Key Takeaways
- FDA approved VENCLEXTA (venetoclax) + acalabrutinib as the first all-oral, fixed-duration first-line therapy for untreated CLL adults.
- AMPLIFY Phase 3 trial showed 35% reduced risk of progression/death vs. chemoimmunotherapy (HR 0.65, p=0.0038).
- Safety profile matches individual drugs; common AEs include neutropenia, headache, diarrhea; low TLS risk (0.3%).
- Expands patient options with time-limited treatment, per AbbVie and CLL Society experts.
Written By: Sana Khan BPharm
Reviewed By: Pharmacally Editorial Team
AbbVie announced a major advancement in chronic lymphocytic leukemia (CLL) treatment with the U.S. Food and Drug Administration (FDA) approval of a supplemental new drug application (sNDA) for the combination of VENCLEXTA® (venetoclax) and acalabrutinib. This regimen targets previously untreated adult patients with CLL. The approval draws from strong data in the Phase 3 AMPLIFY trial, marking the first all-oral, fixed-duration option in the first-line setting.
“The FDA’s approval of VENCLEXTA plus acalabrutinib is a game-changer for CLL patients and a key milestone for AbbVie,” said Svetlana Kobina, vice president, global medical affairs, oncology, AbbVie. “As the first all-oral, fixed-duration regimen for untreated patients, it gives physicians and patients greater flexibility in tackling CLL’s complex treatment challenges.”
Key Trial Results from AMPLIFY
The AMPLIFY trial (NCT03836261), sponsored by AstraZeneca, compared VENCLEXTA plus acalabrutinib alone or with obinutuzumab against standard chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab [FCR] or bendamustine-rituximab [BR]) in patients without del(17p) or TP53 mutations. Patients received the oral combination for a fixed 14 cycles (each 28 days), with VENCLEXTA ramping up over five weeks starting in cycle 3. This contrasts with six cycles of intravenous chemoimmunotherapy.
The combination outperformed chemoimmunotherapy, cutting the risk of disease progression or death by 35% (hazard ratio [HR] 0.65; 95% CI: 0.49-0.87; p=0.0038). Median progression-free survival (PFS) remained unreached for the combination, versus 47.6 months for chemoimmunotherapy. These results position the regimen as a superior, patient-friendly alternative that allows time off treatment.
Safety Profile
The safety of VENCLEXTA and acalabrutinib aligns with their known profiles when used alone. Common adverse reactions (≥20%) include neutropenia, headache, diarrhea, musculoskeletal pain, and COVID-19. Serious reactions (≥2%) feature COVID-19 (including pneumonia at 9%), second primary malignancies (2.7%), and neutropenia (2.1%). Tumor lysis syndrome occurred in just 0.3% of patients, with no new safety signals detected.
“With FDA approval of venetoclax and acalabrutinib as a frontline CLL therapy, U.S. patients now gain a vital all-oral, time-limited option that empowers treatment choices,” said Dr. Brian Koffman, co-founder and chief medical officer emeritus, CLL Society. “We’re thrilled to see more options expanding for those living with CLL.”
Developed by AbbVie and Roche (with Genentech in the U.S.), VENCLEXTA now holds approvals in over 80 countries.
CLL and VENCLEXTA
CLL ranks as one of the most common adult leukemias, arising from lymphocytes white blood cells that mature in the bone marrow and fight infection. In CLL, these cells multiply uncontrollably, crowding out healthy blood cells.
VENCLEXTA, a first-in-class BCL-2 inhibitor, blocks the B-cell lymphoma-2 protein that prevents cancer cells from natural cell death (apoptosis). Acalabrutinib, a BTK inhibitor, disrupts signaling pathways that promote B-cell survival and growth. Together, they offer targeted, oral therapy without chemotherapy’s burdens.
Reference
U.S. Food and Drug Administration (FDA) Approves Combination Treatment of VENCLEXTA® (venetoclax) and Acalabrutinib for Previously Untreated Patients with Chronic Lymphocytic Leukemia (CLL). 20 February 2026, https://news.abbvie.com/2026-02-20-U-S-Food-and-Drug-Administration-FDA-Approves-Combination-Treatment-of-VENCLEXTA-R-venetoclax-and-Acalabrutinib-for-Previously-Untreated-Patients-With-Chronic-Lymphocytic-Leukemia-CLL
Study of Acalabrutinib (ACP-196) in Combination with Venetoclax (ABT-199), With and Without Obinutuzumab (GA101) Versus Chemoimmunotherapy for Previously Untreated CLL (AMPLIFY), ClinicalTrials.gov ID NCT03836261, https://clinicaltrials.gov/study/NCT03836261
Jennifer R. Brown et al, Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia, N Engl J Med 2025;392:748-762, https://www.nejm.org/doi/abs/10.1056/NEJMoa2409804