Nelarabine in Combination with Etoposide and Cyclophosphamide Is Active in First Relapse of Childhood T-Acute Lymphocytic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LL)
Notice bibliographique
Résumé
Abstract Introduction Children with relapsed T-ALL and T-LL have a dismal prognosis, with survival of less than 25% (Goldberg et al, J Clin Oncol 2003; Reismuller et al, Brit J Haematol 2009). Fewer than a third of children with relapsed T-ALL/LL attain a second remission with standard reinduction therapies (Raetz et al, J Clin Oncol 2008). Nelarabine (NEL) is a purine nucleoside analogue prodrug of AraG, which is resistant to cleavage by endogenous purine nucleoside phosphorylase and cytotoxic to T-lymphoblasts at micromolar concentrations. NEL has substantial single-agent activity in first and multiply relapsed T-ALL (Berg et al, J Clin Oncol 2005). In an effort to improve reinduction rates for children with T-ALL and T-lymphoblastic lymphoma (T-LL) in first relapse, we evaluated the safety and preliminary efficacy of NEL in combination with cyclophosphamide (CPM) and etoposide (ETOP) in this setting. Methods T2008-002: A Phase I trial of NECTAR (Nelarabine, Etoposide and Cyclophosphamide in T-ALL Relapse), is an investigator-initiated collaboration between the Therapeutic Advances in Childhood Leukemia & Lymphoma consortium (TACL), the Pediatric Oncology Experimental Therapeutics Investigators' Consortium (POETIC), and the Innovative Therapies for Children with Cancer consortium (ITCC). Eligible patients had first relapse or initial induction failure of T-ALL or T-LL, no CNS-3, no prior stem cell transplantation, and adequate performance status and organ function. The studyÕs primary objective was to establish the recommended phase 2 doses (RP2D) of NEL and CPM in combination with a fixed dose of ETOP. Subjects received a single course of NEL (325-650 mg/m2) and CPM (330-440 mg/m2) at 1 of 3 assigned dose levels in combination with a fixed ETOP dose (100 mg/m2), each for 5 consecutive days. Intrathecal therapy was administered no less than 7 days prior to or 21 days following the start of a course. Responding patients without dose-limiting toxicity (DLT) were eligible for a second course. The primary study endpoint was the occurrence of dose-limiting toxicity (DLT) during course 1. Secondary endpoints included rates of CR2, complete remission without platelet recovery (CRp), or partial response (PR), and minimal residual disease (MRD) levels at the end of each course. Results Of 19 children enrolled on T2008-002, 6 were enrolled at Dose Level (DL) 1 (NEL 325 mg/m2, CPM 330 mg/m2), 7 at DL2 (NEL 650 mg/m2, CPM 330 mg/m2), and 6 at DL3 (NEL 650 mg/m2, CPM 440 mg/m2). Two potential DLTs led to subject removal during course 1, but were later reversed upon committee review and those subjects replaced. 17 patients were evaluable for DLT and response. Confirmed DLTs occurred in 2 patients: 1 at DL2 (grade 2 (Gr2) motor neuropathy and Gr3 sensory neuropathy) and 1 at DL3 (Gr3 sensory neuropathy). Other ³ Gr3 non-hematologic adverse events are listed in the Table. Of 9 T-ALL patients evaluable for response, there were 2 CRs,1 CRp and 1 CR in the bone marrow/PR in an extramedullary site, with responses at all dose levels, for a response rate of 44% in the T-ALL cohort; at the RP2D, 2/4 evaluable T-ALL patients had a response. Of 8 T-LL patients evaluable for response, there were 2 CRs (1 each at DL1 and DL2), for an overall T-LL response rate of 25%. Eight patients received a second course of NECTAR; 9 subsequently underwent HSCT. MRD levels were available for 2 responding T-ALL patients, with 0.027% and 0.07% blasts after Course 1 and 0.07% and <0.001% blasts after Course 2.TableGrade ³3 Non-Hematologic Adverse Events Occurring in >5% of SubjectsToxicity (CTC3.0)Grade ³ 3 Anorexia3 (16%)Aspartate aminotransferase increased2 (11%)Diarrhoea NOS2 (11%)Febrile neutropenia6 (32%)Hyperkalemia2 (11%)Hypoalbuminaemia3 (16%)Hypocalcaemia4 (21%)Hypokalemia8 (42%)Hypotension NOS2 (11%)Nausea3 (16%)Pleural effusion3 (16%)Vomiting NOS2 (11%)Pain-Other2 (11%) Conclusions The recommended phase 2 doses (RP2D) for NECTAR are NEL 650 mg/m2, CPM 440 mg/m2 and ETOP 100 mg/m2, each given daily for 5 days. The activity and toxicity seen in this phase I dose escalation cohort compare favorably with established reinduction regimens in relapsed T-ALL/LL. An ongoing cohort expansion at the RP2D will better define the activity of NECTAR in first relapse of T-ALL and T-LL. Acknowledgments: Glaxo-Smith-Kline; Higgins Family Foundation; Women's Auxiliary Millennium Chair in Haematology/Oncology Disclosures Whitlock: Glaxo-Smith-Kline: Research Funding. Off Label Use: Nelarabine, cyclophosphamide and etoposide for relapsed T-ALL/T-LL are off-label drug uses.. Zwaan:GSK: Research Funding. Gore:GSK: Research Funding.
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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 | 0,000 |
| 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 | 0,001 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
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 ».