A Phase 1 Study of Azacitidine (AZA) in Combination with Fludarabine and Cytarabine in Relapse/Refractory Childhood Leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study
Notice bibliographique
Résumé
Abstract Background: Growing evidence indicates that aberrant DNA hypermethylation is associated with leukemogenesis, drug resistance, and relapse. It has been shown that pre-treating leukemia cells with AZA or decitabine could partially reverse the aberrant DNA methylation, restore the expression of tumor suppressor genes, and sensitize cells to chemotherapeutic agents. Study design: TACL2011-002 was a phase I study with an expansion cohort, examining the use of AZA in sequence with chemotherapy in pediatric leukemia. The objectives were 1) to evaluate the feasibility and toxicity profile of this combination; 2) to obtain preliminary response data in patients with acute myeloblastic leukemia (AML); 3) to study the extent of hypomethylation pre- and post-AZA therapy. Children 1-21 years of age with relapsed/refractory (R/R) leukemia were eligible for the phase I portion. A rolling six design was employed followed by an expansion to 12 response evaluable AML patients at the selected dose. Patients received AZA at a dose of 75mg/m2/day (dose level 1, DL1) subcutaneously on days 1-5, followed by intravenous (IV) fludarabine (30mg/m2/dose daily) and IV cytarabine (2gm/m2/dose daily) on days 6-10. If < 2 patients experienced dose-limiting toxicity (DLT), then DL1 would be the expansion cohort dose. If ≥ 2 patients experienced DLT, the dose of AZA was to be reduced to 50mg/m2/day (DL0). Patients were to receive up to 2 courses of therapy. DNA methylation was evaluated at days 0, 5 and the end of course 1 using PCR and the Infinium HumanMethylation450 assay. Results: Fifteen patients were enrolled, 13 with AML and 2 with ALL. Fourteen patients were evaluable for toxicity and response. One AML patient was removed from study after day 3 due to central nervous system treatment needs and was replaced. The median number of prior treatment regimens was 2 (range 1-5). 5/12 patients with AML had prior hematopoietic stem cell transplant (HSCT) while none with ALL had prior HSCT. Toxicities were typical of intensive chemotherapy regimens. Non-hematologic toxicities ≥ grade 3 attributed to AZA included: febrile neutropenia (n=6), infections (n=3), AST elevation (n=1), oral hemorrhage (n=1), hypokalemia (n=1). No patients experienced DLT. 7/12 AML patients had complete response (CR) or CRi (CR with incomplete count recovery), including 3/5 that had received prior HSCT. 1/2 ALL patients had partial response (PR). DNA methylation analysis was performed in 4 patients to date. Compared to baseline, all patients had DNA demethylation by G-LINE analysis on day 5. At the end of course 1, DNA demethylation persisted in 2 patients who achieved CR, wheras no demethylation were detected in the other 2 patients who were non-responders. Conclusions: AZA at 75mg/m2/day plus fludarabine and cytarabine is well tolerated in pediatric patients with relapsed leukemia. The favorable toxicity profile and encouraging response rates in AML warrants further testing of AZA in this patient population. Methylation analysis is ongoing to assess the possible correlation between DNA demethylation and response. Table Response AML ALL Overall Patient evaluable for response 12 2 14 CR 6 6 CRi 1 1 PR 1 1 2 SD* 1 1 2 PD# 3 3 *SD = Stable Disease; #PD = Progression of Disease ClinicalTrials.gov Identifier: NCT01861002 This study was supported by Gateway for Cancer Research Disclosures Off Label Use: Azacitidine is not approved by FDA to treat childhood leukemia.
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 | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,001 | 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 ».