A Two Step Approach To Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation (Hsct) For High Risk Patients With Hematologic Disorders
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION(2007)
摘要
Post transplant cyclophosphamide (CTX) has been utilized to induce donor host tolerance in allogeneic HSCT. While promising, the long term risk of MDS and AML from exposure of the graft to CTX is unknown and the optimal T cell dose to deliver using this approach remains undefined. To address these issues, nine high-risk patients, median age 55 (range 19–73) underwent haploidentical HSCT from related donors for various hematopoietic disorders using a two step approach. Seven of 9 (77%) patients had evidence of disease at the time of HSCT. In the GVH direction, 7 of 9 were 4/8 matches with their donors at HLA-A, B, C and DRB1; the other 2 patients were 5 /8 and 6 /8 matches. Seven of the 9 patients were given a myeloablative conditioning regimen of TBI (1.5 Gy) BID on days −9 through −6. Two received a nonmyeloablative conditioning regimen of fludarabine and ARA-C on days-11 through −8 and one 2 Gy fraction of TBI on day −6. The patients received 2x108/kg of their donor's CD3+ lymphocytes after completion of TBI on day −6, followed by rest days on day −5 and −4. On days −3 and −2, CTX was given at a dose of 60 mg/kg/day for the purpose of tolerization of the donor lymphocytes. On day 0, donor CD 34+ cells were infused. When possible, the number of non-tolerized T-cells in the CD 34+ product was limited to ≤5x104/kg. Tacrolimus and CellCept were used as GVHD prophylaxis. All of the patients developed fevers between DLI and CTX, with some patients also developing mild diarrhea and a rash, which in one case was biopsy-positive for GVHD. All patients engrafted. One patient developed grade III GVHD, two had grade II GVHD, and the rest had grade 0 or I GVHD. GVHD was easily controlled with corticosteroids which could be rapidly tapered in all but one patient. Four patients have died, two of relapsed disease (d+67, d+91) and two of infectious complications (d+101, d+42). An additional patient is alive, but with evidence of relapsed disease at d + 42. Four patients are well and in CR at days +250, +173, +144, and +118 days post HSCT. Three of the 4 have CD3/CD4 counts of greater than 170 cells/ml. This 2 step transplant procedure promotes the establishment of donor-recipient tolerance by in vivo CTX exposure, but avoids any effects of G-CSF on donor lymphocytes, allows delivery of a precise dose of T cells to all patients, and eliminates CTX exposure of the hematopoietic precursors. Patients who lack matched-sibling donors can be successfully transplanted on this protocol with little significant GVHD. Infection and relapse remain problems, but likely can be reduced through transplantation of patients earlier in their disease course.
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关键词
hematopoietic stem,hematologic disorders,stem cell,hsct
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