Double Therapy with Acalabrutinib and Venetoclax Reduces Death and Disease Progression in Patients with Chronic Lymphocytic Leukemia
|
Reviewed by Dat Tien Nguyen, B.A, ScM.
Translated by Nhi Phuong Quynh Le, B.A |
Posted on March 24th, 2025
|
Chronic lymphocytic leukemia is currently managed with combination regimens that include targeted chemoimmunotherapies such as Bruton’s tyrosine kinase inhibitors, Bcl-2 inhibitors, and anti-CD20 antibodies, among others. These treatments have significantly improved survival and delayed disease progression, but they are also associated with prolonged immunosuppression and cardiovascular toxicity. A study funded by AstraZeneca compared the effectiveness and safety of acalabrutinib, a second-generation Bruton’s tyrosine kinase inhibitor, with the current treatment regimens for chronic lymphocytic leukemia.
The phase 3 clinical trial enrolled 867 treatment-naïve participants diagnosed with chronic lymphocytic leukemia, with an average age of 60. Approximately 45% of these participants were considered high risk for disease progression, being classified as Rai stage III or IV. The study exclusively included patients with an intact chromosome 17 and no mutations in the TP53 gene. Additionally, given the key role of the IGHV gene in the pathogenesis of chronic lymphocytic leukemia, assessments revealed that 58.6% of patients had an unmutated IGHV gene.
Patients were randomly assigned to one of three regimens: the double-therapy group received acalabrutinib–venetoclax, the triple therapy group was treated with acalabrutinib–venetoclax–obinutuzumab, and the control group received standard chemoimmunotherapy (either fludarabine–cyclophosphamide–rituximab or bendamustine–rituximab). The novel agent under investigation, acalabrutinib, is a small molecule that binds to and inhibits Bruton’s tyrosine kinase, a key mediator in B-cell signaling and proliferation. It was administered intravenously at a dose of 100 mg every 28 days for a total of 14 doses.
By the 36th month, researchers observed that the combination of acalabrutinib and venetoclax reduced the risk of death or disease progression by 35% compared to standard chemoimmunotherapy. A subgroup analysis comparing patients with normal versus mutated IGHV revealed no significant differences in efficacy. In terms of safety, neutropenia was the most commonly reported adverse event, though its frequency was lower in the double therapy group than in both the triple-therapy and chemoimmunotherapy groups.
The phase 3 clinical trial enrolled 867 treatment-naïve participants diagnosed with chronic lymphocytic leukemia, with an average age of 60. Approximately 45% of these participants were considered high risk for disease progression, being classified as Rai stage III or IV. The study exclusively included patients with an intact chromosome 17 and no mutations in the TP53 gene. Additionally, given the key role of the IGHV gene in the pathogenesis of chronic lymphocytic leukemia, assessments revealed that 58.6% of patients had an unmutated IGHV gene.
Patients were randomly assigned to one of three regimens: the double-therapy group received acalabrutinib–venetoclax, the triple therapy group was treated with acalabrutinib–venetoclax–obinutuzumab, and the control group received standard chemoimmunotherapy (either fludarabine–cyclophosphamide–rituximab or bendamustine–rituximab). The novel agent under investigation, acalabrutinib, is a small molecule that binds to and inhibits Bruton’s tyrosine kinase, a key mediator in B-cell signaling and proliferation. It was administered intravenously at a dose of 100 mg every 28 days for a total of 14 doses.
By the 36th month, researchers observed that the combination of acalabrutinib and venetoclax reduced the risk of death or disease progression by 35% compared to standard chemoimmunotherapy. A subgroup analysis comparing patients with normal versus mutated IGHV revealed no significant differences in efficacy. In terms of safety, neutropenia was the most commonly reported adverse event, though its frequency was lower in the double therapy group than in both the triple-therapy and chemoimmunotherapy groups.