Abstract 287: CPX-351 cytotoxicity against fresh AML blasts is increased for FLT3-ITD+ cells and correlates with drug uptake and clinical outcomes
Notice bibliographique
Résumé
Abstract Background: CPX-351, a synergistic ratio of cytarabine (Cyt) and daunorubicin (Daun) co-encapsulated in a nano-scale carrier, has demonstrated improved complete remission and overall survival rates compared to conventional Cyt + anthracycline treatments in two randomized clinical trials and is currently being evaluated in a Phase 3 trial vs 7+3 Cyt:Daun. To determine whether these effects are attributable to liposome-mediated altered drug PK or specific AML blast genotypes/phenotypes, we investigated the ex vivo cytotoxic potency of CPX-351 against fresh AML blast samples. Cytotoxicity results were correlated with patient characteristics as well as CPX-351 cellular uptake and molecular phenotype status including FLT3-ITD, NPM1 and CEBPα. Methods: Peripheral blood was obtained at diagnosis from patients with AML. White blood cells were isolated on Ficoll gradients. Cells were incubated over graded concentrations of CPX-351 for 72 hr at which time cell viability was assessed by MTS assay. Cell viability values were normalized to patient-matched untreated cells. Patient-specific IC50 values were calculated and correlated with clinically-relevant disease features. Uptake of intact CPX-351 liposomes by AML cells was determined by monitoring cells for daunorubicin fluorescence by flow cytometry. Results: CPX-351 cytotoxicity was evaluated in 53 AML patient specimens. CPX-351 IC50 values ranged from 0.03:0.006 uM to 10:2 uM (Cyt:Daun), and all values were significantly lower than the 72 hour plasma drug concentration of 60:12 uM Cyt:Daun observed in patients receiving CPX-351. Sensitivity to CPX-351 was similar regardless of cytogentic risk, NPM1 and CEBPα status as well as whether the patients went on to achieve a CR or PD upon receiving standard 7+3 Cyt:Daun after blast samples were taken. Surprisingly, AML blasts exhibiting the FLT3-ITD phenotype exhibited some of the lowest IC50 values and as a group were 5-fold more sensitive to CPX-351 than those with wild type FLT3. Flow cytometric analysis revealed a correlation between uptake of CPX-351 into AML blasts and its cytotoxic potency. Taken together, the data are consistent with clinical observations where CPX-351 retains significant anti-leukemic activity in AML patients exhibiting high-risk characteristics that are typically associated with poor outcomes when treated with conventional regimens. Conclusions: The profile of ex vivo AML blast sensitivity to CPX-351 mirrors the efficacy profile observed clinically and may provide a means to identify specific AML patient genotypes/phenotypes that could benefit most from CPX-351 treatment. The increased sensitivity of FLT3-ITD+ blasts to CPX-351 is an example of how such analyses may identify additional AML patient populations warranting further clinical investigation. Citation Format: Max Gordon, Paul Tardi, Lawrence D. Mayer, Jeffrey Tyner. CPX-351 cytotoxicity against fresh AML blasts is increased for FLT3-ITD+ cells and correlates with drug uptake and clinical outcomes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 287.
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 | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| 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 | 0,000 |
| 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 ».