As reported in The New England Journal of Medicine by Jennifer Brown, MD, and colleagues, the phase III AMPLIFY trial found that fixed-duration acalabrutinib combined with venetoclax or venetoclax/obinutuzumab improved progression-free survival vs chemoimmunotherapy in fit, previously untreated patients with chronic lymphocytic leukemia (CLL).
Jennifer Brown, MD
Study Details
In the open-label trial, 867 patients from sites in 27 countries were randomly assigned 1:1:1 between February 2019 and April 2021 to receive acalabrutinib/venetoclax (n = 291), acalabrutinib/venetoclax/obinutuzumab (n = 286), or chemoimmunotherapy (n = 290; 143 received fludarabine/cyclophosphamide/rituximab and 147 received bendamustine/rituximab). All treatments were given in 28-day cycles.
Treatments consisted of either:
- Acalabrutinib at 100 mg twice daily during cycles 1–14 and venetoclax at 400 mg once daily during cycles 3–14 (after a 5-week ramp-up from 20 mg once daily)
- Acalabrutinib/venetoclax at the same dosages plus obinutuzumab at 1,000 mg during cycles 2–7
- Chemoimmunotherapy consisting of fludarabine/cyclophosphamide/rituximab or bendamustine/rituximab during cycles 1–6 according to standard dosing protocols.
Enrolled patients did not have 17p deletions or TP53 mutations. The primary endpoint of the trial was progression-free survival in the acalabrutinib/venetoclax group vs the chemoimmunotherapy group on blinded independent central review.
Key Findings
At a median follow-up of 40.8 months (range = 0–59 months), estimated 36-month progression-free survival was 76.5% (95% confidence interval [CI] = 71.0%–81.1%) in the acalabrutinib/venetoclax group, 83.1% (95% CI = 78.1%–87.1%) in the acalabrutinib/venetoclax/obinutuzumab group, and 66.5% (95% CI = 59.8%–72.3%) in the chemoimmunotherapy group (including 68.9% with fludarabine/cyclophosphamide/rituximab and 64.5% with bendamustine/rituximab). The hazard ratio (HR) for the acalabrutinib/venetoclax group vs chemoimmunotherapy group was 0.65 (95% CI = 0.49–0.87, P = .004). The acalabrutinib/venetoclax/obinutuzumab group also had significantly better progression-free survival vs the chemoimmunotherapy group (P < .001).
Estimated 36-month overall survival was 94.1% (95% CI = 90.7%–96.3%) in the acalabrutinib/venetoclax group (HR vs chemoimmunotherapy group = 0.33, 95% CI = 0.18-–0.56, P < .001), 87.7% (95% CI = 83.2%–91.0%) in the acalabrutinib/venetoclax/obinutuzumab group (HR vs chemoimmunotherapy group = 0.76, 95% CI = 0.49–1.18), and 85.9% (95% CI = 81.0%–89.6%) in the chemoimmunotherapy group.
Grade ≥ 3 adverse events occurred in 53.6%, 69.4%, and 60.6% of groups, respectively, most commonly neutropenia (32.3%, 46.1%, and 43.2%). Serious adverse events occurred in 24.7%, 38.4%, and 27.4%; adverse events led to discontinuation of treatment in 7.9%, 20.1%, and 10.8%, respectively. Death due to COVID-19 infection occurred in 10, 25, and 21 patients, respectively.
The investigators concluded, “Acalabrutinib/venetoclax with or without obinutuzumab significantly prolonged progression-free survival as compared with chemoimmunotherapy in fit patients with previously untreated CLL.”
Dr. Brown, of the Chronic Lymphocytic Leukemia Center at Dana-Farber Cancer Institute, is the corresponding author for The New England Journal of Medicine article.
Disclosure: The study was funded by AstraZeneca. For full disclosures of the study authors, visit nejm.org.
