非清髓异基因造血干细胞移植联合伊马替尼治疗慢性粒细胞白血病的临床研究

Nonmyleoablative allogeneic stem cell transplantation combined with imatinib in treatment of chronic myeloid leukemia: a clinical study

目的 探讨非清髓造血干细胞移植联合伊马替尼(格列卫、STI571)在治疗慢性粒细胞白血病(CML)中的作用。方法 10例CML患者中3例为慢性期,4例为加速期,3例为急变期。移植前、后口服格列卫(400～1500mg/d)治疗,预处理方案为福达拉宾,环磷酰胺和阿糖胞苷联合抗胸腺细胞球蛋白或CD3单抗。供者HLA配型4例完全相合,2例1个位点不相合,1例2个位点不相合的同胞,1例3个位点不相合的同胞及2例半匹配的母亲供者。干细胞来源为重组人类粒细胞集落刺激因子(rhG- CSF,格拉诺赛特)动员的外周血造血干细胞(PBSC),移植物抗宿主病(GVHD)的预防以环孢菌素A和霉酚酸酯(骁悉)为主,部分病例加用甲氨蝶呤、CD3单抗及CD25单抗(塞尼派)。结果 10例患者均获得不同程度的嵌合状态,3例获得完全嵌合(>95%),7例获得44%～95%的混合嵌合。7例混合嵌合状态的患者经调整免疫抑制剂、供者淋巴细胞/PBSC输注,格列卫治疗,6例患者在移植后1 5～10个月转变为完全嵌合。移植后中性粒细胞>0. 5×109/L所需天数为16d(10～21d);血小板大于20×109/L所需天数为10d(4～15d)。移植期间1例患者移植后45d因肠道感染,颅内出血死亡。另1例患者移植后27d因多脏器衰竭死亡。8例患者随访7～23个月,6例发生Ⅰ～Ⅱ度GVHD,2例发生Ⅲ～Ⅳ度GVHD,除1例因慢性GVHD死?

Objective To study the effect of nonmyeloablative allogeneic peripheral blood stem cell (NST) transplantation combined with imatinib in the treatment of chronic myeloid leukemia (CML). Methods Ten CML patients, 5 males and 5 females, aged 21-41,3 in chronic phase (CP), 4 in accelerated phase (AP) and 3 in blast crisis phase (BP) ,were treated with imatinib (400-1500 mg/d) before ( n =10) and / or after ( n =6) NST transplantation. The donors were HLA-identical ( n =4), 5/6 antigen-matched ( n =2), 4/6 antigen-matched ( n =2), 3/6 antigen-matched ( n =1) siblings or haplo-identical mothers ( n =2). The preparative regimen included cytoxin (CTX), Ara-C, and fludarabine combined with antithymocyte globulin (ATG) or anti-CD3 monoclonal antibody. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (CSA) and mycophenolate mofetil (MMF), or with low-dose methotrexate (MTX) or zenapax. Results All the 10 patients showed donor cell chimerism at different degree: three had full chimerism (>95%) and seven mixed chimerism (44%-95%). Mixed chimerism in 6 cases had been transformed into full chimerism during 1.5-10 months after NST transplantation through immuosuppresive agent withdrawal, donor peripheral blood stem cell/donor lymphocyte infusion or treatment of imatinib. The time needed for increase of the number of neutrophils to more than 0.5×10 9/L was 16 d days (10-21 days). The time needed for increase of the number of platelets more than 20×10 9/L was 10 days (4-15 days). 6 cases had Ⅰ-Ⅱ° acute and chronic GVHD of skin . 2 case had Ⅲ-Ⅳ° chronic GVHD. 2 cases died of transplantation-related complication 27 and 45 days after transplantation respectively. One patient died of Ⅲ-Ⅳ° cGVHD. Seven patients remained alive after a median follow-up of 14.5 months (7-23 months). The time needed for bcr/abl becoming negative was 33-130 days. None case relapsed during the following-up. Conclusion An effective and safer method for CML, especially advanced CML treatment of NST transplantation combined with imatinib before and after transplantation reduces the leukemic cell load before transplantation, inhibits the proliferation of residual leukemic cells, promotes full chimerism change and enhanced the effect of graft versus leukemia.