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Acalabrutinib Plus Venetoclax Superior to Chemoimmunotherapy in Patients With Chronic Lymphocytic Leukemia
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The favorable outcomes were observed in the phase 3 AMPLIFY trial.
Acalabrutinib (Calquence; AstaZeneca) plus venetoclax (Venclexta; AbbVie Inc) with or without obinutuzumab (Gazyva; Genentech) significantly prolonged progression-free survival (PFS) compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukemia (CLL). The positive results were achieved in the phase 3 AMPLIFY trial (NCT03836261).1
AI image of cellular structure of CLL | mage Credit: © AI Photo Stock - stock.adobe.com
CLL is one of the most common types of leukemia in adults that is characterized by the overproduction of white blood cells in the bone marrow, resulting in painless swelling of the lymph nodes in the neck, underarm, stomach, or groin that causes fatigue or weakness, fever and infection, or easy bruising or bleeding. CLL is largely diagnosed in older adults and is rarely seen in children or those under 40. According to the American Cancer Society, CLL is estimated to affect over 23,000 individuals in the United States in 2025.2,3
The development and application of Bruton tyrosine kinase (BTK) inhibitors has greatly improved outcomes for patients with CLL. Acalabrutinib, a second-generation, selective, covalent BTK inhibitor 13, has yielded substantial benefits in PFS and overall survival (OS) in patients with treatment-naive and relapsed/refractory CLL, as well as those with higher-risk genetic features. In the AMPLIFY trial, acalabrutinib in combination with venetoclax and with or without obinutuzumab prolonged PFS in over 800 patients with CLL (median age 61 years (range, 26 to 86), 64.5% men).4,5
The phase 3 open-label trial involved patients with CLL (n = 867), who did not have a 17p deletion or TP53 mutation, and were randomized in a 1:1:1 ratio to receive acalabrutinib plus venetoclax (n = 291; acalabrutinib, cycles 1 to 14; venetoclax, cycles 3 to 14), acalabrutinib plus venetoclax and obinutuzumab (n = 286; as above, plus obinutuzumab, cycles 2 to 7), or chemoimmunotherapy with the investigator’s choice of fludarabine (Fludara; Bayer HealthCare Pharmaceuticals) plus cyclophosphamide (Cytoxanl; Amneal Pharmaceuticals, Inc) and rituximab (Rituxan; Genentech) (n = 143) or bendamustine (Treanda; Teva Pharmaceutical Industries Ltd) and rituximab (n = 147; cycles 1 to 6). The primary end point was PFS in the intention-to-treat population, which was assessed by blinded independent central review.5
At a median follow-up of 40.8 months, the estimated 36-month PFS was 76.5% with acalabrutinib plus venetoclax, 83.1% with acalabrutinib plus venetoclax and obinutuzumab, and 66.5% with chemoimmunotherapy (hazard ratio for disease progression or death with acalabrutinib, venetoclax compared with chemoimmunotherapy, 0.65 [95% CI], 0.49 to 0.87], P = .004; for the comparison of acalabrutinib plus venetoclax and obinutuzumab with chemoimmunotherapy, P < .001).5
The estimated 36-month overall survival was 85.9% with chemoimmunotherapy, 94.1% with acalabrutinib and venetoclax, and 87.7% with acalabrutinib plus venetoclax and obinutuzumab. Of the 3 groups, 32.3%, 46.1%, and 43.2% experienced neutropenia, the most frequent adverse event of clinical interest in grade 3 or above. COVID-19-associated mortality was observed in 10, 25, and 21 patients in the 3 groups, respectively.5
The findings from the phase 3 AMPLIFY trial underscore the efficacy of acalabrutinib-based regimens in prolonging PFS for patients with previously untreated CLL. As treatment strategies continue to evolve, these results highlight the potential of BTK inhibitor-based combinations in improving patient outcomes.
