Chemoimmunotherapy was previously the standard approach for chronic lymphocytic leukemia (CLL) but currently, it has been replaced by targeted treatments. Examples of targeted therapies include Bruton’s tyrosine kinase inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib; the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) inhibitor like venetoclax and anti-CD20 monoclonal antibodies (mAbs) like obinutuzumab.
The chemoimmunotherapy treatments including fludarabine–cyclophosphamide–rituximab (FCR) and bendamustine–rituximab (BR) are administered intravenously. These treatments are associated with prolonged immunosuppression, myelosuppression, immunosuppression, an increased risk of myeloid cancer, and reduced efficacy in patients with unmutated immunoglobulin heavy-chain variable region (IGHV). Previous studies have identified that acalabrutinib was a better option for unmutated IGHV patients, offering lower cardiovascular adverse effects.
The current study aimed to assess the impact of fixed-duration acalabrutinib–venetoclax, with or without Obinutuzumab, on progression-free survival when compared to chemotherapy in patients with previously untreated CLL without deletion of the short arm of chromosome 17 (del[17p]) or tumor Protein p53 (TP53) mutations. This clinical study was designed by AstraZeneca and published in The New England Journal of Medicine.
In this randomized, multi-center, open-label, phase 3, AMPLIFY clinical trial (NCT03836261), a total of 867 patients (male = 64.55, female = 35.5%) were recruited primarily from European (63%) and North American (17.4%) countries, between February 25, 2019, and April 5, 2021. Subjects aged ≥18 years (mean age = 59.9±9.5) with Eastern cooperative oncology group (ECOG) performance status of 0-2 were included. Patients with prior CLL-specific treatments, with del(17p) or TP53 mutations, non-Hodgkin lymphoma (NHL), progressive multifocal leukoencephalopathy (PML), cardiovascular disorders (myocardial infarction, congestive heart failure, arrhythmias), malabsorption syndrome, human immunodeficiency virus (HIV), hepatitis B, hepatitis C, pregnant or breast-feeding women, and undergoing anticoagulation therapy were excluded.
All study participants were randomized in a 1:1:1 ratio into three groups: Group A (acalabrutinib–venetoclax; n = 291, male = 61.2%), Group B (acalabrutinib–venetoclax–obinutuzumab, n = 286, male = 69.2%), and Group C (chemoimmunotherapy, n = 290, male = 63.1%).  All the patients received the medications in 28-day cycles. Patients in the A group received acalabrutinib from cycles 1 to 14 and venetoclax from cycles 3 to 14. B group received as above with the addition of obinutuzumab from cycles 2 to 7. C group received FCR (143 patients) or BR (147 patients) from cycles 1 to 6.Â
The primary efficacy outcome was progression-free survival, while secondary outcomes included event-free survival, overall response, and duration of response were measured by blinded independent central review.
At a 40.8-month median follow-up period, the estimated 36-month progression-free survival was found to be 76.5% for the A group, 83.1% for the B group, and 66.5% for the C group. The hazard ratio of disease progression or death was observed as 0.65 (95% confidence interval [CI], 0.49-0.87) and a P-value of 0.004 for comparison between the A group and C group. A P-value of <0.001 was observed for the comparison between the B group and the C group. Additionally, the estimated 36-month overall survival rates were 94.1%, 87.75, and 85.9% for Groups A, B, and C, respectively.
Neutropenia was the most common grade 3 or higher adverse event, occurring in 32.3% of Group A, 46.1% of Group B, and 43.2% of Group C. Death cases due to coronavirus disease 2019 (COVID-19) were reported in 10, 25, and 21, subjects in 3 groups, respectively.
The limitations of this study include differences in safety and efficacy of treatments within the chemotherapy group, as well as many patients in this group did not receive treatment, potentially impacting comparisons. The timing of the undetectable measurable residual disease (MRD) outcome was suboptimal. The COVID-19 pandemic affected the trial outcome assessment.
In conclusion, fixed-duration acalabrutinib–venetoclax with or without obinutuzumab significantly improved progression-free survival compared to chemoimmunotherapy in patients with previously untreated CLL.
Reference: Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med. Published February 2025. doi:10.1056/NEJMoa2409804
