Safety and Efficacy of Subcutaneous-Administered Omacetaxine Mepesuccinate in Imatinib-Resistant Chronic Myeloid Leukemia (CML) Patients Who Harbor the Bcr- Abl T315I Mutation–Results of An Ongoing Multicenter Phase 2/3 Study.
Notice bibliographique
Résumé
Abstract Abstract 644 Background: Omacetaxine is a first-in-class cetaxine with clinical activity against Ph+ CML and a mechanism of action independent of tyrosine kinase inhibition. Currently available tyrosine kinase inhibitors (TKIs) have not demonstrated activity in CML patients (Pts) who harbor the Bcr-Abl T315I mutation. Study Goals: To evaluate the safety and efficacy of subcutaneously (SC) administered omacetaxine in Pts with imatinib (IM)-resistant T315I+ Ph+ CML. Methods: Eligible Pts include adult CML Pts in chronic, accelerated, or blast disease phase (CP, AP, BP) with a confirmed Bcr-Abl T315I mutation and resistance to IM therapy. Induction schedule: 1.25 mg/m2 SC omacetaxine twice daily for 14 days every 28 days until hematologic response. Maintenance dosing: 1.25 mg/m2 SC omacetaxine twice daily for 7 days every 28 days. Study Results: To date, 90 Pts have been enrolled, with data available for analysis on 66 Pts (40 CP, 16 AP and 10 BP). The median age was 58 yrs (19-83) with 70% male Pts and a median disease duration of 54 mo (5-285). All Pts failed prior IM therapy, and 79% failed two or more prior TKIs. The presence of baseline T315I mutation was confirmed in all Pts. Baseline clonal evolution was evident in 10 (25%) CP, 6 (38%) AP, and 7 (70%) BP Pts. Eight CP Pts entered the study in CHR. The median follow-up for all Pts was 6.4 mo (0.2 to 29.6). Efficacy: In CP Pts, CHR was achieved in 26 Pts and maintained in 8 Pts for an overall CHR rate of 85%; the median duration of CHR was 7.7+ mo (1.7 to 23.6). Overall cytogenetic response was 27.5% with 6 (15%) Pts achieving a major cytogenetic response (MCyR, 4 complete, 2 partial). The median duration of MCyR was 6+ mo (0.8 to 16.1). Major molecular response was achieved in 15% of Pts and a reduction of baseline T315I mutated clone occurred in 56.7% of CP Pts. In AP Pts, overall hematologic response was achieved in 6 (37.5%) Pts with 5 CHR and 1 return to chronic phase (RCP). Median duration of response was 3.9+ mo (1.7 to 14.8). One AP Pt achieved a complete cytogenetic response; duration 1.9+ mo. In BP Pts, overall hematologic response was achieved in 3 (30%) Pts with 2 CHR and 1 RCP. The median overall survival for CP Pts has not been reached and 35 (88%) Pts were alive at the time of data cut- off. The median overall survival was 18.8 mo for AP and 1.8 mo for BP Pts. Median time to progression was 11.2, 3.1, and 1.2 mo for CP, AP, and BP Pts, respectively. Safety: Grade 3/4 related events occurred in 45 of 66 (68%) Pts. The most commonly reported events were thrombocytopenia (58%), anemia (36%) and neutropenia (33%). Non-hematologic toxicities were primarily grade 1/2 with the most frequently reported events of diarrhea (44%), fatigue (35%), pyrexia (32%), nausea (26%), and asthenia (21%). Grade 3/4 non-hematologic toxicities were uncommon with no events occurring in >5% of Pts and infection (3%) the most common event. Treatment delays occurred in approximately 50% of the Pts with median duration of approximately 12 days for all disease phases and cycles (CP=12, AP=10, and BP=12 days). The primary causes of delay were thrombocytopenia, neutropenia and pancytopenia. Sixteen deaths occurred during the study (5 CP, 4 AP, and 7 BP).Three deaths (1 CP, 1 AP, and 1 BP) were considered to have a possible relationship to omacetaxine: sepsis, pancytopenia, and sudden death with unknown cause, respectively. Conclusions: Omacetaxine administered by subcutaneous injection produces durable hematologic and cytogenetic responses with a safety profile consisting mainly of hematologic toxicities. Omacetaxine may provide a treatment option for this patient population who currently has no available approved drug therapies. Disclosures: Cortes-Franco: ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Khoury:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nicolini:ChemGenex: Research Funding. Corm:ChemGenex: Research Funding. Lipton:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jones:ChemGenex: Research Funding. Hochhaus:ChemGenex: Research Funding. Craig:ChemGenex: Employment. Benichou:ChemGenex: Employment. Humphriss:ChemGenex: Employment. Kantarjian:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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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 | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 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) | 0,000 | 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 ».