A Phase I Combination Study of Ribavirin and Low Dose Cytarabine Arabinoside (ara-C) in M4/M5 Acute Myeloid Leukemia (AML) and AML with High eIF4E,
Notice bibliographique
Résumé
Abstract Abstract 3606 The conventional therapy for acute myeloid leukemia (AML), including cytarabine and an anthracycline with or without transplant, results in a durable remission in only a minority of AML patients. Furthermore, half of all newly diagnosed AML patients are over the age of 65, and many are poor candidates for high dose chemotherapy due to comorbidities and poor performance status. Thus, new effective treatment strategies are needed. Overexpression of the eukaryotic translation initiation factor 4E (eIF4E) occurs in greater than 30% of all cancers including M4 and M5 subtypes of AML. eIF4E is an oncogene that selectively regulates expression post-transcriptionally, both at the levels of mRNA translation and export, for genes that are critical for cell division, growth and angiogenesis. Novel strategies to target eIF4E are entering clinical development and have shown some promising activity in cancer. We have identified ribavirin as an inhibitor of eIF4E with anti-cancer activity in patients with AML. Ribavirin is a well-characterized and well-tolerated anti-viral drug. We have shown that it inhibits oncogenic transformation mediated by overexpression of eIF4E and reduces clonogenic potential of cancer cells with elevated levels of eIF4E. Our phase II proof-of-principle clinical trial examining the efficacy of ribavirin treatment in elderly or relapsed M4 and M5 AML patients was the first clinical study to target eIF4E in human malignancy, and demonstrated that ribavirin effectively targets eIF4E in patients, leading to clinical improvement. Unfortunately, all patients who achieved a response acquired resistance and relapsed shortly thereafter. We have found that ara-C and ribavirin have an additive effect on primary leukemia specimens in vitro. Hence, a Phase I trial was commenced combining low dose ara-C with ribavirin in AML patients. The primary objective of the trial was to determine the maximum tolerated dose and recommended phase II dose of ribavirin and low dose ara-C. Additional objectives were to determine safety and to examine molecular correlates and the pharmacokinetic/pharmacodynamic profile of the combination treatment. A total of 17 patients were enrolled on study and evaluated for safety. No dose limiting toxicities have been observed to date. The current dose being tested is 4400 mg/day of ribavirin and ara-C 20 mg subcutaneous twice a day for 10 days and dose escalation continues. We have observed that ribavirin plasma levels are substantially lower than obtained in the monotherapy trial. In addition, of the 12 patients who completed at least one cycle of therapy, we have seen one complete response (CR), 2 blasts responses, and one stable disease. The patient with CR had treatment-related AML due to breast cancer therapy and had relapsed shortly after an allogeneic stem cell transplantation. She achieved a CR after 5 cycles of low dose ara-C and ribavirin. After 6 cycles, the patient was put on maintenance ribavirin monotherapy and continues to be in remission after 16 cycles. Interestingly, in this patient, toxicities due to ara-C led to its dose reduction that correlated with a near doubling of plasma ribavirin levels prior to achieving remission, suggesting that ara-C may alter absorption of ribavirin. A full molecular response was observed in patients with clinical response and none in patients that did not respond, indicating that ribavirin levels were sufficient to affect eIF4E localization and levels. Further safety, pharmacokinetic, pharmacodynamic, and response data will be presented. Disclosures: Off Label Use: Use of investigational agent Ribavirin for the treatment of AML. Bergeron:Celgene: Research Funding; Merck: Research Funding; Roche: Honoraria.
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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 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,002 | 0,001 |
| Méta-épidémiologie (sens large) | 0,002 | 0,001 |
| Bibliométrie | 0,001 | 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 | 0,002 | 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 ».