中医药治疗骨髓增生异常综合征的研究进展

骨髓增生异常综合征（MDS）是一组起源于造血髓系定向干细胞或多能干细胞的异质性克隆性疾病,主要特征是无效造血和高危演变为急性髓系白血病（AML）。目前国内外尚无特效治疗方法,根据IPSS评分0列低危及中危．1组患者通常采用低强度治疗,包括免疫调节治疗、免疫抑制治疗、细胞因子、去甲基化药物及临床试验药物等,而中危-2和高危组患者采用高强度治疗,包括造血干细胞移植、去甲基化药物、化疗及临床试验药物等。     

较低危骨髓增生异常综合征的治疗进展

正骨髓增生异常综合征(myelodysplastic syndromes,MDS)是起源于造血干细胞的一组异质性髓系克隆性疾病,表现为骨髓病态造血及无效造血,血细胞一系或多系减少伴形态异常,高风险向急性髓系白血病(acute myeloid leukemia,AML)转化。将IPSS≤1、WPSS≤2或IPSS-R≤4.5定义为相对低危MDS。对于大多数较低危MDS,治疗目标是减少输血需求和降低向高风险疾病或AML的转变,以及提高生命质量     

静脉滴注白消安和氟达拉滨预处理方案行异基因造血干细胞移植治疗髓系血液病疗效观察

目的探讨静脉滴注白消安(Bu)和氟达拉滨(Flu)作为预处理方案,进行异基因造血干细胞移植治疗髓系血液病的疗效。方法选取2003年10月至2005年4月成都军区昆明总医院血液科髓系血液病患者9例,其中急性非淋巴细胞白血病(ANLL)3例,慢性粒细胞白血病(CML)5例,骨髓增生异常综合征(MDS)1例,均进行同胞白细胞抗原(HLA)全相合异基因造血干细胞移植。预处理方案采用移植前第6天至移植前第3天静脉滴注白消安3.2mg/(kg.d),共4d;移植前第6天至移植前第2天静脉滴注氟达拉滨30mg/(m2.d),共5d。环孢素A和霉酚酸酯(骁悉)联合应用预防移植物抗宿主病(GVHD)。结果9例患者均成功植入,中性粒细胞>0.5×109/L的平均时间为12d;血小板(PLT)>20×109/L的平均时间为14d。中位观察时间为31个月。除轻微胃肠道反应外,无严重的预处理相关毒性,移植后1个月检测证实均为供者型完全植入。发生急性GVHD2例,慢性GVHD1例。9例患者中8例无病存活。结论静脉滴注Bu/Flu预处理方案,移植相关毒性小,治疗髓系血液病安全有效。     

含全身照射预处理方案行HLA不相合非去T造血干细胞移植治疗白血病8例临床分析

目的探讨采用全身照射(TBI)预处理方案行人类白细胞抗原(HLA)配型不相合亲缘供者非去T异基因造血干细胞移植(allo-HSCT)治疗白血病的疗效。方法2002年4月至2007年1月北京大学血液病研究所8例采用TBI预处理方案行HLA不合非去T亲缘供者allo-HSCT的白血病患者,其中急性髓性白血病(AML)3例,急性淋巴细胞性白血病(ALL)4例,慢性粒细胞白血病1例;预处理方案采用TBI加环磷酰胺(CY)方案4例,TBI加氟达拉滨(FLU)方案4例;干细胞来源包括骨髓和外周血造血干细胞移植6例,外周血造血干细胞移植(PBSCT)2例;移植物抗宿主病(GVHD)预防采用经典的环孢素A(CsA) 霉酚酸酯(MMF) 短程甲氨蝶呤(MTX)方案。结果8例供者采集单个核细胞(MNC)中位数为7.39(6.27~12.46)×108/kg,粒细胞植入中位时间11(11~13)d,血小板植入中位时间13(11~21)d。5例发生Ⅰ~Ⅱ度急性GVHD,2例出现慢性广泛性GVHD,无严重急性GVHD或因GVHD死亡病例。中位随访时间9(3~53)个月,除1例复发存活外,其余病例无病存活。结论对于HLA不相合异基因造血干细胞移植,TBI方案是一种比较安全、有效的非去T预处理方案,对于高危和二次移植患者同样有效。     

非清髓单倍体造血干细胞移植联合格列卫治疗慢性粒细胞白血病

目的:探讨格列卫联合非清髓性单倍体造血干细胞移植在治疗慢性粒细胞白血病(CML)中的作用。方法:4例CML患者,采用移植前、后口服格列卫,以环磷酰胺、阿糖胞苷、抗胸腺细胞球蛋白、赛尼派、环胞素A等作非清髓性预处理的单倍体异基因外周血造血干细胞移植。结果:移植过程顺利,4例患者均植入成功,嵌合性植入。中性粒细胞>0.5×109/L天数,16(10~21)d;血小板>20×109/L天数,10(4~15)d。3例发生Ⅰ~Ⅱ度皮肤急性移植物抗宿主病(GVHD),1例发生Ⅳ度皮肤慢性GVHD。1例+27d死于肺部感染并多脏器功能衰竭,1例死于Ⅳ度皮肤慢性GVHD并发感染。2例无病存活(随访16个月仍健在),且Ph+染色体,bcr-abl融合基因转阴。结论:非清髓单倍体造血干细胞移植联合格列卫治疗CML,具有降低移植前白血病细胞负荷,抑制残留白血病细胞增殖,促进供者完全嵌合状态的转变,增强抗移植物白血病(GVL)效应的作用,是一种有效的治疗方法,值得进一步临床研究。     

短串联重复序列多态性检测非清髓造血干细胞移植造血嵌合体的研究

近来 ,随着非清髓异基因造血干细胞移植 (NST)的开展 ,造血嵌合体的研究已成为异基因造血干细胞移植 (Allo SCT)的热点课题。我们利用短串联重复序列 (STRs)的高度多态性和竞争性 (STR PCR)的高度敏感性建立了相对定量检测移植后造血嵌合体的技术方法 ,并对 2 7例HLA相合的NST患者的造血嵌合体进行动态的前瞻性研究 ,探讨嵌合与移植排斥的关系。一、资料和方法1 供受者 :2 0 0 0年 3月至 2 0 0 1年 12月共对 2 7例NST患者进行嵌合体检测。其中我院 2 1例 ,沈阳第 2 0 1医院 6例 ;男 18例 ,女 9例 ,年龄 2 1～ 5 9岁 ,中位年龄 36…     

自体造血干细胞移植对急性髓系白血病的治疗进展

自20世纪80年代至今,自体造血干细胞移植已成为一种治疗急性髓系白血病(AML)的主要疗法。目前自体造血干细胞移植成为因难以找到人类白细胞抗原(HLA)配型相合者而不能行异基因造血干细胞移植的主要治疗手段。该文综述了自体造血干细胞移植在低危、中高危AML及难治性或复发性AML患者中的治疗进展,追踪了降低自体造血干细胞移植治疗AML复发率的策略。     

Clinical research of high-risk and refractory acute myeloid leukemia with allogeneic hematopoietic stem cell transplantation therapy

目的 探讨异基因造血干细胞移植( allo- HSCT)治疗高危难治急性髓系白血病(AML)的疗效和移植时机.方法 选取allo-HSCT治疗的AML患者47例,其中高危AML 17例,难治AML20例,骨髓增生异常综合征(MDS)转AML10例.第1次完全缓解期(CR1 )23例,第2次完全缓解期(CR2)11例,未缓解进展期(NR)13例.接受同胞供者骨髓和(或)外周血干细胞移植16例,非血缘脐血移植31例.所有患者均采用清髓性预处理方案,环孢素联合霉酚酸酯预防移植物抗宿主病(GVHD).结果 47例患者46例(97.9％)获得植入,中性粒细胞绝对计数≥0.5×109/L和血小板≥20×109/L的中位时间分别为14.5(10 ～ 36)天和26(12-90)天.16例发生急性GVHD(34.8％),Ⅲ度以上4例.在可评估的39例患者中,10例出现慢性GVHD( 25.6％),复发6例(12.8％),移植相关死亡12例(25.5％),32例(68.1％)患者存活.高危难治AML患者CR1、CR2、NR期移植生存率分别为75.5％、72.7％和40.0％.MDS转AML患者CR和NR期移植生存率分别为0％和75.0％.结论 allo-HSCT有助于提高高危难治AML疗效,降低复发率,提高生存率,且最好在首次缓解期进行移植.对于MDS转AML患者可立即行allo-HSCT,无需等待化疗达完全缓解.     

中危急性髓系白血病患者缓解后移植的策略选择

正急性髓系白血病(acute myeloid leukemia,AML)是一组起源于髓系干、祖细胞的高度异质性疾病。60岁以下的成人AML患者经联合诱导化疗后80%都可以达到完全缓解(complete remission,CR)[1-2],但对于中危AML,化疗或自体造血干细胞移植后复发率高达55%～60%,5年生存率低于30%。因此,异基因造血干细胞移植(allogeneic hematopoietic stem cell transp     

高危骨髓增生异常综合征:移植的时机选择

正骨髓增生异常综合征(myelodysplastic syndrome,MDS)是一组发生在造血干细胞水平的克隆性疾病,表现为外周血细胞一系或多系减少,骨髓病态造血、无效造血,高风险向急性髓系白血病转化。MDS治疗总体疗效欠佳,目前异基因造血干细胞移植(allo-HSCT)仍然是唯一能治愈该病的治疗手段。近20年来,其有效性和安全性已有很大改善,但由于移植后的高发病率和高死亡率,以及MDS的强异质性,如何判断哪些患者需要移植必须依赖一个可     

Treatment outcome of myelodysplastic syndrome patients younger than 60 years old

We evaluated the clinical outcome of 92 patients younger than 60 years who were treated between January 1987 and May 2003. Low, Int-1, Int-2 and High risk groups categorized by IPSS consisted of 7, 34, 24 and 27 patients, respectively. There was no significant difference in the overall survival between 30 patients who received allogeneic stem cell transplantation and 62 patients who did not. Allogeneic stem cell transplantation provided significantly better outcomes in the Int-2 and the High risk groups. Risk factors for overall survival were age and disease status at transplantation. Acute and chronic GVHD did not influence the relapse free survival rate. Allogeneic stem cell transplantation is a curative therapy for MDS. It is necessary to reduce transplantation related death and to perform stem cell transplantation as soon as possible for patients with Int-2 or High risk of IPSS.     

The impact of intensive antileukaemic treatment strategies on prognosis of myelodysplastic syndrome patients aged less than 61 years according to International Prognostic Scoring System risk groups

The present study applied the International Prognostic Scoring System (IPSS) to 306 consecutive myelodysplastic syndrome (MDS) patients diagnosed between August 1977 and September 2000 at the University Medical Centre Nijmegen. The aim was to investigate whether the IPSS could be used as a prognostic tool in MDS patients aged less than 61 years who were treated with acute myeloid leukaemia (AML)-like chemotherapy with or without transplantation, and whether the scoring system discriminated between the subgroups of patients who benefit from intensive treatment strategies. The patients were retrospectively assigned to the IPSS risk categories and compared with the IPSS workshop patients. Eighty-three of 159 patients aged < 61 years, classified as intermediate 1, intermediate 2 and high risk according to the IPSS, received intensive treatment consisting of chemotherapy only (n = 30), chemotherapy followed by either autologous stem cell transplantation (n = 7) or allogeneic stem cell transplantation (n = 46). After intensive treatment, the median survival was 2.6 years for the intermediate 1 risk group (n = 33), 3.4 years for the intermediate 2 risk group (n = 27) and 0.9 years for the high-risk group (n = 23). We conclude that the IPSS is an improved scoring system for patients receiving supportive care. Nevertheless, the scoring system does not seem to be the best method for predicting outcome after intensive antileukaemic treatment. In particular, intermediate 2 risk patients may benefit from intensive treatment.     

单倍体移植治疗白血病疗效观察

目的探讨单倍体移植治疗白血病的疗效。方法在单倍体移植时采用阿糖胞苷（Ara-c）、马利兰（Bu）、环磷酰胺（CTX）、甲基环己亚硝脲（Me-CCNU）联合作为预处理方案,用CTX、重组人粒细胞集落刺激因子（rhG-CSF）、环孢素A（CSA）、麦考酚酸酯（MMF）、抗胸腺细胞球蛋白（ATG）、白细胞介素11（IL-11）及甲氨蝶呤（MTX）联合预防急性移植物抗宿主病（aGVHD）,治疗7例白血病;结果 7例患者完全植入,白细胞〉1.0×109/L中位时间为16.9 d,Ⅲ~Ⅳ度aGVHD发生率为14.3%,中位随访时间25.6个月,无复发,至今仍存活。结论单倍体移植治疗白血病时,用Ara-c、Bu、CTX、Me-CCNU联合作为预处理方案,用CTX、rhG-CSF、CSA、MMF、ATG、IL-11及MTX联合预防aGVHD是安全、有效的。     

Reduced-intensity stem cell transplantation from an HLA-identical sibling donor in patients with myeloid malignancies

The purpose of this study was to evaluate the feasibility and efficacy of allogeneic hematopoietic stem cell transplantation with a reduced-intensity regimen (RIST) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). In all, 36 patients (median age 55 years) underwent RIST from an HLA-matched related donor between September 1999 and December 2002. The diagnoses included AML (n=14), leukemia evolving from MDS (n=10), and MDS (refractory anemia with excess blasts n=6, refractory anemia n=6). The RIST regimen consisted of purine analog (cladribine or fludarabine)/busulfan, with or without antithymocyte globulin. The regimen was well tolerated, and 34 patients achieved durable engraftment and most achieved remission after RIST. A total of 17 patients developed grade II-IV acute GVHD, and 27 developed chronic GVHD. Eight patients relapsed, and five of them received antithymocyte globulin (ATG) as part of the preparative regimen. A total of 12 patients died (four disease progression, six transplantation-related complications, and two others). Estimated 1-year disease-free survival (DFS) in low- and high-risk groups was 85 and 64%, respectively. We conclude that RIST can be performed safely in elderly patients with myeloid malignancies, and has therapeutic potential for those who fail conventional chemotherapy. In view of the significant association between GVHD or ATG and DFS, defined management of GVHD following RIST should become a major target of clinical research.     

A fludarabine-based dose-reduced conditioning regimen followed by allogeneic stem cell transplantation from related or unrelated donors in patients with myelodysplastic syndrome.

We investigated the feasibility and efficacy of a fludarabine-based dose-reduced conditioning regimen followed by stem cell transplantation from related (n = 5) or unrelated HLA-matched donors (n = 7) in 12 patients with high risk MDS, who were not eligible for a standard myeloablative conditioning regimen. The conditioning regimen consisted of fludarabine 30 mg/m(2) daily for 6 days, busulfan 4 mg/kg daily for 2 days and anti-thymocyte globulin (ATG, rabbit) 10 mg/kg daily for 4 days in 11 patients, while one patient received fludarabine, ATG, cyclophosphamide and thiotepa. Graft-versus-host disease prophylaxis consisted of cyclosporine and a short course of methotrexate. The median age of the patients was 53 years (range 37-59). The median percentage of blasts in bone marrow aspirate at transplantation was 15% (range <5% to 35%). Diagnosis at transplant was RA (n = 1), RAEB (n = 5), RAEB-T (n = 5) and sAML (n = 1). A complex karyotype including monosomy 7 was noted in five patients. The reasons for using a dose-reduced conditioning regimen were prior autologous/syngeneic BMT (n = 4), active fungal infection (n = 2) or age/reduced performance status (n = 6). Engraftment was observed in all patients with complete donor chimerism. The incidence of acute GVHD (grade II-IV) was 33%. Eight patients died during follow-up due to relapse (n = 4), liver toxicity (n = 2), aspergillus (n = 1) or aGVHD grade IV (n = 1). After a median follow-up of 19 months, the 2-year estimated disease-free survival is 12% (95% CI: 2-23%) and the overall survival is 26% (95% CI: 4-52%). Fludarabine dose-reduced conditioning prior to allogeneic stem cell transplantation in high risk MDS patients, who were not eligible for standard transplantation, resulted in stable engraftment with complete chimerism, but the toxicity and relapse rate were considerable.     

Thiotepa, busulfan, and cyclophosphamide as a preparative regimen for allogeneic transplantation for advanced myelodysplastic syndrome and acute myelogenous leukemia.

Sixty-two adults underwent marrow or blood stem cell transplantation from an HLA-matched related donor using high-dose thiotepa, busulfan, and cyclophosphamide (TBC) as the preparative regimen for treatment of advanced myelodysplastic syndrome (MDS) (refractory anemia with excess blasts with or without transformation) or acute myelogenous leukemia (AML) past first remission. All evaluable patients engrafted and had complete donor chimerism. A grade 3-4 regimen-related toxicity occurred in eight (13%) patients, and a diagnosis of MDS was the only independent risk factor for grade 3-4 regimen-related toxicity (hazard ratio 9.25, P = 0.01). Day-100 treatment-related mortality (TRM) was 19%. Poor-prognosis cytogenetics increased the risk of day-100 TRM (hazard ratio 11.4, P = 0.003), and use of tacrolimus for graft-versus-host disease prophylaxis reduced the risk of day-100 TRM (hazard ratio 0.13, P = 0.027). For all patients, the three-year relapse rate was 43% (95% CI, 28%-58%). Refractoriness to conventional induction chemotherapy prior to transplantation was an independent risk factor for relapse (hazard ratio 10.8, P = 0.02). Three-year survival was 26% (95% CI, 14%-37%); survival rates were 29% for those transplanted for AML in second remission, 31% transplanted for AML in relapse, and 17% with MDS, and there were no independent risk factors for survival. TBC is an active preparative regimen for advanced AML. Patients with advanced MDS appeared to have a higher risk of toxicity and early mortality, and alternative preparative regimens should be considered for these patients.     

Evidence for a graft-versus-leukemia effect after allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes

We report the results of a prospective study of a reduced-intensity conditioning (RIC) regimen followed by allogeneic peripheral blood stem cell transplantation (PBSCT) from an HLA-identical sibling in 37 patients with acute myeloid leukemia (AML; n = 17) or myelodysplastic syndrome (MDS; n = 20). The median age was 57 years, and 22 (59%) were beyond the early phase of their disease. The incidence of grade II to IV acute graft-versus-host disease (GVHD) was 19% (5% grade III-IV), and the 1-year incidence of chronic extensive GVHD was 46%. With a median follow-up of 297 days (355 days in 24 survivors), the 1-year probability of transplant-related mortality was 5%, and the 1-year progression-free survival was 66%. The 1-year incidence of disease progression in patients with and without GVHD was 13% (95% CI, 4%-34%) and 58% (95% CI, 36%-96%), respectively (P =.008). These results suggest that a graft-versus-leukemia effect plays a crucial role in reducing the risk of relapse after a RIC allograft in AML and MDS.     

Low-dose alemtuzumab (Campath) in myeloablative allogeneic stem cell transplantation for CD52-positive malignancies: decreased incidence of acute graft-versus-host-disease with unique pharmacokinetics

Alemtuzumab is effective in reducing the risk of acute graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (ASCT). Alemtuzumab may also delay immune reconstitution and reduce graft-versus-leukemia effects. The optimal dose has not been established. We investigated engraftment, acute GVHD incidence and severity, and pharmacokinetics of alemtuzumab associated with the use of low-dose alemtuzumab/cyclophosphamide/total body irradiation and ASCT for patients with aggressive CD52-positive hematologic malignancies. In all, 12 patients were treated. Alemtuzumab 10 mg daily on days -7 to -3 was given intravenously. Tacrolimus and methotrexate were used for GVHD prophylaxis. Alemtuzemab was not detected in any of the 36 sequential serum samples tested between days -1 and +21 of transplant. All patients engrafted rapidly; the median time to an absolute neutrophil count >0.5 x 10(9)/l was 14 days (range 11-17 days), and the median time to a platelet count >20 x 10(9)/l was 16 days (range 6-30 days). By 1 month after transplant, nine patients had 100% donor chimerism, while three had mixed donor chimerism. At 3 months, 11 had achieved 100% donor chimerism. No cases of grade III/IV acute GVHD occurred. At a median follow-up interval of 14.7 months (range 4-24), seven patients remained alive, and five remained free of disease.     

Fludarabine and melphalan-based conditioning for patients with advanced hematological malignancies relapsing after a previous hematopoietic stem cell transplant

Severe regimen-related toxicity often complicates second transplant procedures performed in patients with hematological malignancies that have relapsed after an initial hematopoietic stem cell (HSC) transplant. Therefore, we studied the safety and efficacy of a reduced-intensity fludarabine and melphalan based conditioning regimen in 11 patients who had relapsed following an autologous (n = 7) or allogeneic (n = 4) HSC transplant. All patients received allogeneic peripheral blood HSC from either an HLA-identical (n = 7) or an HLA-mismatched (n = 4) relative. Diagnoses included AML (n = 9), ALL (n = 1), or Hodgkin's disease (n = 1). Only one patient was in complete remission at the time of second transplant. The median interval between first transplant and relapse was 163 days (range 58-1885). Recipients of HLA-mismatched transplants received antithymocyte globulin in addition to fludarabine and melphalan as part of the conditioning regimen. All 11 patients received acute GVHD prophylaxis consisting of tacrolimus and methotrexate. Ten of 11 patients achieved hematopoietic engraftment with a median time to absolute neutrophil count >0.5 x 10(9)/l and to platelet count of >20 x 10(9)/l of 14 and 19 days, respectively. All engrafting patients achieved 100% donor chimerism on initial analysis, except for one with persistent leukemia at day +19. Two patients experienced grade 3 regimen-related toxicity, manifesting as acute renal failure. Acute GVHD grades 2-4 occurred in two recipients and chronic GVHD in four. The 100-day mortality from all causes was 36%. Ten of 11 patients (91%) died a median of 140 days (range 9-996) after the second transplant. The causes of death included relapse (n = 5), sepsis (n = 4), and idiopathic pneumonia syndrome (n = 1). One patient with AML survives in remission at 880 days post-transplant. We conclude that fludarabine- and melphalan-based conditioning promotes full donor chimerism, even following HLA-mismatched transplants. However, the regimen may be more beneficial when applied to patients undergoing allogeneic HSC transplantation earlier in their disease course.     

BEAM-alemtuzumab reduced-intensity allogeneic stem cell transplantation for lymphoproliferative diseases: GVHD,toxicity, and survival in 65 patients

We report the outcomes of reduced-intensity allogeneic stem cell transplantation using BEAM-alemtuzumab conditioning (carmustine, etoposide, cytosine arabinoside, melphalan, and alemtuzumab 10 mg/d on days -5 to -1) in 6 United Kingdom transplant centers. Sixty-five patients with lymphoproliferative diseases underwent sibling (n = 57) or matched unrelated donor (n = 8) transplantation. Sustained donor engraftment occurred in 60 (97%) of 62 patients. Of the 56 patients undergoing chimerism studies, 35 (63%) had full donor chimerism. Overall, 73% were in complete remission (CR) after transplantation. At a median follow-up of 1.4 years (range, 0.1-5.6 years), 37 remain alive and in CR. Acute graft-versus-host disease (GVHD) occurred in 11 (17%) of 64, grades I-II only. Estimated 1-year transplantation-related mortality (TRM) was 8% for patients undergoing first transplantation but was significantly worse for those who had previously undergone autologous transplantation. Six patients relapsed (estimated 2-year relapse risk, 20%). Histologic diagnosis (mantle cell lymphoma and high-grade non-Hodgkin lymphoma) and age at transplantation (> 46 years) were significantly associated with higher relapse risk and worse event-free survival. Relapse did not occur in any patient who developed acute or chronic GVHD. This study demonstrates that reduced-intensity allogeneic stem cell transplantation for lymphoproliferative diseases using a BEAM-alemtuzumab preparative regimen is associated with sustained donor engraftment, a high response rate, minimal toxicity, and a low incidence of GVHD.