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1.
Am J Hematol ; 97(8): 1023-1034, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35617104

RESUMEN

The phase III study was designed to compare event-free survival (EFS) after treosulfan-based conditioning with a widely applied reduced-intensity conditioning (RIC) busulfan regimen in older or comorbid patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). A previously reported confirmatory interim analysis of the randomized clinical study including 476 patients demonstrated statistically significant noninferiority for treosulfan with clinically meaningful improvement in EFS. Here, the final study results and pre-specified subgroup analyses of all 570 randomized patients with completed longer-term follow-up are presented. Patients presenting HCT-specific comorbidity index >2 or aged ≥50 years were randomly assigned (1:1) to intravenous (IV) fludarabine with either treosulfan (30 g/m2 IV) or busulfan (6.4 mg/kg IV) after stratification by disease risk group, donor type, and participating institution. The primary endpoint was EFS with disease recurrence, graft failure, or death from any cause as events. EFS of patients (median age 60 years) was superior after treosulfan compared to RIC busulfan: 36-months-EFS rate 59.5% (95% CI, 52.2-66.1) vs. 49.7% (95% CI, 43.3-55.7) with a hazard ratio (HR) of 0.64 (95% CI, 0.49-0.84), p = 0.0006. Likewise, overall survival (OS) with treosulfan was superior compared to busulfan: 36-month-OS rate 66.8% vs. 56.3%; HR 0.64 (95% CI, 0.48-0.87), p = 0.0037. Post hoc analyses revealed that these differences were consistent with the confirmatory interim analysis, and thereby the treosulfan regimen appears particularly suitable for older AML and MDS patients.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Anciano , Busulfano/análogos & derivados , Busulfano/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Acondicionamiento Pretrasplante/métodos , Vidarabina/uso terapéutico
2.
Cytotherapy ; 15(4): 492-506, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23480952

RESUMEN

BACKGROUND AIMS: Dendritic cells (DC) have been vigorously investigated as an immunological basis for therapeutic vaccination against cancer and infections, even among patients after allogeneic stem cell transplantation. METHODS: Effective induction of cell-mediated immunity strongly depends on the ability of DC to (i) migrate to the draining lymphoid organs mediated by chemokine receptors, (ii) prime T cells through high expression of costimulatory molecules and major histocompatibility complexes and (iii) secret Th1-polarizing cytokines such as Interleukin-12 (IL-12). However, there is no protocol to generate fully matured and functional DC according to methodical requirements of current good manufacturing practice (CGMP) guidelines. RESULTS: We established a protocol conforming to CGMP standards that permits the generation of fully matured and functional DC on the basis of cell culture in adherence bags with the use of serum-free media with a maturation cocktail, containing tumor necrosis factor-alpha/Interferon-alpha/polyinosinic:polycytidylic acid. Our DC superiorly display three critical features for an effective induction of cell-mediated immunity without evidence of exhaustion, along with its ability to prime infectious or tumor-specific T cells in a short-term cell culture. CONCLUSIONS: Our newly developed protocol offers an attractive method to produce fully matured Th1-polarizing DC with proven migratory and stimulatory capacity for any clinical application according to CGMP standards.


Asunto(s)
Células Dendríticas , Activación de Linfocitos , Células TH1/inmunología , Células TH1/metabolismo , Técnicas de Cultivo de Célula , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Movimiento Celular , Células Cultivadas , Células Dendríticas/citología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Humanos , Inmunidad Celular/efectos de los fármacos , Interferón-alfa/farmacología , Interleucina-10/biosíntesis , Interleucina-10/genética , Interleucina-12/genética , Interleucina-12/metabolismo , Leucocitos Mononucleares/inmunología , Poli I-C/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Necrosis Tumoral alfa/farmacología
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