Fixed-Duration Acalabrutinib Plus Venetoclax with or without Obinutuzumab Versus Chemoimmunotherapy for First-Line Treatment of Chronic Lymphocytic Leukemia: Interim Analysis of the Multicenter, Open-Label, Randomized, Phase 3 AMPLIFY Trial
Bibliographic record
Abstract
Background: In patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL), both continuous Bruton tyrosine kinase inhibitor (BTKi) monotherapy and fixed-duration venetoclax-based combination regimens are highly effective. However, existing fixed-duration regimens using first-generation BTKis have important efficacy and/or safety limitations. AMPLIFY is the first randomized study to evaluate a fixed-duration regimen of venetoclax with a second-generation BTKi. This prespecified interim analysis of AMPLIFY assessed the efficacy and safety of fixed-duration acalabrutinib-venetoclax (±obinutuzumab) vs investigator's choice of chemoimmunotherapy in fit patients with TN CLL. Methods: AMPLIFY (ACE-CL-311; NCT03836261) is an ongoing, randomized, open-label, phase 3 trial in patients with TN CLL aged ≥18 years with Eastern Cooperative Oncology Group performance status ≤2 and without del(17p) or TP53 mutation. Patients were randomized 1:1:1 to receive acalabrutinib-venetoclax (AV; oral acalabrutinib 100 mg BID [cycles 1-14]; oral venetoclax QD [cycles 3-14 with 5-week dose ramp-up [20, 50, 100, 200, 400 mg]), acalabrutinib-venetoclax-obinutuzumab (AVO; AV dosing as above, plus intravenous obinutuzumab 1000 mg cycles 2 [days 1, 8, and 15] and 3−7 [day 1]), or investigator's choice of fludarabine-cyclophosphamide-rituximab (FCR) or bendamustine-rituximab (BR) per standard dosing protocol (cycles 1−6). The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival (PFS) of AV vs FCR/BR in the intent-to-treat population (all randomized patients). Secondary endpoints include BICR-assessed PFS (AVO vs FCR/BR), undetectable minimal residual disease (uMRD; 10-4 cutoff) rate assessed in peripheral blood (AV vs FCR/BR, AVO vs FCR/BR), and overall survival (OS) (AV vs FCR/BR, AVO vs FCR/BR). Results: A total of 867 patients were randomized (AV, n=291; AVO, n=286; FCR/BR, n=290) with median age 61 years (IQR 54.0-66.0), 64.5% male, and 58.6% with unmutated IGHV. At a median follow-up of 41 months, both AV and AVO provided a statistically significant improvement in BICR-assessed PFS over the control arm (hazard ratios [HR] vs FCR/BR: 0.65 and 0.42, P=0.0038 and P<0.0001, respectively); median PFS was not reached in the AV or AVO arms and was 47.6 months for FCR/BR. Estimated 36-month PFS rates were 76.5%, 83.1%, and 66.5%, respectively. BICR-assessed ORR was higher with AV (92.8%, 95% CI 89.4-95.4) and AVO (92.7%, 95% CI 89.2-95.3) vs FCR/BR (75.2%, 95% CI 70.0-79.9; descriptive P<0.0001 for both comparisons). AV demonstrated an OS benefit trend over FCR/BR (HR 0.33, nominal P<0.0001). Deaths that occurred prior to the data cutoff on April 30, 2024 were reported in 18, 37, and 42 patients in the AV, AVO, and FCR/BR groups, respectively, of which COVID-related deaths occurred in 10, 25, and 21 patients. The most common grade ≥3 adverse event (AE) was neutropenia across all arms, reported in 26.8% of patients in the AV group, 35.2% in the AVO group, and 32.4% in the FCR/BR group. Among events of clinical interest, tumor lysis syndrome, atrial fibrillation (any grade), and hypertension (grade ≥3) were reported in 0.3%, 0.7%, and 2.7% (AV); 0.4%, 2.1%, and 2.1% (AVO); and 3.1%, 0.8%, and 0.8% (FCR/BR) of patients, respectively. Serious AEs occurred in 24.7% of patients in the AV group, 38.4% in the AVO group, and 27.4% in the FCR/BR group. MRD data will be presented. Conclusions: AMPLIFY met its primary endpoint, demonstrating superior BICR-assessed PFS with AV vs FCR/BR, with similar findings seen with AVO vs FCR/BR. The combinations of AV and AVO provided deep and durable responses with manageable safety profiles, with AV offering the first all-oral fixed-duration regimen that combines venetoclax with a second-generation BTKi in fit patients with TN CLL.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".