Up to seven years of follow-up in the RESONATE-2 study of first-line ibrutinib treatment for patients with chronic lymphocytic leukemia.
Bibliographic record
Abstract
7523 Background: Ibrutinib, a once-daily Bruton’s tyrosine kinase inhibitor, is the only targeted therapy with significant progression-free survival (PFS) and overall survival (OS) benefit in multiple randomized phase 3 studies versus established therapies in patients (pts) with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Extended long-term follow-up data for the RESONATE-2 study of first-line ibrutinib vs chlorambucil in older pts with CLL/SLL are reported. Methods: In the phase 3 RESONATE-2 study, older pts (≥65 years [y]) with previously untreated CLL/SLL and without del(17p) (N=269) were randomly assigned 1:1 to once-daily single-agent ibrutinib 420 mg until disease progression (PD) or unacceptable toxicity (n=136) or chlorambucil 0.5–0.8 mg/kg up to 12 cycles (n=133). Outcomes included PFS, OS, overall response rate (ORR), and safety. Long-term responses were investigator-assessed per 2008 iwCLL criteria. Results: With up to 7y of follow-up (median, 74.9 months; range, 0.1–86.8), significant PFS benefit was sustained for pts treated with ibrutinib vs chlorambucil (hazard ratio [HR] 0.160 [95% confidence interval (CI): 0.111–0.230]). At 6.5y, PFS was 61% in pts treated with ibrutinib vs 9% in pts treated with chlorambucil. This PFS benefit was observed across all subgroups, including in ibrutinib-treated pts with high-risk genomic features of unmutated IGHV (HR 0.109 [95% CI: 0.063–0.189]) or del(11q) (HR 0.033 [95% CI: 0.010–0.107]). OS at 6.5y was 78% with ibrutinib treatment. ORR was 92% for ibrutinib-treated pts with complete response (CR/CRi) rate increasing to 34% with this follow-up. Ongoing rates of grade ≥3 adverse events (AEs) of interest remained low for hypertension (5–6y interval: 5%, n=4; 6–7y: 4%, n=3) and atrial fibrillation (5–6y: 1%, n=1; 6–7y: 1%, n=1); no grade ≥3 major hemorrhage occurred in 5–7y. Dose reductions due to grade ≥3 AEs occurred in 1% (n=1) of pts during the 5–6y and 6–7y intervals. Across full follow-up, 31 pts had dose reductions due to any-grade AEs of whom 22/31 (71%) had resolution or improvement the AE. Primary reason for discontinuations in 5–7y was PD (5–6y: 5%, n=4; 6–7y: 6%, n=4). Any-grade AEs leading to discontinuations were seen in 3% (n=2) of pts from 5–6y and none in 6–7y. With over 7y of follow-up, 47% of pts remain on single-agent ibrutinib. Conclusions: Extended long-term data from RESONATE-2 demonstrate the sustained PFS and OS benefit of first-line ibrutinib treatment for pts with CLL, including for pts with high-risk genomic features. Responses continue to deepen over time. Rates of grade ≥3 AEs of interest continued to be low at up to 7y follow-up and further discontinuations and dose reductions due to AEs were rare; most AEs leading to dose reduction resolved or improved. Ibrutinib remains well tolerated with no new safety signals observed. Clinical trial information: NCT01722487, NCT01724346.
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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 | 0.005 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".