Acalabrutinib ± Obinutuzumab Vs Obinutuzumab + Chlorambucil in Treatment-Naive Chronic Lymphocytic Leukemia: 6-Year Follow-up of Elevate-TN
Bibliographic record
Abstract
Background: Previous reports of ELEVATE-TN (NCT02475681) at median follow-up of up to 58.2 months (mo) demonstrated superior efficacy of acalabrutinib (A) ± obinutuzumab (O) compared with O + chlorambucil (Clb) in patients (pts) with treatment-naive (TN) chronic lymphocytic leukemia (CLL). Herein, updated results at 74.5 mo of follow-up are reported. Methods: Pts received A monotherapy, A+O, or O+Clb. Pts who progressed on O+Clb could cross over to A monotherapy. Investigator (INV)-assessed progression-free survival (PFS), INV-assessed overall response rate (ORR), overall survival (OS), and safety were evaluated. All analyses are ad-hoc and P-values are descriptive. Results: A total of 535 pts (A, n=179; A+O, n=179; O+Clb, n=177) were randomized: median age was 70 years, 63% had unmutated immunoglobulin heavy chain variable region genes (uIGHV), and 14% had del(17p) and/or TP53 mutation ( TP53m). At a median follow-up of 74.5 mo (range, 0.0-89.0; data cutoff March 3, 2023), median PFS was not reached (NR) for A+O and A vs 27.8 mo for O+Clb (hazard ratio [HR] vs O+Clb: 0.14 and 0.23, respectively; P<0.0001 for both; HR A+O vs A: 0.58; P=0.0229); estimated 72-mo PFS rates were 78%, 62%, and 17%, respectively (Figure 1). For the 79 pts who crossed over from O+Clb to A, median PFS2 (time to second disease progression or death) was NR; estimated 72-mo PFS2 rate was 54%. Median OS was NR in any treatment arm and was significantly longer with A+O vs O+Clb (HR: 0.62; P=0.0349); estimated 72-mo OS rates were 84% for A+O, 76% for A, and 75% for O+Clb ( Figure 2). In 337 pts with uIGHV, median PFS was NR in both the A+O and A arms vs 22.2 mo for O+Clb (HR: 0.08 and 0.12, respectively; P<0.0001 for both), and estimated 72-mo PFS rates were 75%, 60%, and 5%, respectively, with median OS NR in all treatment arms and estimated 72-mo OS rates of 84%, 76%, and 74%, respectively. In 73 pts with del(17p) and/or TP53m, median PFS was 73.1 mo for A+O and NR for A vs 17.5 mo for O+Clb (HR: 0.28 and 0.23, respectively; P≤0.0009 for both), and estimated 72-mo PFS rates were 56%, 56%, and 18%, respectively. Median OS was NR in both the A+O and A arms vs 74.9 mo for O+Clb (HR: 0.53 and 0.46, respectively, neither statistically significant) and estimated 72-mo OS rates were 68%, 72%, and 53%, respectively. ORR was significantly higher with A+O (96%; 95% confidence interval [CI]: 92-98; P<0.0001) and A (90%; 95% CI: 85-94; P=0.0499) vs O+Clb (83%; 95% CI: 77-88). Combined complete response (CR) plus CR with incomplete hematologic recovery rates were higher with A+O (37%) and A (19%) vs O+Clb (14%; P≤0.0499 for both). Median treatment exposure was 74.4 mo and 72.0 mo for A in the A+O and A arms, respectively; 5.5 mo and 5.6 mo for O in the A+O and O+Clb arms, respectively; and 5.5 mo for Clb in O+Clb arm. Adverse events (AEs) for the O+Clb arm have been previously reported. The most common (≥5% of pts) grade ≥3 AEs for A+O and A, respectively, were neutropenia (31% and 12%), thrombocytopenia (8% and 3%), diarrhea (6% and 1%), COVID-19 (9% and 7%), pneumonia (7% and 6%), syncope (5% and 2%), and hypertension (4% and 5%). For events of clinical interest, grade ≥3 atrial fibrillation, hypertension, and secondary primary malignances were reported in 2%, 4%, and 10% of pts treated with A+O and 2%, 5%, and 5% of pts treated with A, respectively. Treatment is ongoing in 54% (A+O; n=96) and 47% (A; n=84) of pts; the most common reasons for treatment discontinuation were AEs, observed in 21% (n=38) of pts treated with A+O and 18% (n=32) of pts treated with A, and progressive disease, observed in 6% (n=10) of pts treated with A+O and 14% (n=25) of pts treated with A. For pts who crossed over from O+Clb to A, 41% (n=32) discontinued A due to AEs in 13% (n=10) of pts and progressive disease in 16% (n=13) of pts. Conclusions: With a median follow-up of 74.5 mo, the efficacy and safety of A+O and A monotherapy were maintained in pts with TN CLL, including in pts with high-risk genetic features. At 6 years of follow-up, PFS was significantly longer in pts treated with A+O vs A. Median OS was NR in any treatment arm and was significantly longer in pts treated with A+O vs O+Clb.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".