Phase 1/2 Study in Pediatric Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) Receiving Blinatumomab Treatment
Bibliographic record
Abstract
Abstract Introduction: Blinatumomab, an investigational bispecific T-cell engager (BiTE®) antibody construct, has been shown to induce remission in adult patients with relapsed/refractory BCP-ALL. Medically important adverse events (AEs) related to blinatumomab treatment in adults are cytokine release syndrome (CRS) and neurological events. We report the primary analysis of the phase 1 portion of a multicenter phase 1/2 study of blinatumomab in pediatric patients with relapsed/refractory BCP-ALL. Methods: In this continuing study, eligible patients are <18 years old and must have BCP-ALL that is in second or later bone marrow relapse, in any marrow relapse after allogeneic hematopoietic stem cell transplantation (HSCT), or refractory to induction or reinduction therapy. Patients receive blinatumomab for 28 days by continuous intravenous infusion followed by a 14-day treatment-free period (for up to five cycles). Escalating dosing levels of 5, 15, and 30 μg/m²/day and stepwise dosing of 5–15 or 15–30 μg/m²/day were evaluated. The primary endpoint of the phase 1 portion of the study was maximum tolerated dose (MTD). Secondary endpoints included toxicity, complete remission (CR) rate, overall survival (OS), relapse-free survival (RFS), pharmacokinetics evaluation, and cytokine measurement. Results: In the phase 1 portion, 41 patients received a total of 73 cycles (median of 2 cycles received, range of 1 to 5). Eight (20%) patients had refractory disease and seven (17%) had experienced at least two bone marrow relapses. Twenty-six (63%) patients had relapsed following HSCT. Dose-limiting toxicities (DLTs) are listed in Table 1. The MTD was established at 15 µg/m²/day. To decrease the risk of CRS, a stepwise dose of 5–15 μg/m²/day was recommended for the phase 2 part of the study (5 µg/m²/day for 7 days, then 15 µg/m²/day). This dose was subsequently assessed in two age groups (2–6 and 7–17 years) in the phase 1 expansion part with one of 18 patients developing grade 3 CRS. No patient in the expansion cohort developed grade 4 or 5 CRS. Across all dosing levels, 13 (32%) patients had CR with 10 (77%) achieving minimal residual disease (MRD) negativity. Of these 13 patients, nine (69%) underwent HSCT. Among patients who achieved CR, median RFS was 8.3 months (95% CI: 3.0–16.0 months). Median OS was 5.7 months (95% CI: 3.3–9.7 months; Figure 1) with a median follow-up time of 12.4 months. Across all dosing levels, the most common AEs regardless of causality were pyrexia (78%), headache (37%), hypertension (32%), nausea (29%), abdominal pain (27%), pain in the extremity (27%), and anemia (27%). Pharmacokinetic parameters, including steady-state concentration (Css), clearance, and half-life were similar to those from adult patients with relapsed/refractory BCP-ALL who received body surface area-based blinatumomab dosing. Transient elevations of serum cytokines were observed mostly within the first two days after starting blinatumomab, in particular IL-6, IFN-gamma, IL-10, and, to a lesser extent, IL-2 and TNF-α. Conclusions: In the phase 1 portion of this study in pediatric patients with relapsed/refractory BCP-ALL, the MTD was 15 µg/m²/day. CRS was dose-limiting, but stepwise dosing of 5–15 μg/m²/day has been effective in ameliorating CRS. Thirty-two percent of patients achieved CR and more than half were able to proceed to allogeneic HSCT. Figure 1 Figure 1. Disclosures von Stackelberg: Amgen: Consultancy, Honoraria. Off Label Use: This presentation will discuss the off-label use of blinatumomab, as this agent is not approved for use by the FDA, EMA or any other regulatory authorities.. Zugmaier:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Rheingold:Novartis: Consultancy. Hu:Amgen Inc.: Employment, Equity Ownership. Mergen:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Fischer:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Zhu:Amgen Inc.: Employment, Equity Ownership. Hijazi:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Gore:Amgen Inc.: Travel Support Other.
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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) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| 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".