Acalabrutinib-Venetoclax Combination Prolonged PFS Versus Chemoimmunotherapy for Patients With Untreated CLL

Investigators in the AMPLIFY trial evaluated whether a new first-line treatment is more effective than the standard of care for patients with chronic lymphocytic leukemia (CLL).

AMPLIFY is a phase 3, open-label trial that included patients from 133 hospitals in 27 countries who had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2 and did not have the 17p deletion or TP53 mutation. The investigators randomly assigned patients, in a 1:1:1 ratio, to receive acalabrutinib-venetoclax (A-V), acalabrutinib-venetoclax-obinutuzumab (A-V-O), or chemoimmunotherapy with investigator’s choice of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab. The treatments were given in 28-day cycles.

Of the 867 patients in the study, 291received A-V, 286 received A-V-O, and 290 received chemoimmunotherapy (143 received fludarabine-cyclophosphamide-rituximab, and 147, bendamustine-rituximab). The median age of patients was 61 years, and 64.5% of patients were men. Of the total study population, 58.6% had an unmutated immunoglobulin heavy-chain variable region gene (IGHV).

The primary end point was progression-free survival (PFS). The researchers concluded that the A-V combination with or without obinutuzumab significantly prolonged PFS more than chemoimmunotherapy. The results were published in the New England Journal of Medicine. At 36 months, PFS was 76.5%, 83.1%, and 66.5% for the A-V group, the A-V-O group, and the chemoimmunotherapy group, respectively. Overall survival (OS) at 36 months was 94.1%, 87.7%, and 85.9% for the A-V, A-V-O, and chemoimmunotherapy groups, respectively.

An independent blinded committee evaluated safety and efficacy by testing blood and bone marrow throughout the trial. Adverse effects include neutropenia, which occurred in 32.3%, 46.1%, and 43.2% of the A-V, A-V-O, and chemoimmunotherapy groups, respectively. Some patients had side effects that caused them to stop taking acalabrutinib, about 7.6% in the A-V group and 13.7% in the A-V-O group. Side effects also led to lowering the dose of at least one study drug in 14.1% of patients in the A-V group, 20.8% in the A-V-O group, and 11.2% in the chemoimmunotherapy group. This trial occurred during the COVID-19 pandemic, and 56 deaths were due to the virus: 10 in the A-V group, 25 in the A-V-O group, and 21 in the chemoimmunotherapy group.

Chemoimmunotherapy was once the standard of care for CLL. This study highlights a shift toward targeted, time-limited regimens in modern CLL therapy.