SUMMARY: The FDA on February 19, 2026, approved Acalabrutinib (CALQUENCE®) in combination with Venetoclax (VENCLEXTA®) for adults with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).
The American Cancer Society estimates that for 2026, about 22,760 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4350 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and CLL is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitor, time limited therapy with BCL2 inhibitor Venetoclax given along with anti-CD20 antibody Obinutuzumab (GAZYVA®), or under certain circumstances, chemoimmunotherapy.
Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including CLL, Mantle Cell Lymphoma (MCL), and Waldenstrom Macroglobulinemia (WM). Four BTK inhibitors are presently approved by the FDA. They include first generation Ibrutinib (IMBRUVICA®) and second generation agents such as Acalabrutinib (CALQUENCE®), Zanubrutinib (BRUKINSA®) and non-covalent BTKi, Pirtobrutinib (JAYPIRCA®).
The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL cells and regulates clonal selection and cell survival. Venetoclax is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. Venetoclax is frequently combined with the infusion-based drug Obinutuzumab, which can impose a logistical burden on patients. The combination of Acalabrutinib plus Venetoclax, were noted to be synergistic.
The AMPLIFY trial is a randomized, global, multi-center, open-label Phase III study designed to assess the efficacy and safety of Acalabrutinib in combination with Venetoclax, with or without Obinutuzumab, compared to investigators choice of standard chemoimmunotherapy. In this study, 867 patients (N=867) across 171 locations worldwide with previously untreated CLL were randomized 1:1:1 to receive a fixed-duration regimen of Acalabrutinib and Venetoclax with Obinutuzumab (AVO; N=286), Acalabrutinib and Venetoclax without Obinutuzumab (AV; N=291), or Standard-of-Care chemoimmunotherapy with either Fludarabine plus Cyclophosphamide and Rituximab (FCR) or Bendamustine plus Rituximab (BR) (FCR/BR; N=290). The median patient age was 61 years, 64.5% were male, and 58.6% had CLL with unmutated IGHV. Eligible patients had an ECOG performance status of 0 to 2 and active disease, requiring treatment as per the International Workshop on CLL 2018 criteria. Patients with prior CLL-specific treatments, 17p deletions, TP53 mutations, transformation of CLL to aggressive Non-Hodgkin Lymphoma, Central Nervous System involvement, or a history of Progressive Multifocal Leukoencephalopathy were excluded. The Primary endpoint of the trial was Progression Free Survival (PFS) as assessed by an Independent Review Committee (IRC). Key Secondary endpoints included PFS assessed by investigators, undetectable Minimal Residual Disease (uMRD; 10-4 cutoff) rate assessed in peripheral blood in the treatment groups, Overall Survival (OS), Overall Response Rate (ORR), Duration of Response, and Time to next treatment.
Efficacy Outcomes (Median Follow-Up: 41 Months)
Progression-Free Survival (PFS) — BICR Assessed
- AVO vs FCR/BR
- HR: 0.42
- P < 0.0001
- 58% reduction in risk of progression or death
- AV vs FCR/BR
- HR: 0.65
- P = 0.0038
- 35% reduction in risk of progression or death
- 36-Month PFS Rates
- AVO: 83%
- AV: 76.8%
- FCR/BR: 66.5%
- Median PFS
- AVO: Not reached
- AV: Not reached
- FCR/BR: 47.6 months
Overall Response Rate (ORR) — BICR Assessed
- AVO: 92.7%
- AV: 92.8%
- FCR/BR: 75.2%
- P < 0.0001 for both AVO vs FCR/BR and AV vs FCR/BR
Overall Survival (OS)
- AV vs FCR/BR
- HR: 0.33
- P < 0.0001
- Demonstrated a strong trend toward improved Overall Survival
Serious Adverse Events occurred in 38.4% (AVO group), 24.7% of patients (AV group), and 27.4% (FCR/BR group). Grade 3 or more neutropenia among the treatment groups, was noted in 35.2%, 26.8% and 32.4%, respectively. COVID-19-related deaths affected 25 patients in the AVO group, 10 patients in the AV group, and 21 patients in the FCR/BR group.
Conclusion
The AMPLIFY study met its Primary endpoint, demonstrating superior Progression-Free Survival (PFS) with both AVO and AV compared with standard chemoimmunotherapy.
Key Takeaways
- Both combinations produced deep and durable responses
- Represent a more effective, fixed-duration treatment strategy
- Offer a shift away from traditional chemoimmunotherapy
Clinical Distinction Between Regimens
AV (Acalabrutinib + Venetoclax):
- First all-oral, fixed-duration regimen
- Designed for fit, treatment-naïve CLL patients
- Provides meaningful convenience
- Demonstrates a manageable safety profile
AVO (Acalabrutinib + Venetoclax + Obinutuzumab):
- Further improved efficacy outcomes
- Associated with:
- Higher rates of serious adverse events
- Increased COVID-19–related deaths
Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia. Brown JR, Seymour JF, Wojciech Jurczak, et al. for the AMPLIFY investigators. N Engl J Med 2025;392:748-762
