| Objective1. To explore the impact of single nucleotide polymorphisms of interleukin-18 promotor on outcome in HLA-matched donor, HLA-mismatched related and unrelated donor hematopoietic stem cell transplantation (HSCT).2. To explore the impact of TNF-a, TGF-β,IFN-y, IL-6, IL-10 cytokine gene polymorphisms on outcome in HLA matched sibling HSCT.MethodsIn the first cohort we detected single-nucleotide polymorphisms in the IL-18 promotor with PCR-sequence-specific primer analysis (PCR-SSP) among 116 transplant recipients and their HLA matched or mismatched donors. In the second cohort of HLA identical sibling transplant, we analyzed the following SNP in 54 recipient and donor pairs:TNF-α-308 A/G, TGF-βcodon 10 T/C, codon 25 C/G, IFN-γ+874 T/A, IL-6-174 C/G, IL-10-1082 A/G,-819 T/C,-592 C/A.Results1. In HLA-matched donor HSCT, for patients having donors with IL-18-137 G/G and-137 G/C genotype, the median time of neutrophil recovery (>0.5×109/L) were 14 (11-22) and 16 (11-19) days, respectively(P=0.033), and the incidence of extensive chronic graft versus host disease (cGVHD) was 19.4% and 3.2%, respectively(P=0.034). For IL-18-607 C/C and-607 C/A donor genotype, chronic graft versus host disease (cGVHD) was 26.3% and 10.8%, respectively(P=0.082). Neither donor nor recipient genotype had significant influence on the GVHD, hematopoietic reconstitution and DFS in HLA mismatched HSCT.2. In HLA-matched sibling HSCT, IFN-γ+874 T/A (associated with higher IFN-y level) in recipient significantly decreased the probablity of extensive cGVHD compared to IFN-γ+874 A/A genotype (0 vs.28.6%, P=0.044), wheras IL-10 ATA/ATA (-1082,-819,-592) genotype (associated with higher IL-10 level) in patient significantly improved TRM (36.2% vs.59.5%, P=0.047) and DFS (57.1% vs.28.4%, P=0.048). Furthermore, lack of both IFN-γ+874 T and IL-10 ATA/ATA genotype in recipient significantly increased the incidence of gradeⅡ-ⅣaGVHD (23.7% vs.3.7%, P=0.042) and TRM (70.5% vs.35.0%, P=0.017) and eventually resulted in decreased DFS (20.1% vs.55.6%, P=0.024). The posession of IFN-γ+874 T in either patient or donor significantly decreased the probablity of invasive fungal disease and septicemia (22.2% vs.50.0%, P=0.050).Conclusion1. In HLA-matched related or unrelated donor HSCT, IL-18-137 G homozygous genotype in donor facilitated neutrophil reconstitution, but increased the probability of extensive cGVHD. Nevertheless, neither-137 nor-607 genotype had influence on the outcome in HLA mismatched allo-HSCT.2. In HLA-matched sibling HSCT, the presence of recipient IFN-γ+874 T allele significantly decreased the risk of extensive cGVHD. Posession of either IL-10 ATA homozygous genotype or IFN-γ+874 T allele in recipient was a protective gene factor for severe aGVHD and DFS. ObjectiveTo analyze the efficacy of Fludarabine (Flu) and Cytosine arabinoside (Ara-c) containing preparative regimen in patients with myeloid hematological malignancies receiving allogeneic hematopoietic stem cell transplantation(allo-HSCT), and to explore optimal doses of this combination.MethodsFrom April 2005 to March 2008, a total of 60 consecutive patients with myeloid hematological malignancies were treated with allo-HSCT after completing a Busulfan (Bu)-Cyclophosphamide (Cy) preparative regimen modified by Flu/Ara-c.ResultsAll patients achieved engraftment, the overall median time of neutrophil recovery (>0.5×109/L) and platelet recovery (> 20×109/L) were 14 (11-20) and 18 (9-41) days, respectively. No critical regimen related toxicity event was observed during the conditioning. Only 1 patient (1.7%) developed hepatic veno-occlusive disease (VOD), the incidence of treatment-related mortality (TRM) within 100 days was 3.3%. The incidence of gradeⅡ-Ⅳacute graft-versus-host disease (aGVHD) and chronic graft versus host disease (cGVHD) of the evaluble patients was 16.7% and 38.6%, respectively. The 3 year disease free survival (DFS), overall survival (OS), relapse rate (RR), TRM and cumulative incidences of cGVHD were 66.6%,70.7%,27.2%, 14.7% and 42.9%, respectively. And patients were divided into subgroups according to the days of intravenous Bu administration to further explore optimal Bu dose. Bu4 subgroup showed a trend towards worse DFS (49.9% vs.71.7%, P=0.050) due to significantly higher TRM (50.1% vs.20.3%, P=0.012) with a shorter follow-up compared to the other. And Bu2 and Bu3 regimens led to comparable DFS (72.4% vs. 72.2%, P=0.712), though a higher proportion of patients in Bu2 than in Bu3 subgroup benefited from donor lymphocyte infusion after relapse. ConclusionBu-Cy regimen modified by Flu/Ara-c has a minimal extrahematalogic toxicity, and resulted in a low risk of relapse, low incidence and severety of GVHD in patients with myeloid hematological malignancies receiving allo-HSCT. In particular, the combination of Bu 3.2mg/kg/d iv. or 4 mg/kg/d x3, Cy 50mg/kg/d x 2, Flu 30mg/m2/d×3 and Ara-c 2g/m2/d x 3 might be a feasible myeloablative conditioning regimen.
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