<i>Pegaspargase Re-Challenge after Grade 2 Hypersensitivity Reaction in Childhood Acute Lymphoblastic Leukemia: Results from DFCI 16-001</i>
Notice bibliographique
Résumé
Introduction: Hypersensitivity reactions with asparaginase occur frequently in pediatric patients (pts) with acute lymphoblastic leukemia (ALL). The standard approach for pts with reaction to E.coli-derived asparaginase is to switch to Erwinia asparaginase, given concern that clinical reactions reflect presence of neutralizing antibodies; however, Erwinia requires more frequent dosing and is often unavailable. Therapeutic drug monitoring allows for discrimination between pts with pegaspargase hypersensitivity who have sub-therapeutic asparaginase activity and those still able to derive therapeutic benefit from pegaspargase. We prospectively piloted re-challenging pts with pegaspargase after initial Grade 2 hypersensitivity to this agent, with premedication at re-challenge and assessment of serum asparaginase activity (SAA). Methods: Pts aged 1 to < 22 years with newly diagnosed ALL were eligible for DFCI 16-001. Pts received 1 dose of intravenous pegaspargase during Induction, and every 2 weeks for 15 total doses in Post-Induction phases, without routine premedication. Pts were monitored during/after pegaspargase for allergy, with CTCAE version 4.0 event grading. Those with ≥Grade 3 allergy discontinued pegaspargase and were switched to Erwinia. Those with Grade 2 allergic reaction were eligible for pegaspargase re-challenge with pre-medication (acetaminophen, diphenhydramine, and hydrocortisone, or per institutional standard) and slower infusion rate. If < 50% of the intended dose had been administered when reaction occurred, re-challenge was within 1-7 days of initial reaction. If ≥ 50% of the intended dose had been given, re-challenge was at next planned pegaspargase dose. SAA was measured 1-hour, 7-days, and 14-days after the re-challenge infusion (if dose completed). If 1-hour or 7-day level ≥ 0.1 IU/mL, and 14-day level ≥ 0.025 IU/mL, SAA was considered adequate, and the pt continued to receive pegaspargase with premedication. Pts with an inadequate SAA level, or with new ≥ Grade 2 allergic reaction with the re-challenge dose were considered to have failed re-challenge and were changed to Erwinia (or enrolled on a clinical trial of recombinant crisantaspase, an alternative Erwinia preparation). Results: Between 3/2017- 7/2020, 317 eligible pts enrolled. Overall, 81 of 299 (27%) total evaluable pts experienced a first allergic reaction to pegaspargase, 68 pts with Grade 2 reaction, 13 with Grade ≥3. During Induction, 17 of 299 (6%) evaluable pts had allergic reaction to pegaspargase; all Grade 2. Of the 17 Grade 2 reactions, 13 pts (76%) underwent re-challenge in Induction, 9 (69%) re-challenges successful and 4 failed. Post-Induction, 64 of 241 evaluable pts (27%) had a first allergic reaction; 51 Grade 2 and 13 Grade ≥3. Thirty-six of 51 (71%) pts with Grade 2 allergy during Post-Induction underwent re-challenge, as did 1 additional pt with allergy during Induction who was re-challenged with first Post-Induction pegaspargase dose (per protocol guideline, due to receiving ≥50% of Induction dose). Among these re-challenges, 16 were successful, 21 failed. Overall, 25 of 50 (50%) pts who were re-challenged after Grade 2 reaction had a successful challenge and were able to continue pegaspargase. Among the 25 pts with failed re-challenge, 6 pts (24%) had inadequate SAA alone as cause of failure, 17 pts (68%) had an allergic reaction with the re-challenge dose, and 2 (8%) additional patients had both allergic reaction and documented inadequate SAA. Three pts who were successfully re-challenged had a subsequent allergic reaction to pegaspargase. Among the 22 pts who experienced another allergic reaction with pegaspargase (at re-challenge or subsequent dose), 19 pts (86%) experienced Grade 2, and 3 pts experienced Grade 3 reaction. Conclusion: Fifty percent of pts with a Grade 2 reaction to pegaspargase were able to tolerate and achieve adequate SAA when re-challenged with premedication. For those who did react with or after re-challenge, reactions were not more severe. The re-challenge approach limits premedication exposure only to a minority of pts with a history of prior reaction and substantially decreases the number of pts needing to switch to Erwinia asparaginase, which can be challenging to deliver due to administration schedule and drug shortage. Disclosures Place: Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Silverman:Takeda: Other: advisory board; Servier: Other: advisory board; Syndax: Other: advisory board.
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 | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».