期刊
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
卷 8, 期 7, 页码 377-386出版社
ELSEVIER SCIENCE INC
DOI: 10.1053/bbmt.2002.v8.pm12171484
关键词
nonmyeloablative bone marrow transplantation; cyclophosphamide; HLA-mismatched related donors
资金
- NCI NIH HHS [CA15396, CA06973] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [P30CA006973, P01CA015396] Funding Source: NIH RePORTER
Cyclophosphamide (Cy) is a potent immunosuppressive agent that is selectively toxic to lymphocytes proliferating in response to recent antigen stimulation. In animal models, both graft rejection and GVHD after histoincompatible BMT can be inhibited by the posttransplantation administration of high-dose Cy. Therefore, a phase I clinical trial was undertaken to determine the minimal conditioning, including posttransplantation Cy, that permits the stable engraftment of partially HLA-mismatched marrow (up to 3 HLA antigens) from first-degree relatives. Thirteen patients (median age, 53 years) with high-risk hematologic malignancies received conditioning with fludarabine, 30 mg/m(2) per day from days -6 to -2, and TBI, 2 Gy on day-1. All patients received Cy, 50 mg/kg on day 3, mycophenolate mofetil from day 4 to day 35, and tacrolimus from day 4 to day greater than or equal to50. Three patients in cohort 1 received no additional conditioning, and 2 experienced graft rejection. Ten patients in cohort 2 received identical conditioning with the addition of Cy 14.5 mg/kg on days -6 and -5. Sustained donor cell engraftment occurred in 8 of these patients, with a median time to absolute neutrophil count >500/muL of 15 days (range, 13-16 days) and to unsupported platelet count >20,000/muL of 14 days (range, 0-26 days). All patients with engraftment achieved greater than or equal to95% donor chimerism within 60 days of transplantation. Two patients with myelodysplastic syndrome rejected their grafts but experienced autologous neutrophil recovery at 24 and 44 days. Histologic acute GVHD developed in 6 patients (grade II in 3 patients, grade III in 3 patients) at a median of 99 days (range, 38-143 days) after transplantation and was fatal in 1 patient. At a median-follow-up of 191 days (range, 124-423 days), 6 of 10 patients in cohort 2 were alive, and 5 were in complete remission of their disease, including both patients with graft rejection. These data demonstrate that partially HI,A-mismatched bone marrow can engraft rapidly and stably after nonmyeloablative conditioning that includes posttransplantation Cy. Clinically significant antitumor responses occur, even among patients who reject their donor grafts.
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