PS1023 MUTANT IDH1 INHIBITOR IVOSIDENIB (AG‐120) IN COMBINATION WITH AZACITIDINE FOR NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA
Notice bibliographique
Résumé
Background: Mutations in isocitrate dehydrogenase 1 ( IDH1 ) are reported in 6–10% of patients with acute myeloid leukemia (AML). Ivosidenib (IVO; AG‐120) is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) that is approved for the treatment of adults with mIDH1 relapsed or refractory AML. In vitro , combination treatment of m IDH1 leukemic cell lines with IVO and azacitidine (AZA) enhanced cellular differentiation and apoptosis. Aims: We report results from an ongoing phase 1b study of patients with mIDH1 newly diagnosed (ND) AML who were ineligible for intensive treatment, and who received IVO in combination with AZA (NCT02677922). Methods: Patients received IVO 500 mg once daily continuously, and subcutaneous AZA 75 mg/m 2 on Days 1–7 in 28‐day cycles. Overall response rate (ORR) comprised complete remission (CR) + CR with incomplete hematologic or platelet recovery (CRi/CRp) + partial remission + morphologic leukemia‐free state (MLFS). CR with partial hematologic recovery (CRh) was defined as CR with absolute neutrophil count >0.5 × 10 9 /L (500/μL) and platelets >50 × 10 9 /L (50,000/μL). Exploratory analysis included digital PCR assessment of m IDH1 allele frequency in bone marrow mononuclear cells (≤0.04% sensitivity). Results: As of Oct 9, 2018, 23 patients had received IVO+AZA (11 men; median age 76 years [range, 61–88]). Median duration of exposure was 11 months (range, 0.3–25.3); 12 patients remained on treatment at data cutoff. All‐grade adverse events (AEs) regardless of cause in ≥30% of patients were thrombocytopenia (65%), nausea (61%), diarrhea (57%), anemia (52%), constipation (52%), febrile neutropenia (39%), pyrexia (39%), vomiting (35%), fatigue (35%), hypokalemia (35%), dizziness (35%), insomnia (35%), and neutropenia (30%). AEs of special interest included electrocardiogram (ECG) QT prolonged (26%), IDH differentiation syndrome (17%), and leukocytosis (13%). Grade 3/4 AEs in ≥10% of patients were thrombocytopenia (61%), anemia (44%), febrile neutropenia (39%), neutropenia (26%), sepsis (22%), and ECG QT prolonged (13%). ORR was 78% (n = 18), including a CR rate of 57%, a CRi/CRp rate of 13%, and an MLFS rate of 9%. The CR+CRh rate was 70% (n = 16). Median time to response was 1.8 months (range, 0.7–3.8) and to CR was 3.5 months (range, 0.8–6.0); median response duration not yet reached. m IDH1 clearance was seen in 10 of 16 patients (63%) with CR/CRh, including 9 of 13 (69%) with CR. Summary/Conclusion: IVO+AZA was well tolerated, and had a safety profile consistent with IVO or AZA monotherapy. All‐grade cytopenia‐related AEs were infrequent relative to other nonintensive therapies. CR rate and ORR exceeded those of AZA alone (Dombret et al. Blood 2015) and a majority of responders achieved m IDH1 mutation clearance. Based on these findings, a phase 3 double‐blind placebo‐controlled study of IVO+AZA (AGILE, NCT03173248) is actively enrolling patients.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| 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) | 0,001 | 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 tête enseignante, 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 ».