A Phase I Study with Long-Term Follow-Up of Autologous Stem Cell Transplantation Using Photodynamic Treatment of Marrow Grafts for Relapsed/Refractory Acute Leukemia.
Notice bibliographique
Résumé
Abstract Autologous transplantation for acute leukemia is complicated by an elevated risk of leukemia relapse. Effective purging of stem cell grafts along with dose-intensive consolidation may be beneficial to patients who are ineligible for allogeneic transplantation. In pre-clinical studies, the photosensitizing agent benzoporphyrin derivative-monoacid A (BPD-MA) (QLT, Vancouver, Canada) demonstrated the ability to selectively target leukemia cells, generating fluorescence levels 2- to 20-fold higher on these cells than on normal cells. When exposed to light, BPD-MA induced in vitro photodynamic killing that was drug-dose, light-dose and cell-density dependent. This agent eliminated 3 to 6 logs of leukemia cell lines among normal hematopoietic cells as evaluated using in vitro limiting dilution assays and in vivo infusion of such treated grafts in murine recipients. In contrast, BPD-MA used in the same conditions was toxic to only one log of normal hematopoietic progenitors. These impressive results prompted us to perform a clinical Phase I trial to address the feasibility and safety of BPD-MA photodynamic therapy (PDT) for purging of marrow grafts prior to autologous transplantation in patients with high risk acute leukemia. Patients with acute leukemia in second or subsequent complete remission (CR), or with initial refractory disease were eligible. We evaluated 11 patients (6 female) with relapsed (n=10) or refractory (n=1) acute leukemia (acute myeloid leukemia = 10 pts; acute lymphoblastic leukemia = 1 pt) who were ineligible for allogeneic transplantation due to lack of an appropriate donor (8 patients) or age > 55 (3 patients). Median age at transplant was 44 years (range 17–63). All patients were transplanted with marrow grafts harvested immediately before the transplant and exposed to increasing doses of BPD-MA (10, 20 and 25 ng/ml) under a constant light dose (15 joules/cm2). Photodynamic treatment reduced mononuclear cell number by 28 ± 4.9%. Hematopoietic precursors in the graft were decreased by 59–81% (CFU-GM: 10.3 to 4.2x104/kg, p=0.018; BFU-E: 6.0 to 2.1x104/kg, p=0.007; and CFU-GEMM: 2.0 to 0.4x103/kg, p=0.015). Patients received busulphan (16 mg/kg) and cyclophosphamide (150 mg/kg) as myeloablative conditioning followed by infusion of the PDT treated stem cell graft. Median time to neutrophil (>0.5 x 109/l) and platelet engraftment (>20 x 109/l) was 27 days (range 17–68) and 81 days (51–224), respectively. Failure to engraft with neutrophils (>0.5 x 109/l) on day 40 occurred in 2 patients at 25 ng/ml BPD-MA, and maximum tolerated PDT dose was defined as 20 ng/ml BPD-MA. There was no procedure-related mortality, we observed usual rates of infectious complications, and non-hematologic toxicity was not identified. The estimated 5-year overall and disease-free survival is identical at 36 ± 14% with 4 patients alive in CR 41 to 91 months (median, 60 months) after transplantation. These results show that marrow purging with BPD-MA allows hematopoietic engraftment and adds no significant toxicity to the transplant procedure. The long-term follow-up in our study indicates that autologous marrow transplantation with photodynamic purging using BPD-MA is feasible and associated with encouraging rates of disease-free survival for patients with relapsed or refractory acute leukemia.
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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 | 0,000 |
| 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 ».