Phase I Study Demonstrates Activity and Tolerability of Diphtheria Toxin Interleukin-3 Fusion Protein in Patients with AML and MDS.
Notice bibliographique
Résumé
Abstract Interleukin-3 receptor (IL-3R) proteins are over-expressed on blasts and cancer stem cells of multiple hematologic malignancies. The recombinant diphtheria toxin fusion protein, DT388IL3, specifically targets IL-3R and is composed of the catalytic and translocation domains of diphtheria toxin (DT388) fused to human interleukin-3 (IL3). DT388IL3 demonstrated selective toxicity to acute myeloid leukemia (AML) stem cells both in vitro and in vivo, and was prepared for a Phase I clinical study in AML and myelodysplasia (MDS) patients. FDA approval (BB IND#11314) and IRB approvals were obtained. 80 AML and MDS patients were screened and 38 AML and 3 MDS patients were treated. The median age of treated patients was 62 years (range, 25–81 years). There were 22 males and 19 females. AML disease was de novo in 5, 1st relapse in 12, 2nd relapse in 8, and refractory in 12. MDS disease was high-grade in one and intermediate-grade in 2. Five AML patients had a history of MDS, and one had a history of secondary AML. One patient each had previously received an autologous or allogeneic stem cell transplant. AML cytogenetics was unfavorable in 15, intermediate in 21, and not done in 2. Seven patients were treated with 4 ug/kg, eight patients with 5.3 ug/kg, thirteen patients with 7.1 ug/kg, seven with 9.4 ug/kg, and six with 12.5 ug/kg DT388IL3 for up to six treatments (one cycle). Of note, patients have not yet received a second cycle. Drug-related toxicities were mild to moderate and transient including fever, chills, hypotension, transaminasemia, hypoxemia, and hypoalbuminemia. Pretreatment anti-DT antibody levels ranged from 0 – 9.6ug/mL (mean = 2.3ug/mL); day 15 post-treatment antibody levels were 0 – 600ug/mL (mean = 92ug/mL); day 30 antibody levels were 1.1 – 306ug/mL (mean = 82ug/mL). Day 1 Cmax ranged from 0 – 350 ng/mL and correlated with dose; Day 12 Cmax ranged from 0 – 179 ng/mL and correlated with Day 12 anti-DT antibody levels. Development of anti-DT antibody levels at Day 15 and 30 did not interfere with response. Consistent with an absence of toxicity to normal hematopoietic progenitors, responses occurred in the absence of prolonged myelosuppression. Among 38 evaluable AML patients, we have observed one CR of 8 months duration, 2 partial remissions (PRs) lasting one and three months, and 3 minimal responses with clearance of peripheral blasts and marrow blast cytoreductions of 89%, 90%, and 90% lasting one to two months. In one evaluable MDS patient, we achieved a PR lasting four months with improvement in hematologic parameters and conversion to transfusion independence. Patient accrual is proceeding with correlative IL3R content of blasts and cancer stem cells. These results of activity and tolerability are encouraging and suggest that DT388IL3 may achieve a role in the management of patients with myeloid malignancies.
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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) | 0,001 | 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 | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».