FDA Approval of CLL Combo Marks New Era for Leukemia Care

The FDA has approved the combination of AstraZeneca’s acalabrutinib (Calquence) and AbbVie’s venetoclax (Venclexta), marking a historic first for the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).^1,2 This landmark decision establishes the combination as the only all-oral, fixed-dose combination regimen available for adult patients with the hematologic cancers in the first-line setting. Its intended use is for patients who are treatment naive.

“With the FDA approval of the combination of venetoclax and acalabrutinib for use as a front-line therapy in CLL, patients in the USA now have an all oral, time-limited option that can be important for many in choosing their treatment," said Brian Koffman, MDCM (retired), DCFP, FCFP, DABFP, MSEd, cofounder and chief medical officer emeritus, CLL Society, in a statement.¹ "CLL Society is pleased to see the number of choices available for patients growing."

Data from the phase 3 AMPLIFY trial (NCT03836261) of 984 patients supported the supplemental new drug application.³ The ongoing global, multicenter trial is comparing outcomes among 3 groups of patients randomized 1:1:1 to a combination regimen: acalabrutinib plus venetoclax, with and without obinutuzumab; fludarabine/cyclophosphamide/rituximab (FCR); or bendamustine/rituximab (BR). Patients who receive acalabrutinib plus venetoclax have 14 treatment cycles, and patients who receive chemotherapy have 6 treatment cycles.

The novel combination provided statistically significant and clinically meaningful improvement in progression-free survival (PFS). Even after 3 years, 77% of patients had not experienced disease progression compared with 67% who received investigator’s choice of standard-of-care chemotherapy. Median PFS also was not reached in the treatment cohort vs 47 months, respectively, and risk of death was reduced by an overall 35% (HR, 0.65; 95% CI, 0.49-0.87; P = .0038).

Experts and advocates alike welcome the approval, noting that it addresses a critical need for more flexible, less burdensome treatment options. By combining a selective second-generation Bruton tyrosine kinase (BTK) inhibitor (acalabrutinib) with a BCL-2 inhibitor (venetoclax), the regimen delivers a highly effective alternative to standard chemotherapy and continuous therapies that patients often find difficult to tolerate over time.

A key advantage of the new protocol is its fixed 14-month duration, which offers patients a clear treatment end point and the potential for significant time off treatment. It could transform management of the most common type of adult leukemia,⁴ with the ability to empower physicians to better tailor treatment plans to individual patient goals while offering renewed hope for long-term disease control.

Results presented at the 2025 European Hematology Association Congress also show that the combination of acalabrutinib and venetoclax plus obinutuzimab (AVO) produced higher rates of undetectable measurable residual disease vs chemoimmunotherapy as measured via flow cytometry and next-generation sequencing in the 3 treatment arms.⁵ These rates were 95% (AVO) vs 45% (acalabrutinib and venetoclax) vs 73% (FCR/BR), and the differences remained evident for up to 36 months after therapy ended.

The safety profile remains consistent with the known adverse effects (AEs) of the individual medications, with common AEs from the combination (seen in at least 2% of patients who receive it) including COVID-19 and COVID-19 pneumonia (9%), second primary malignancies (2.7%), and neutropenia (2.1%); incidence of tumor lysis syndrome also was very low (0.3%).

“The continuous regimens frequently used to treat [CLL] often come with side effects that may become burdensome to patients over time,” Jennifer Brown, MD, PhD, principal investigator of the AMPLIFY trial, said in a statement.² “The US approval of the Calquence 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.” Brown is also director of the CLL Center of the Division of Hematologic Malignancies, Dana-Farber Cancer Institute, and the Worthington and Margaret Collette Professor of Medicine at Harvard Medical School.

Acalabrutinib plus venetoclax is now approved in the US, the European Union, Canada, and the United Kingdom, among many other countries, and additional regulatory applications are under review.

References

1. U.S. Food and Drug Administration (FDA) approves combination treatment of Venclexta (venetoclax) and acalabrutinib for previously untreated patients with chronic lymphocytic leukemia (CLL). News release. AbbVie. February 20, 2026. Accessed February 20, 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
2. Calquence plus venetoclax approved in the US as first all-oral, fixed-duration combination for patients with chronic lymphocytic leukaemia in the 1st-line setting. News release. AstraZeneca. February 20, 2026. Accessed February 20, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/fixed-duration-calquence-combo-approved-in-us.html
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
4. Chronic lymphocytic leukemia. Cleveland Clinic. Updated January 31, 2023. Accessed February 20, 2026. https://my.clevelandclinic.org/health/diseases/6210-chronic-lymphocytic-leukemia
5. Mattina C. COVID-19 deaths cloud interpretation of acalabrutinib-venetoclax combo results. AJMC^®. June 13, 2025. Accessed February 20, 2026. https://www.ajmc.com/view/covid-19-deaths-cloud-interpretation-of-acalabrutinib-venetoclax-combo-results