS that was not estimable (NE; 95% CI, 51.1-NE) with a median PFS follow-up of 42.6 months, compared with a median PFS of 47.6 months (95% CI, 43.3-NE) with a median PFS follow-up of 41.0 months in the investigator’s choice arm.

The AV combination reduced the risk of disease progression or death by 35% (HR, 0.65; 95% CI, 0.49-0.87; P = .0038). Eighteen deaths (6%) occurred in the AV arm vs 42 (14%) in the investigator’s choice arm.

The recommended dose of the combination calls for 100 mg of oral acalabrutinib taken 12 hours apart up to 14 28-day cycles and oral venetoclax beginning at cycle 3 starting at 20 mg following the 5-week ramp-up dosing schedule, and then moving to the full 400 mg dose, for up to 12 cycles.

Acalabrutinib has been associated with serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrythmias, and hepatotoxicity. Venetoclax has been associated with tumor lysis syndromes, neutropenia, infections, and embryo-fetal toxicity.

In the AMPLIFY trial, serious adverse events occurred in 25% of patients receiving the AV combinations, and serious or grade 3 or higher infections occurred in 14%.

Ramp-Up Dosing for Venetoclax

Venetoclax should be administered first at 20 mg in week 1, at 50 mg in week 2, at 100 mg in week 3, at 200 mg in week 4, and 400 mg in week 5 and beyond. For patients needing dose interruptions, restart doses across step-up dosing schedules should be at 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, and 300 mg, respectively. During the ramp-up phase, the reduced dose should be continued for 1 week before increasing the dose. If a dose interruption continues for more than 1 week during the ramp-up phase or more than 2 weeks following the completion of the ramp-up, the risk of tumor lysis syndrome should be reassessed.

References

1. FDA approves acalabrutinib with venetoclax for chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. February 20, 2026. Accessed February 20, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-acalabrutinib-venetoclax-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma
2. Venclexta. Prescribing information. AbbVie Inc. February 2026. Accessed February 20, 2026. https://www.rxabbvie.com/pdf/venclexta.pdf