Acalabrutinib Combinations as Initial Therapy for Chronic Lymphocytic Leukemia

Frontline treatment of chronic lymphocytic leukemia (CLL) with a Bruton tyrosine kinase inhibitor (BTKi) has largely replaced chemoimmunotherapy, with BTKi therapy typically continued until disease progression or unacceptable toxicity occurs. Researchers report a multinational, industry-sponsored, phase 3 trial comparing fixed-duration acalabrutinib combinations against chemoimmunotherapy in 867 previously untreated patients with CLL. Patients were randomized to 28-day cycles of the BTKi acalabrutinib (A; twice daily, cycles 1–14) plus the B-cell lymphoma-2 inhibitor venetoclax (V; cycles 2–14), or the same regimen plus the anti-CD20 antibody obinutuzumab (O; cycles 2–7), or investigator's choice of 6 cycles of bendamustine-rituximab or fludarabine-cyclophosphamide-rituximab. Patients with TP53 mutation or deletion were excluded, as were those >65 years old with CIRS-Geriatric scores >6.

With a median follow-up of 40.8 months, estimated 36-month progression-free survival (PFS) was significantly improved with AV or AVO versus chemoimmunotherapy (76.5% and 83.1% vs. 66.5%). The 3-year overall survival (OS) was significantly improved with AV versus chemoimmunotherapy (94.1% vs. 85.9%). PFS was improved with AVO versus AV in patients with IGHV-unmutated CLL. Atrial fibrillation of any grade occurred in <1% of the AV and chemoimmunotherapy arms and 2.1% of the AVO arm. Second primary cancers were diagnosed in 5.2% and 4.2% of the AV and AVO arms versus 0.8% of the chemoimmunotherapy arm. Grade 3 or higher infections were more frequent with AVO. Deaths from any cause, including COVID-19 infection, were less common with AV (n=18) than with AVO (n=37) or chemoimmunotherapy (n=42).