Chemosensitization and Mobilization Of AML/ALL/MDS With Plerixafor (AMD 3100), a CXCR4 Antagonist: A Phase I Study Of Plerixafor + Cytarabine and Etoposide In Pediatric Patients With Acute Leukemia and MDS
Notice bibliographique
Résumé
Abstract Background The protection afforded to leukemic blasts by the bone marrow microenvironment has been identified as an important mechanism of chemoresistance. Interaction between stroma-derived growth factor-1 alpha (SDF-1α) and its receptor, CXC chemoreceptor 4 (CXCR4) are implicated in chemotaxis, homing, and survival/apoptosis of normal and malignant hematopoietic cells in the bone marrow. Preclinical data demonstrates that plerixafor (AMD3100), a CXCR4 antagonist, disrupts tumor-stroma interactions and mobilizes leukemia cells from their protective stromal environment. Combinations of CXCR4 antagonists with chemotherapy have demonstrated preclinical synergy. Chemosensitization using plerixafor prior to cytotoxic chemotherapy has been tested in adults with acute leukemia. We report the first Phase I study of plerixafor (NCT01319864) delivered prior to chemotherapy in children with relapsed/refractory acute leukemia and MDS. Study Design Patients > 3 and < 30 years of age with relapsed or refractory AML, ALL, MDS or mixed phenotype acute leukemia were eligible for enrollment. Plerixafor was administered intravenously (IV) once daily followed 4 hours later by cytarabine (1 gm/m2 every 12 hours) and IV etoposide (150 mg/m2 daily) for a total of 5 days of therapy. Plerixafor pharmacokinetic studies were performed on days 1 and 5. Correlative biology studies included measurement of peripheral blood mobilization of leukemic blasts by flow cytometry, quantitative expression of CXCR4 on leukemic blasts, and the change in surface expression of CXCR4 on residual blasts after course 1 of therapy. Results Eighteen evaluable patients (11 AML, 6 ALL, 1 MDS) were treated at 4 dose levels of plerixafor (6, 9, 12, and 15 mg/m2/dose) utilizing a Rolling 6 design. The median number of prior regimens was 2.8 (range 1-7) for ALL and 2.1 (range 1-4) for AML. Six patients had high risk cytogenetics (3 ALL, 2 AML, 1 MDS). Three patients with ALL and 4 with AML had prior hematopoietic stem cell transplant (HSCT). Toxicities were consistent with intensive relapsed leukemia regimens. The most common Grade 1 and 2 toxicities attributed to plerixafor occurring in >10% of patients were anorexia, nausea, vomiting, diarrhea, fatigue, and dizziness. There were no dose limiting toxicities and no delay in count recovery attributable to plerixafor. There were responses in 3 (2 complete response (CR), 1 complete response with incomplete hematologic recovery (CRi)) of 11 AML patients (27%) and no responses in those with ALL or MDS. Peripheral leukemia-specific blast counts (measured by flow cytometry before and 4 hours after the first dose of plerixafor) demonstrated mobilization of leukemic blasts in 14 of 16 patients with samples available, with median fold increase of 3.4 (range 1.3 to 17). The degree of leukemic blast mobilization correlated positively with quantitative leukemia blast surface CXCR4 protein expression (expressed as median fluorescence index relative to isotype control), with a Pearson’s correlation co-efficient of 0.56, p=0.02. Mean ± SD plerixafor AUC values at 12 and 15 mg/m2 were 5074 ± 380 and 5732 ± 573 ng*h/mL, respectively. Drug clearance was similar between days 1 and 5 (p=0.195). Conclusion The favorable safety profile of plerixafor and biologic rationale demonstrated in this clinical trial support further clinical study of chemosensitization using CXCR4 antagonists in overcoming chemoresistance. Disclosures: Off Label Use: Plerixafor is not approved for chemosensitization in the treatment of acute leukemia.
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 | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,001 |
| Méta-épidémiologie (sens large) | 0,002 | 0,001 |
| Bibliométrie | 0,001 | 0,001 |
| 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 | 0,001 | 0,003 |
| 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 ».