Study: Fixed-Duration Acalabrutinib–Venetoclax Regimens Improve Progression-Free Survival in Untreated CLL

Acalabrutinib–venetoclax, with or without obinutuzumab, demonstrated superior progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukemia (CLL).

For their study, Brown and colleagues addressed the need for more effective first-line treatment strategies for fit patients with untreated CLL. While chemoimmunotherapy has been the standard of care, targeted therapies such as BTK and BCL2 inhibitors have demonstrated efficacy in CLL management. Whether a fixed-duration, targeted regimen could improve outcomes compared with traditional chemoimmunotherapy was previously unclear.

To fill this gap, Brown and colleagues developed a phase 3, open-label trial, enrolling 867 patients aged 18 years or older with an Eastern Cooperative Oncology Group performance-status score of 0 to 2 and no 17p deletion or TP53 mutation. Among the 867 enrolled patients, the median age was 61 years, 64.5% were men, and 58.6% had unmutated IGHV. Participants were randomized in a 1:1:1 ratio to receive acalabrutinib–venetoclax, acalabrutinib–venetoclax–obinutuzumab, or investigator-choice chemoimmunotherapy (fludarabine–cyclophosphamide–rituximab or bendamustine–rituximab). The primary endpoint was progression-free survival assessed by blinded independent central review.

At a median follow-up of 40.8 months, estimated 36-month progression-free survival was 76.5% with acalabrutinib–venetoclax, 83.1% with acalabrutinib–venetoclax–obinutuzumab, and 66.5% with chemoimmunotherapy. The combination of acalabrutinib–venetoclax significantly reduced the risk of disease progression or death compared with chemoimmunotherapy (hazard ratio, 0.65; 95% confidence interval, 0.49-0.87; P = .004). Overall survival at 36 months was also higher in the acalabrutinib–venetoclax group (94.1%) compared with chemoimmunotherapy (85.9%). Grade 3 or higher neutropenia was more common in the acalabrutinib–venetoclax–obinutuzumab (46.1%) and chemoimmunotherapy (43.2%) groups compared with acalabrutinib–venetoclax (32.3%). Deaths from COVID-19 were reported across all groups (10, 25, and 21 patients, respectively).

"Acalabrutinib–venetoclax with or without obinutuzumab significantly prolonged progression-free survival as compared with chemoimmunotherapy in fit patients with previously untreated CLL."

Reference
Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med. Published online February 5, 2025. doi:10.1056/NEJMoa2409804