Ibrutinib Treatment of Pediatric Chronic Graft-versus-Host Disease: Primary Results from the Phase 1/2 iMAGINE Study
Bibliographic record
Abstract
Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. Clinical data surrounding cGVHD therapies in younger children are limited and critically needed. Primary endpoints were to determine the recommended pediatric equivalent dose (RPED) and assess pharmacokinetics (PK) and safety. Secondary endpoints included overall response rate (ORR; comprising complete response and partial response) according to the 2014 National Institutes of Health criteria at 24 weeks, overall survival, and duration of response (DOR). Here we present the primary results from the open-label, multicenter, international phase 1/2 iMAGINE study (PCYC-1146-IM), which evaluated the PK, safety, and efficacy of ibrutinib in patients age ≥1 to <22 years with treatment-naive (TN) or relapsed/refractory (R/R) moderate/severe cGVHD. Patients age <12 years received once-daily ibrutinib starting at 120 mg/m2 and escalating to 240 mg/m2 (full adult dose equivalent) after 14 days if free from ibrutinib-related grade ≥3 toxicity; patients age ≥12 years received once-daily ibrutinib 420 mg. Fifty-nine patients (12 TN and 47 with R/R cGVHD; median age, 13 years; range, 1 to 19 years) were enrolled. Plasma concentration-time profiles for ibrutinib 240 mg/m2 (the RPED) were comparable to those observed in adults with cGVHD at a dose of 420 mg/day. Safety was consistent with the known profile of ibrutinib in cGVHD. ORR by 24 weeks was 64% (38 of 59), including 83% (10 of 12) for the TN subgroup and 60% (28 of 47) for R/R. Among 46 responders (median follow-up, 20 months; range, 2 to 32 months), 12-month DOR for each subgroup was 60% (95% confidence interval [CI], 25% to 83%) in TN patients and 58% (95% CI, 35% to 75%) in R/R patients. Responses were durable, with numerically higher rates than those previously observed with ibrutinib in adults, demonstrating that ibrutinib provides clinically meaningful activity with acceptable safety in children with moderate/severe cGVHD.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".