FDA Approves Acalabrutinib Plus Venetoclax for Previously Untreated CLL/SLL

The FDA has approved acalabrutinib (Calquence) in combination with venetoclax (Venclexta) for first-line treatment of adult patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), marking the first US approval of an all-oral, fixed-duration regimen involving a second-generation Bruton tyrosine kinase (BTK) inhibitor in this patient population.¹

The decision stems from positive data from the phase 3 AMPLIFY trial (NCT03836261) showing success in its primary end point of progression-free survival (PFS). Specifically, the trial demonstrated that the combination of acalabrutinib and venetoclax significantly prolonged PFS compared with standard-of-care chemoimmunotherapy (estimated 36-month PFS, 76.5% vs 66.5%), reducing the risk of progression or death by 35% (P =.004). Significant PFS improvements with the combination were also noted when combined with obinutuzumab (Gazyva; P <.001).²

The safety profile observed in the AMPLIFY trial was consistent with the known toxicities of the individual agents. The most common grade 3 or higher adverse event (AE) was neutropenia, with rates of 32.3% in the population receiving the combination without obinutuzumab, 46.1% with obinutuzumab, and 43.2% with chemoimmunotherapy.

The supplemental new drug application for the combination was submitted to the FDA in July 2025 seeking approval of the fixed-duration regimen in this treatment setting. The shift toward fixed-duration therapy represents a significant evolution in the management of CLL; while continuous BTK inhibitor therapy has been the standard of care, it requires indefinite treatment until disease progression or unacceptable toxicity. Although effective, continuous therapy can be associated with cumulative toxicities such as atrial fibrillation, bleeding events, and hypertension, as well as ongoing financial burden for patients and healthcare systems.

By providing a time-limited treatment option, the regimen allows patients to achieve deep clinical responses and subsequently transition into a treatment-free period, potentially reducing the burden of long-term toxicity and healthcare costs associated with continuous BTK inhibitor therapy. Fixed-duration strategies are also aligned with patient preferences for clearly defined treatment timelines and the possibility of sustained remission off therapy, an increasingly important consideration in shared decision-making.

“The continuous regimens frequently used to treat [CLL] often come with [adverse] effects that may become burdensome to patients over time,” said Jennifer Brown, MD, PhD, Dana-Farber Cancer Institute and Harvard Medical School, in a news release.¹ “The US approval of the [acalabrutinib] combination offers patients an all-oral, 14-month, fixed-duration treatment option that is highly effective and well-tolerated, and gives physicians greater flexibility to tailor treatment plans for individual patient needs and goals.”

About the AMPLIFY Trial

The AMPLIFY trial was a randomized, global, open-label phase 3 study that enrolled a total of 867 adult patients with previously untreated CLL without a 17p deletion or TP53 mutation to evaluate the efficacy and safety of acalabrutinib combined with venetoclax with or without obinutuzumab vs investigator’s choice of chemoimmunotherapy.³ The median age of the patient population was 61 years, and more than half (58.6%) of the population had unmutated IGHV.

Patients were randomized on a 1:1:1 basis to receive either acalabrutinib and venetoclax (n = 291), acalabrutinib and venetoclax plus obinutuzumab (n = 286), or chemoimmunotherapy (n = 290). Of the 290 patients receiving chemoimmunotherapy, 143 received a regimen of fludarabine, cyclophosphamide, and rituximab (Rituxan), while the remaining 147 received bendamustine and rituximab.

The primary end point was PFS in the intention-to-treat population, as assessed by blinded independent central review.

REFERENCES

1. CALQUENCE® plus venetoclax approved in the US as first all-oral, fixed-duration combination for patients with chronic lymphocytic leukemia in the 1st-line setting. News release. AstraZeneca. February 20, 2026. Accessed February 20, 2026. https://tinyurl.com/2jktcp2u

2. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Eng J Med. 2025;392(8):748-762. doi:10.1056/nejmoa2409804

3. 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. Updated December 27, 2024. Accessed February 20, 2026. https://clinicaltrials.gov/study/NCT03836261