Acalabrutinib With Venetoclax Approved for Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Expert Perspectives
By Lyn Brook
Published
The FDA approved acalabrutinib (Calquence®, AstraZeneca) in combination with venetoclax (Venclexta®, AbbVie Inc. and Genentech Inc.) for adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). This chemotherapy-free, fixed-duration oral doublet offers a new front-line treatment option for patients with CLL/SLL.
Why This Approval Matters
CLL and SLL are the most common leukemias in adults, and while targeted therapies have transformed outcomes, many patients still receive chemoimmunotherapy as initial treatment. The combination of acalabrutinib, a next-generation BTK inhibitor, with venetoclax, a BCL2 inhibitor, represents a chemotherapy-free, all-oral, fixed-duration regimen that targets two distinct and complementary pathways driving CLL/SLL cell survival. This approval provides an effective alternative to chemoimmunotherapy with a favorable survival profile in previously untreated patients without del(17p) or TP53 mutations.
Breaking Down AMPLIFY
Efficacy was established in AMPLIFY (NCT03836261), a phase 3, multicenter trial in adults with previously untreated CLL without del(17p) or TP53 mutation. Patients were randomized to receive either:
Experimental arm: Acalabrutinib plus venetoclax (AV)
Control arm: Investigator's choice of chemoimmunotherapy — fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine and rituximab (BR)
The primary efficacy end point was progression-free survival (PFS) as assessed by an independent review committee. With a median PFS follow-up of 42.6 months:
PFS: Median was not estimable in the AV arm compared with 47.6 months in the FCR/BR arm
Survival: With a median follow-up of 41.0 months, there were 18 deaths (6%) in the AV arm compared with 42 deaths (14%) in the FCR/BR arm, reflecting a meaningful early survival advantage with the chemotherapy-free doublet
Managing Adverse Events
In AMPLIFY, serious adverse reactions occurred in 25% of patients receiving acalabrutinib plus venetoclax, with serious or grade ≥3 infections reported in 14%.
Key warnings and precautions for acalabrutinib include:
Serious and opportunistic infections
Hemorrhage
Cytopenias
Second primary malignancies
Cardiac arrhythmias
Hepatotoxicity
Key warnings and precautions for venetoclax include:
Tumor lysis syndrome (TLS)
Neutropenia
Infections
Embryo-fetal toxicity
Dosing and Administration
The recommended regimen consists of up to 14 cycles of acalabrutinib and 12 cycles of venetoclax, with each cycle lasting 28 days:
Acalabrutinib: 100 mg orally approximately every 12 hours beginning at Cycle 1, continued until disease progression, unacceptable toxicity, or completion of 14 cycles.
Venetoclax: Initiated at Cycle 3 using a five-week ramp-up schedule starting at 20 mg per day per the prescribing information. Following ramp-up, the recommended dose is 400 mg orally, once daily until disease progression, unacceptable toxicity, or the last day of Cycle 14.
References
Clinicaltrials.gov (2024). Study of acalabrutinib (ACP-196) in combination with venetoclax (ABT-199), with and without obinutuzumab (GA101) versus chemoimmunotherapy for previously untreated CLL (AMPLIFY). NLM identifier: NCT03836261.