The phase 3 AMPLIFY trial's interim results, presented at the American Society of Hematology (ASH) Annual Meeting, reveal that a combination of acalabrutinib and venetoclax, with or without obinutuzumab, demonstrates superior efficacy compared to chemoimmunotherapy in treatment-naive chronic lymphocytic leukemia (CLL) patients. The study, which excluded patients with 17p deletion or TP53 mutation, suggests a potential shift in the frontline treatment approach for CLL.
AMPLIFY Trial Design and Key Endpoints
The AMPLIFY trial randomly assigned 867 patients to receive either acalabrutinib plus venetoclax (AV), acalabrutinib plus venetoclax and obinutuzumab (AVO), or chemoimmunotherapy (bendamustine with rituximab [BR] or fludarabine with cyclophosphamide and rituximab [FCR]). The primary endpoint was progression-free survival (PFS) of AV versus FCR/BR. Secondary endpoints included PFS of AVO versus FCR/BR, undetectable minimal residual disease (uMRD), and overall survival (OS) of AV/AVO versus FCR/BR.
Efficacy Outcomes
At a median follow-up of 40.8 months, the median PFS was not reached in the AV and AVO arms, while it was 47.6 months for the FCR/BR arm. The 36-month PFS rate was 83.1% in the AVO arm, 76.5% in the AV arm, and 66.5% in the FCR/BR arm. Notably, the rates of uMRD were highest in the AVO arm (95%) compared to the FCR/BR (72.9%) and AV arms (45%) at the end of treatment. Overall survival was also prolonged with AV versus FCR/BR, with a 36-month OS rate of 94.1% versus 85.9%, respectively (HR, 0.33; 95% CI, 0.18-0.56).
Safety and Tolerability
Grade 3 or higher neutropenia was more frequent in the AVO arm (35.2%) compared to the AV (26.8%) and chemoimmunotherapy arms (32.4%). However, febrile neutropenia was higher in the FCR/BR arm (9.3%) compared to AVO (2.5%) and AV (1.7%). Infusion-related reactions were more common in the BR/FCR arm (32.8%) than in the AVO (19.7%) or AV arms (0%). Deaths due to COVID-19 were higher in the AVO (8.7%) and FCR/BR arms (7.2%) compared to the AV arm (3.4%).
Clinical Implications
The AMPLIFY trial suggests that fixed-duration AV and AVO regimens significantly improve PFS in treatment-naive CLL patients. The all-oral AV combination may offer a valuable option for patients who cannot tolerate obinutuzumab infusions. The high uMRD rates achieved with AVO are particularly promising, potentially leading to longer remissions. However, questions remain regarding the management of patients who remain MRD positive after completing the fixed-duration treatment.
According to Dr. Jennifer Brown, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute, the results of this study have been submitted to the New England Journal of Medicine for publication. Once fully published, the data are likely to be incorporated into the National Comprehensive Cancer Network guidelines for treating treatment-naive CLL patients without 17p deletion or TP53 mutation.
