Phase 1/2 Study in Pediatric Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) Receiving Blinatumomab Treatment
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,002 | 0,001 |
| Méta-épidémiologie (sens large) | 0,002 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,003 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».