应用亲缘异基因造血干细胞移植与STI571治疗非慢性期慢性粒细胞白血病效果的比较

STI571 versus allogenic hematopoietic stem cell transplantation for non-chronic phase chronic myelogenous leukemia

目的:评价亲缘异基因造血干细胞移植与酪氨酸激酶抑制剂STI571治疗非慢性期慢性粒细胞白血病的有效性及安全性。方法:①对象:所有患者在治疗前均经骨髓细胞学、细胞遗传学和/或分子遗传学检查确诊为加速或急变期慢性粒细胞白血病。实验经医学伦理委员会批准,患者均知情同意。STI571治疗组23例患者,男13例,女10例,平均年龄32岁,2002-04/2006-06陆续开始应用STI571,观察截止时间为2006-10,平均用药17.5个月。造血干细胞移植组7例患者,1999-07/2006-04收治,男6例,女1例,平均年龄35.4岁;健康亲缘性异基因造血干细胞供者7例,均与受者经HLA配型证实为全相合。②STI571治疗:23例患者每日口服STI571 600mg,此过程未给予其他治疗慢性粒细胞白血病的药物。出现以下任一情况药量增至800mg:治疗3个月仍未达到血液学完全缓解;达到血液学缓解后复发;达到主要遗传学缓解后复发。出现以下任一情况给予停药或减量:中性粒细胞<1×109 L-1或血小板<50×109 L-1;出现≥Ⅱ级非血液学不良反应。每周复查血常规,根据血象和骨髓象调整剂量,每3个月进行骨髓象及细胞遗传学检查。③干细胞移植的相关干预方案:7例患者均采用经典/改良BuCy2方案进行预处理,再给予短程甲氨蝶呤联合环孢菌素A方案预防移植物抗宿主病,其中部分患者加用抗淋巴细胞球蛋白预防移植物抗宿主病。环孢菌素A于移植前1d以10mg/(kg·d)分2次口服,并逐渐调整其血浓度至200～400μg/L;移植后1d静脉注射甲氨蝶呤15mg/m2,移植后3,6,11d静脉注射甲氨蝶呤10mg/m2。④有效性评估:包括血液学效应(血液学完全缓解、部分缓解、未缓解)、血液学复发及疾病进展、细胞遗传学反应(根据Ph+细胞所占比例分为完全缓解、大部分缓解、小部分缓解、微缓解、不缓解、主要遗传学反应、遗传学复发)。⑤安全性评估:按WHO不良反应分度标准分为0～4度。结果:30例患者均进入结果分析。①血液学和细胞遗传学效应:STI571治疗组23例患者均可评价血液学和细胞遗传学效应,12例(52.2%)保持血液学完全缓解,5例(21.7%)发生主要遗传学效应,其中4例(17.4%)为遗传学完全缓解。造血干细胞移植组7例患者于移植后3～6个月均可评价血液学和细胞遗传学效应,且获得血液学和细胞遗传学完全缓解,与STI571治疗组比较差异有显著性意义(P<0.05)。②两组患者的生存情况:两组患者的总体存活率行Kaplan-Meier法比较,差异无显著性意义(χ2=0.04,P=0.85)。③不良事件与副反应:STI571治疗组在治疗期间,没有患者因药物不良副作用而停药、死亡,7例(30.4%)患者发生III/IV级白细胞和/或血小板减少。造血干细胞移植组2例(28.6%)发生Ⅲ～Ⅳ度急性移植物抗宿主病,3例(42.9%)发生慢性移植物抗宿主病,给予相应治疗后3例无效死亡;移植60d内发生细菌或真菌感染4例,监测出巨细胞病毒血症2例,经治疗后均得到控制;2例患者发生出血性膀胱炎,经治疗后病情缓解。结论:亲缘异基因造血干细胞移植后血液学完全缓解率、细胞遗传学完全缓解率显著优于STI571治疗,但两种方法最终的患者生存率基本相似。

AIM： To evaluate the efficacy and safety of STI571 and related allogenic hematopoietic stem cell transplantation （alIo-HSCT） for non-chronic phase chronic myelogenous leukemia （CML）. METHODS： ①Object： All the patients were diagnosed as CML in accelerating or blast phase by bone marrow cyto-morphology, cytogenetics and/or molecular genetics before treatment. The experiment was approved by medical ethics committee and got permission of all the patients. Twenty-three patients with a median age of 32 years, 13 males and 10 females, were treated with STI571. They started STI571 treatment one after another from April 2002 to June 2006, and the observation lasted up to October 2006 with a median of 17.5 months. Seven patients underwent alIo-HSCT from July 1999 to April 2006, including 6 males and 1 female, with a median age of 35.4 years. All the patients were HLA matched.②STI571 treatment： All of 23 patients orally took STI571 600 mg daily, and no other drugs for CML were given concomitantly. An increase to 400 mg twice daily was permitted in patients, in those a complete hematologic response had not been achieved after 3 months of treatment, those whose disease relapsed after the achievement of a complete hematologic response, and those whose disease relapsed after the achievement of a major cytogenetic response. Therapy was interrupted if a patient had a grade 3 or 4 hematologic toxic effect （a neutrophil count of less than 1×10^9 L^-1, or a platelet count of less than 50×10^9 L^-1）, or grade 2 non-hematologic toxic effects occurred. Blood routine test was done weekly, bone marrow morphologic and cytogenetic examinations were done every three months. ③ Some schedules in the transplantation group： All of the 7 cases received BuCy2 or modified BuCy2 as preconditioning regimens. The graft-versus-host disease （GVHD） was prevented by cyclosporin A and short-term methotrexate （MTX） regimen in all patients, antilymphocytic globulin was added to some of them. Oral administration of cyclosporin A began at 1 day before transplantation with a dose of 10 mg/kg, twice daily, and gradually adjusted to 200- 400 μg/L blood concentration. MTX was given intravenously 15 mg/m^2 at the first day and 10 mg/m^2 at the third, sixth and eleventh days post-transplantation. ④Evaluation of efficacy included hematologic response （complete hematologic response, partial hematologic response and non-hematologic response）, hematologic relapse and disease progress, cytogenetic response that divided into complete, substantially partial, fractionally partial, mini, and non remission, major cytogenetic response and genetic relapse. ⑤Evaluation of safety was graded as 0-4 degree according to WHO adverse effects criteria. RESULTS： All of the 30 patients were included in the analysis.①Hematologic and cytogenetic response： In the STI571 group： All of the 23 patients were evaluable for both hematologic and cytogenetic response. 12 cases （52.2%） of them remained complete hematologic response, 5 cases （21.7%） of them achieved major cytogenetic response, and 4 （17.4%） of them achieved complete cytogenetic response. In the HSCT group, the evaluations of hematologic and cytogenetic response for all the seven patients were finished 3-6 months post-transplantation. All of them achieved complete hematologic and cytogenetic responses, which was significantly different to that of STI571 group （P 〈 0.05）. ②Survival of patients in two groups： Total survival rate of the two groups was calculated by the Kaplan-Meier method and no difference was found between the two groups （χ2=0.04, P =0.85）.③Adverse events and side effects： In STI571 group, none of the patients was withdrew or died of drug side effects, Ⅲ or Ⅳdegree leucocytopenia and/or thrombocytopenia occurred in 7 cases （30.4%）. In HSCT group, 2 cases （28.6%） occurred Ⅲor Ⅳ degree acute GVHD and 3 cases （42.9%） occurred chronic GVHD. Among the five patients with severe GVHD, 3 of them died. Within 60 days post-transplantation, 4 patients developed bacterial or fungal infection, 2 patients developed hemorrhagic cystitis and cytomegaloviremia was detected in 2 patients, all of them were controlled or recovered after proper treatment. CONCLUSION： Related alIo-HSCT is significantly better than STI571 treatment in complete hematologic response and complete cytogenetic response, but no significant difference is found in the survival rate between the two methods.