Abstract

We have experienced many HLA-mismatched unrelated donor hematopoietic stem cell transplantation (HSCT) for patients with high-risk AML. The availability of unrelated donors, who were categorized as high-risk for acute GvHD posttransplant, based on well understanding of impact of HLA allele or antigen mismatch immunobiology on various clinical outcomes, was investigated. With the use of different immunosuppression conditioning regimens, according to the patient-risk grouping, will allow stable HLA-mismatched unrelated donor HSCT to meet the needs best of the individual patient. Beginning on March 2004, 23 consecutive adult patients were enrolled in treatment protocols and follow-up was carried out through July 31, 2006. Patients with AML, age in the range between 17 and 58, who were all in 1st or 2nd complete remission, had high-risk assessment, in various performance status, received mainly total body irradiation containing conventional myeloablative transplantation. Specifically, for patients who were supposed to receive peripheral blood stem cells (PBSCs) from HLA-mismatched unrelated donors at the level of HLA antigen (N=5) or 1-2 alleles (N=7) at the HLA-A, B, Cw, and DR loci; if antithymocyte globulin (ATG;Thymoglobulin, SangStat), at a dose of 1.25 mg per kilogram of body weight per day, was given intravenously on days D-3 and D-2 followed by FK-506 from D-1 and short-term methotrexate at D+1, D+3, D+6, D+11 at a dose of 5mg/m2 intravenously, they were enrolled as group A (N=10). In contrast, if mycofenolate mofetil was started from D+21 and tapered out until D+60 instead of ATG, they were in the group B (N=13). Patients with unrelated donors were screened for HLA-A, B, and DRB1 alleles with the use of high-resolution (DNA sequencing) molecular typing method. Median age for group A, B were 36 (range, 17–58), 32 (range, 17–48), respectively. Sex ratio was similar between 2 groups. Group A received with a median CD34 dose of 4.2 (3.6–8.8) ×106/kg compared with 2.4 (1.6–5.5) ×106/kg of the group B. Median time to neutrophil (>0.5×109/kg) and platelet (>20×109/kg) regeneration was 13 vs 15 days, 14 vs 17 days in the group A and B respectively. After median follow-up of 9 months (range, 2–20) and 16 months (range, 3–29) for each group, acute GvHD was observed in 40% and 77%, respectively. However, 31% was greater than grade II acute GvHD in the group B and one of them died due to severe GvHD grade IV, despite none (0%) in the group A. Only 2 patients (29%) in the group A developed limited type chronic GvHD, but 3 patients in the group B together with 3 of extensive type (46% in total). Also, one case of graft rejection was observed in the group B (4%). The cumulative incidence of each group transplant related mortality (TRM) was 0% and 15%, respectively. The relapse rate was 0% in each group. Therefore, in our experience, in order to reduce TRM using unrelated donor PBSCs, particularly in the HLA-mismatched setting, it is required to cautiously apply ATG as a critical immunosuppression used in this group A as the benefits from reduction of GvHD/rejection.

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