Lack of effect of bendamustine on Fridericia corrected QT interval (QTcF) in a phase III study of bendamustine-rituximab in advanced indolent non-Hodgkin’s lymphoma (NHL) or mantle cell lymphoma (MCL).
Bibliographic record
Abstract
e19518 Background: Clinical data on the arrhythmogenic potential of bendamustine are limited. Bendamustine and rituximab (BR) are commonly combined, and rituximab concentrations are essentially constant ≥1.5 hours due to its long half-life. This BR single-arm study assessed the effects of bendamustine on QTcF over 1.5 hours in previously untreated adults with advanced indolent NHL or MCL. Methods: Patients in this open-label study were aged ≥18 years with QTc on screening electrocardiogram (ECG) ≤450 ms. Exclusion criteria included low serum potassium or magnesium and history of cardiac conditions with QT prolongation risk. Bendamustine 90 mg/m2 was given on days 1 and 2 and rituximab 375 mg/m2 on day 1 of each 28-day cycle. On day 2 of cycle 1, ECGs and blood sampling were performed ~15 min prior to bendamustine infusion (baseline), at the end of infusion (EOI)/Cmax, and 1 h post-EOI. The primary measure was change in QTcF at EOI. Secondary measures included outlier analyses of QTcF intervals, pharmacokinetic/pharmacodynamic (PK/PD) analysis, and changes in ECG morphology. The ECG analysis included patients with ≥1 ECG at baseline and on treatment. Results: There were 53 enrolled patients (92% white; 60% male; mean age 63.0 y, range 37-84 y; mean body surface area 2.0 m2, range 1.4-2.6 m2). No clinically relevant signal of any bendamustine effect on cardiac repolarization was detected based on the mean change in QTcF from baseline and outlier analyses (Table). In the PK/PD analyses, predicted change in QTcF for bendamustine and its metabolites, M3 and M4, were not significant: 5.4 ms (upper CI 7.6 ms), 6.0 ms (8.8 ms), and 7.1 ms (10.1 ms), respectively, but there were few data. No new ECG morphologic changes were seen. Conclusions: In this small population with previously untreated advanced NHL or MCL, bendamustine was associated with a small increase in mean QTcF that was not clinically meaningful. Support: Teva BPP R&D, Inc. Clinical trial information: NCT01073163. [Table: see text]
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 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".