非体外去T细胞单倍体外周血干细胞移植治疗恶性血液病

背景：应用亲属人类白细胞抗原单倍体相合供者进行造血干细胞移植，几乎可使所有需要移植治疗的患者都能在亲属间及时找到供者。但由于人类白细胞抗原不合的免疫学障碍，应用常规方式移植不但排斥率高而且重度移植物抗宿主病发病率显著增高。目的：观察应用清髓性预处理联合多种免疫抑制方案进行非体外去T细胞的人类白细胞抗原单倍体相合外周血干细胞移植治疗恶性血液病的疗效。设计、时间及地点：病例观察，于2002—07／2008-06在新疆医科大学第一附属医院血液科，血液病研究所完成。对象：恶性血液病患者42例，年龄10～48岁。供受者人类白细胞抗原配型1个位点不合者7例，2～3个位点不合者35例。方法：预处理方案为清髓性的，预防移植物抗宿主病均以环孢素加短程甲氨蝶呤为基础方案，人类白细胞抗原1个位点不合时加用霉酚酸酯，人类白细胞抗原2～3个位点不合时再加用抗胸腺细胞球蛋白及抗CD25甲抗-移植物为经粒细胞集落刺激因子动员的未进行体外去除T细胞的外周血干细胞，移植的CD34＋细胞11×10^8／kg。主要观察指标：观察患者移植物抗宿主病发生情况及移植后1，3，6，12及18个月供、受者人类白细胞抗原相合及单倍体移植受者T、B亚群变化。结果：42例患者均获得完全、持久供者干细胞植入，发生急性移植物抗宿主病19例，Ⅰ度16例，Ⅱ度3例，2年累积发病率为50．8％；在随访大于6个月的31例患者中发生慢性移植物抗宿主病23例，局限型20例。广泛型3例，2年累积发病率为57．1％，无患者死于移植物抗宿主病。人类白细胞抗原单倍体非去T细胞外周血干细胞移植后T、B亚群下降及恢复与人类白细胞抗原相合移植无统计学差异。结论：在小样本临床治疗中，应用清髓性预处理联合多种免疫抑制剂进行非体外去T细胞亲属间人类白细胞抗原单倍体相合外周血干细胞移植治疗恶性血液病安全有效，今后需扩大样本量进一步证实其临床疗效。

Haploidentical peripheral blood stem cell transplantation without in vitro T-cell depletion for the treatment of malignant hematological diseases

BACKGROUND: Lack of human leucocyte antigen-matched family donors has restricted the application of hematopoietic cell transplantation. Due to immunological disorder of humam leucocyte antigen misfit, common way for haploidentical transplantation is associated with poor engraftment and severe graft-versus-host disease. Because not every patient has HLA-Jdentical family member, a substantial proportion of patients will receive haploidentical transplantation. OBJECTIVE: To explore the curative effect on malignant hematological diseases of haploidentical peripheral blood stem cell transplantation (PBSCT) using myeloablative conditioning regimen in combination of proper immunosuppressants without in vitro T-cell depletion. DESIGN, TIME AND SETTING: A case observation was performed at the Department of Hematology in the First Affiliated Hospital of Xinjiang Medical University from July 2002 to June 2008. PARTICIPANTS: Forty-two patients with malignant hematological diseases, including 29 standard-risk patients and 13 high-risk patients, age from 10 to 48 years, were transplanted with cells from a haploidentical family donor with 1-3 mismatched loci of HLA antigens. Seven patients had 1 locus mismatched donors and thirty-five patients had 2-3 loci mismatched donors. METHODS: The patients have received myeloablative conditioning regimen. A two-agent based graft-versus-host disease (GVHD) prophylaxis was used as cyclospodne A and a short course of methotrexate. Mycophenolate mofetile was added for 1 locus mismatched patients. Mycophenolate mofetile, antithymocyte globulin and CD25 mono-colonal antibody were added for 2-3 loci mismatched patients. The grafts were granulocyte colony-stimulating factor-mobilized peripheral blood stem cells without in vitro T-cell depletion. MAIN OUTCOME MEASURES: Engraftment, GVHD incidence and severity, relapse and leukemia-free survival and the immune function of patients in months 1, 3, 6, 12 and 18 postoperatively. RESULTS: Totally 42 patients achieved complete and sustained donor-type engraftment. Nineteen patients developed acute GVHD, the 2-year cumulative incidences of acute GVHD were 50.8%, gradeⅠ acute GVHD occurred in 16 cases and grade Ⅱ in 3 cases. Thirty-one patients were followed up more than 6 months, 23 of them developed chronic GVHD with limited in 20 and extensive in 3, the 2-year cumulative incidences of chronic GVHD were 57.1%. No patients died of GVHD. There were no significant differences in the reduction and recovery of T cells and B cells between HLA haploidentical PBSCT without in vitro T cell depletion and HLA-matched PBSCT. CONCLUSION: Haploidentical PBSCT is feasible and safe for malignant hematological diseases to use myeloablative conditioning regiment combination of intensive immunosuppressants without in vitro T cell depletion. A large amount of clinical cases need to be investigated in the near future.