成人人类白细胞抗原全相合与不相合造血干细胞移植后急性移植物抗宿主病的临床特点与预后

 目的 比较成人人类白细胞抗原(HLA)全相合与HLA不相合异基因造血干细胞移植(allo-HSCT)后急性移植物抗宿主病(aGVHD)的临床特点与疗效。方法 回顾性分析2010年1月至2011年12月于北京大学血液病研究所进行亲缘allo-HSCT患者的临床病历资料,分析不同类型移植后aGVHD的发病类型与特点以及临床疗效的差异。结果 544例患者中,HLA不相合移植后的aGVHD发生率为50.2%,明显高于HLA全相合移植(20.4%,P<0.001),且发生得更早,但Ⅲ°~Ⅳ° aGVHD的累积发生率两组之间差异并无统计学意义(4.5%比6.8%, P=0.066);全相合移植中肠道aGVHD发生率较高(31.1%),而在不相合移植中以皮肤aGVHD为主(66.5%),肠道和肝脏aGVHD发生率均较全相合移植低;全相合移植发生aGVHD时发热患者比例较不相合移植低(28.9% 比47.6%,P=0.028);全相合移植与不相合移植相比,aGVHD总体治愈率低,特别是Ⅲ°~Ⅳ° aGVHD最终疗效差,二线治疗后的完全缓解率低于不相合移植(88.9%比98.8%,P=0.006),aGVHD相关病死率高于不相合移植(11.1%比2.4%,P=0.024)。结论 HLA不相合移植后aGVHD发生率明显高于全相合患者,但重度aGVHD发生率两组间差异无统计学意义,两组患者一线治疗缓解率相近,但HLA不相合移植患者二线治疗后aGVHD总体缓解率更高。     

移植前及预处理期间肝功能异常对异基因造血干细胞移植效果的影响

 目的 探讨异基因造血干细胞移植(allo-HSCT)患者移植前和预处理期间肝功能异常的特征及其与肝脏合并症和预后的关系。方法 回顾性分析196例allo-HSCT治疗血液系统疾病患者,采集其移植前和预处理期间肝功能数据,观察其对造血重建、移植相关肝脏并发症、生存和移植相关死亡的影响。结果 196例患者中,38例移植前存在肝功能异常,159例预处理期间发生肝功能异常,28例(17.6%)出现3度肝损害,无4度肝损害出现。移植前和预处理期间肝功能异常对造血重建时间、肝静脉阻塞病(HVOD)、肝脏急性移植物抗宿主病(aGVHD)和慢性移植物抗宿主病(cGVHD)发生无显著影响。单因素分析显示年龄(P=0.022)、移植前疾病状态高危(P=0.003)、移植前AST(P=0.019)和TBil水平升高(P=0.015)、Ⅲ~Ⅳ度肝脏aGVHD(P=0.000)和HVOD(P=0.000)是影响总生存(OS)率的危险因素。多因素Cox回归分析显示移植前疾病状态为高危(P=0.002)、Ⅲ~Ⅳ度肝脏aGVHD(P=0.000)是影响OS率的独立危险因素,同时也是影响移植相关死亡(TRM)率的独立危险因素(P值分别为0.002和0.000),而移植前和预处理期间肝功能异常对OS率和TRM率无显著影响。结论 1~2度肝功能异常患者,在密切监测肝功能、充分保肝治疗及积极预防HVOD基础上,可考虑进行allo-HSCT。
        

同胞全相合异基因造血干细胞移植治疗95例骨髓增生异常综合征患者的临床分析

 目的 探讨同胞全相合异基因造血干细胞移植(allo-HSCT)治疗骨髓增生异常综合征(MDS)的疗效与时机。方法 回顾分析2003年1月—2012年12月采用同胞全相合allo-HSCT治疗MDS及MDS转急性髓性白血病(AML)95例。采用改良马利兰+环磷酰胺或氟达拉滨的预处理方案,行骨髓和/或外周血干细胞移植。结果 95例患者中93例白细胞植活,Ⅱ~Ⅳ度急性移植物抗宿主病(aGVHD)累计发生率为12.9%±3.5%;慢性移植物抗宿主病(cGVHD) 3年累计发生率为80.3%±4.9%。3年累计复发率(RR)为25.9%±4.7%,非复发死亡率(NRM)为16.1%±4.0%。3年预期总生存(OS)率及无病生存 (DFS) 率分别为69.9%±5.0%和58.0%±5.4%。多因素分析显示,发生Ⅱ~Ⅳ度aGVHD和不发生cGVHD是OS的独立危险因素;国际预后积分系统(IPSS)分组是DFS的独立预后因素。将难治性贫血伴原始细胞增多转化型(RAEB-t)及MDS转AML患者(31例)分为移植前未化疗、化疗未缓解、化疗缓解3组,3年OS率分别为33.9%、32.7%、100.0%,化疗缓解组OS率明显高于另外两组(P<0.05),DFS率、RR率差异无统计学意义。结论 同胞全相合allo-HSCT是治疗MDS的有效手段,IPSS可预测移植后疗效,对于移植前疾病进展的患者,争取缓解后行allo-HSCT可能提高疗效,但尚需进一步临床对照研究。
        

FLT3-ITD突变高等位基因比率在急性髓系白血病中的预后意义

目的:探讨FLT3-ITD突变高等位基因比率在急性髓系白血病(AML)患者中的预后意义。方法:筛选100例检测到FLT3-ITD等位基因比率的AML初诊患者的临床资料,对其临床特征及预后因素进行统计学分析。结果:100例患者初诊时中位白细胞计数为80.1×10~9/L(2×10~9/L～326×10~9/L),中位骨髓原始细胞比例数为68.5%(21%～95%),细胞遗传学检查示正常核型66例。将FLT3-ITD等位基因比率阈值设置在1.0,分为低等位基因比率组(1.0,64例)和高等位基因比率组(≥1.0,36例)进行分析,这些患者的初次完全缓解(CR1)率总体为70.0%,低等位基因比率组和高等位基因比率组间CR1率差异有统计学意义(82.8%vs 47.2%,P0.001)。在接受异基因造血干细胞移植(allo-HSCT)的65例患者中,低等位基因比率组的无复发生存(RFS)和总生存(OS)明显优于高等位基因比率组(RFS:P=0.007,OS:P=0.014)。而对于高等位基因比率组患者,allo-HSCT与化疗比较,未能明显改善其RFS及OS(RFS:P=0.539,OS:P=0.579)。在未进行allo-HSCT的患者中,低等位基因比率组和高等位基因比率组间RFS和OS差异无统计学意义(RFS:P=0.538,OS:P=0.854)。伴有其他突变(CEBPA、NPM1、DNMT3A)的FLT3-ITD高等位基因比率患者的CR1、OS、RFS,与低等位基因比率患者比较差异无统计学意义(P0.05)。对患者的预后因素进行分析发现,CR1、外周白细胞计数及allo-HSCT在单因素、多因素分析中均对RFS、OS有影响。FLT3-ITD高等位基因比率的AML患者能检测到13号染色体长臂杂合性丢失(LOH),且等位基因比率值越高,LOH检测到的频率越高。结论:FLT3-ITD突变高等位基因比率的AML患者具有较高的白细胞计数,多合并NPM1突变、CR1率低及OS、RFS短的特征。对于不同化疗效果均差,即使进行allo-HSCT也未能明显改善其OS及RFS。高等位基因比率患者存在LOH状态,等位基因比率值越高,LOH频率越高。     

微小残留病监测指导下的危险分层治疗提高t(8;21)急性髓性白血病的疗效

 2013年5月国际血液学顶级期刊Blood(影响因子9.06)发表了北京大学血液病研究所黄晓军教授团队历时7年完成的一项研究“微小残留病监测指导下的危险分层治疗提高t(8;21)急性髓性白血病的疗效”^[1]。该研究为前瞻性、多中心研究,首次观察微小残留病(MRD)监测指导下的危险分层治疗能否提高t(8;21)急性髓性白血病(AML)的疗效。
   本课题组利用实时定量PCR动态监测MRD,据此建立新的危险分层体系。如果经过2个疗程巩固化疗后,MRD(RUNX1/RUNX1T1分子表达水平)下降大于3个对数级并且维持半年者定义为低危组,其余患者定义为高危组。低危组患者选择大剂量化疗治疗,而高危组患者选择异基因造血干细胞移植(allo-HSCT)。研究结果显示,通过危险分层治疗后5年复发率为15%,5年总体生存率达到82.7%,达到了目前国际最好的疗效。通过亚组分析发现,allo-HSCT比大剂量化疗能显著降低高危组患者的复发率(累积复发率分别为22.1%和78.9%, P<0.0001)并提高生存率(无病生存率分别为61.7%和19.6%, P=0.001);而对低危组患者未能显著降低复发率,反而因移植相关死亡导致生存率下降。低危组患者接受大剂量化疗的复发率仅为5.3%,而无病生存率达到94.7%。多因素分析显示MRD和治疗选择是影响复发和生存的独立预后因素。     

北京部分社区2型糖尿病患者降糖用药情况分析

 目的 通过调查北京市部分社区2型糖尿病患者降糖用药情况,了解不同版本《国家基本药物目录》中降糖药物(简称国家基本降糖药物)的覆盖情况。方法 纳入北京市4个社区卫生服务中心的2型糖尿病患者900例,以糖化血红蛋白(HbA1c)<7%为目标控制血糖,随访1年后比较不同版本国家基本降糖药物使用覆盖率的变化。结果 (1)基线时:应用2012年版国家基本降糖药物的比例(91.4%)明显高于应用2009年版目录药物的比例(42.9%)(χ²=481.09,P<0.05)。7种国家基本降糖药物中,阿卡波糖(48.9%)、二甲双胍(40.7%)和重组人胰岛素(31.1%)的覆盖率较高(χ²=1519.65,P<0.05)。(2)1年后随访:总人群HbA1c达标率(53.6%)较基线时(32.3%)提高(χ²=77.26,P<0.05)。应用2012年版国家基本降糖药物的比例(85.5%)仍明显高于应用2009年版目录药物的比例(37.4%)(χ²=376.367,P<0.05)。阿卡波糖(49.7%)、二甲双胍(36.3%)和重组人胰岛素(30.4%)的覆盖率仍较高(χ²=1320.70,P<0.05)。结论 2012年版的国家基本降糖药物较2009年版可更好地满足北京社区2型糖尿病患者的需求。
        

异基因造血干细胞移植治疗髓系恶性血液病移植前临床特征与预后的相关性研究

目的 :回顾性分析髓系白血病接受异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation,allo-HSCT)患者的预后相关因素。方法 :纳入175例接受allo-HSCT治疗患者,其中男性105例,女性70例,中位年龄37(28,46)岁,急性髓系白血病(acute myeloid leukemia,AML)145例,骨髓增生异常综合征(myelodysplasia syndrome,MDS)30例。根据移植前疾病状态将患者分为早期和进展期2组。早期患者包括AML第1次完全缓解(first complete remission,CR1)期和低中危MDS共116例;进展期患者包括AML非CR1期和高危MDS共59例。所有患者按照欧洲血液和骨髓移植组(European Group for Blood and Marrow Transplantation,EBMT)移植评分分为低危组(EBMT积分0~2分)86例和高危组(EBMT积分≥3分)89例。allo-HSCT干细胞供体来源为人类白细胞抗原(human leukocyte antigen,HLA)全相合同胞供体(Sib)85例,HLA相合非血缘供体(mismatched unrelated donor,MUD)64例和亲缘半相合(Haplo)26例。单因素分析患者年龄、性别、移植前疾病阶段、EBMT积分、供者来源对移植后整体生存(overall survival,OS)率、无事件生存(event free survival,EFS)率、非复发死亡率(non relapse mortality,NRM)和复发率(relapse rate,RR)的影响。结果 :所有患者中位随访12.7(3.9,45.1)个月,预期3年OS率、EFS率、NRM和RR分别为51.4%±4.0%、46.8%±4.0%、31.6%±3.7%和29.0%±4.4%。其中疾病早期移植与进展期移植2组,EBMT积分低危和高危2组OS率、EFS率、RR、NRM差异均有统计学意义(均P<0.05)。在所有移植患者或疾病早期移植组和进展期移植组中供体来源移植后OS率等指标差异均无统计学意义。结论:移植前状态及EBMT积分对髓系白血病接受allo-HSCT的整体疗效具有重要意义,不同移植供者移植后疗效相近。     

症状指数对胃食管反流性咳嗽的诊断价值

 目的 探讨症状指数(SI)诊断胃食管反流性咳嗽(GERC)的价值及其诊断临界值。方法 回顾性分析118例可疑GERC患者的多通道食管腔内阻抗-pH监测记录,结合日记卡分别计算总SI、酸反流SI和非酸反流SI,根据药物抗反流治疗效果,评估SI对GERC的诊断价值,并与症状相关概率(SAP) 的诊断效率进行比较。结果 100例(84.7%)确诊为GERC。以总SI诊断GERC时,诊断临界值为“≥45%”时的诊断效率最高,敏感度和特异度分别为56.0%和83.3%,Youden指数为0.393;酸反流SI和非酸反流SI诊断酸或非酸GERC时,两者的最佳诊断临界值均为“≥30%”,诊断效率也相似。和SAP≥75%相比,总SI≥45%诊断GERC的灵敏度较低 (56.0%比75.0%, χ²=7.988, P=0.005),特异度较高(83.3%比44.4%, χ²=5.900,P=0.015),而阳性预计值、阴性预计值与SAP相比的差异无统计学意义。联合应用总SI和SAP能提高GERC的诊断效能。结论 总SI诊断GERC的价值与SAP相似,最佳取值以≥45%为宜。
        

构建移植后复发防治的综合体系

 异基因造血干细胞移植(allo-HSCT)是血液恶性肿瘤有效乃至唯一根治方法。国际骨髓移植登记组(CIBMTR)的资料显示,复发主要发生在移植后4~18个月,在非血缘和同胞相合移植后的死因中占33%和47%,位列移植失败的首要原因^[1]。
近年来,随着单倍型移植的进展,造血干细胞移植(HSCT)进入“人人都能移植”的时代,供者已不再是移植的主要问题。移植后白血病复发则显得更为重要。因此,有必要加强对移植后复发防治的研究,构建移植后复发防治的综合体系。     

急性髓细胞白血病患者NPM1与FLT3基因突变的研究

目的 探讨急性髓细胞白血病（AML）患者中NPM1基因与FLT3基因内部串联重复（ITD）突变的发生率,并了解其临床特征及预后。方法 收集86例成人AML患者初诊时骨髓单个核细胞,采用基因组DNA-PCR方法分别扩增其NPM1和FLT3基因,毛细管电泳方法分析NPM1第12外显子突变,琼脂糖电泳分析FLT3-ITD突变,随访判断其预后。结果 86例AML患者中共检出NPM1基因突变29例（33．7％）,FLT3-ITD突变15例（17,4％）。两种突变在50例染色体正常核型AML中的发生率分别为46．0％和24．0％,明显高于异常核型AML患者。7例中6例NPM1^＋／FLT3-ITD^＋双阳性AML患者表现为正常核型,外周血白细胞均〉50×10^9几。单纯NPM1^＋或FLT3-ITD^＋AML患者初诊时也表现为高白细胞（P〈0.05）,NPM1^＋AML患者CD34表达率较低（P〈0．001）、临床完全缓解（CR）率略高（66.7％、53.3％,P〉0.05）、总生存率（OS）高（P〉0.05）;而FLT3-ITD^＋AML患者CR率略低（50．0％、58．8％,P〉0.05）、OS低（P〉0.05）。NPM1^＋／FLT3-ITD^-、NPM^-／FLT3-ITD^-、NPM^＋／FLT3-ITD^＋、NPM1-／FLT3-ITD^＋四组患者的CR率分别为66．7％、62．5％、50．0％、42．9％（P〉0．05）,各组间OS差异无统计学意义（P〉0．05）。结论 NPM1和FLT3-ITD突变是AML（尤其正常核型AML）患者常见的分子学异常,且与其临床特点、疗效及预后有一定相关性。     

Allogeneic stem cell transplantation in second rather than first complete remission in selected patients with good-risk acute myeloid leukemia

Through two consecutive trials, a policy that considered allogeneic stem cell transplantation (SCT) from a sibling donor in second rather than first complete remission (CR) in selected younger patients with acute myeloid leukemia (AML) with t(8;21)/inv(16) (core binding factor (CBF) group) or a normal karyotype (NN group) was followed by Acute Leukemia French Association (ALFA) centers. The outcome of 92 of these patients in first relapse (32 CBF, 60 NN) was reviewed with the aim of validating this strategy. The presence of an FLT3 internal tandem duplication (ITD) was retrospectively assessed in 50 patients. A total of 61 patients (66%) reached a second CR. Donor availability was an independent prognostic factor for survival in the whole patient population as well as in the CBF subset, but not in NN patients, further supporting this strategy for CBF-AMLs. In NN patients, FLT3-ITD was the main bad-prognosis factor for second CR achievement and survival, leading to consider SCT earlier, at least in FLT3-ITD patients with a donor.     

异基因造血干细胞移植治疗白血病76例临床观察

目的观察不同来源的异基因造血干细胞移植治疗白血病的疗效并探讨主要并发症的处理方案。方法对2001年9月至2007年3月第四军医大学西京医院血液科76例白血病患者行异基因造血干细胞移植治疗,其中慢性粒细胞白血病34例,急性髓性白血病24例,急性淋巴细胞白血病15例,T细胞淋巴瘤/白血病3例。人类白细胞抗原(HLA)全相合的同胞供者57例,1个HLA位点不合同胞供者3例,HLA单倍型半相合同胞供者7例,非血缘供者9例。预处理方案采用改良的马利兰联合环磷酰胺(BUCY)或改良的环磷酰胺联合全身放疗及阿糖胞苷或鬼臼乙叉甙(CyTBI Ara-c/VP-16)方案。采用标准的环孢素A(CsA)联合短期甲氨蝶呤(MTX)方案预防移植物抗宿主病(GVHD);无关供者移植加用抗人胸腺细胞球蛋白,单倍型半相合移植同时加用CD25单克隆抗体。结果96.1%(73/76)获得植入。24.7%(18/73)出现急性GVHD,32.9%(24/73)出现慢性GVHD;合并重症肝静脉闭塞病2例;并发纯红细胞性再生障碍性贫血5例。随访3~72个月,现存活56.6%(43/76),43.4%(33/76)在移植后1~36个月时死亡,19例死于白血病复发,14例死于移植相关并发症。结论多种来源的异基因造血干细胞移植是治疗白血病的有效方法,于慢性粒细胞白血病慢性期、急性白血病缓解期移植效果较好,移植前处于高危难治状态的病例复发率仍较高。     

Different clinical importance of FLT3 internal tandem duplications in AML according to FAB classification: possible existence of distinct leukemogenesis involving monocyte differentiation pathway

Impact of FLT3 receptor tyrosine kinase activation via internal tandem duplication (ITD) of the juxtamembrane region on outcome of acute myeloid leukemia (AML) is still controversial. Recent researches reveal a role of FLT3 in monocyte differentiation in hematopoiesis. We analyzed the clinical impact of FLT3 alterations in adult AML patients excluding acute promyelocytic leukemia (APL) who received induction chemotherapy according to morphologic classification. Retrospective review of medical records from three centers in Korea between 1997 and 2007 was performed. Polymerase chain reaction was performed on genomic DNA derived from blood samples of patients before induction chemotherapy for FLT3-ITD detection. We assessed overall survival (OS), first disease-free survival (1-DFS), and response to induction chemotherapy. One hundred eighty-four patients (median age 49.1 years, range 16.0–76.5) with AML excluding APL received induction chemotherapy from three centers. FLT3-ITD was detected in 22 patients. One hundred forty-one patients were below age 60. One hundred seventy-nine patients received induction chemotherapy with cytarabine and idarubicin (AId) regimen. One hundred nineteen patients achieved complete remission (CR) after first induction chemotherapy. FLT3-ITD was not related to achievement of CR. 1-DFS was longer in patients without FLT3-ITD (median 1-DFS 16.5 vs. 8.5 months, p?=?0.025). 1-DFS was not different according to FLT3-ITD status in nonmonocyte lineage leukemia (p?=?0.355), while 1-DFS was shorter in monocyte lineage leukemia for FLT3-ITD positive patients (20.9 vs. 2.4 months, p?<?0.001). FLT3-ITD had no impact on OS except for monocyte lineage, where OS was significantly shorter in FLT3-ITD positive group (39.4 vs. 6.0 months, p?=?0.026). Moreover FLT3-ITD was stronger prognostic factors in monocyte lineage AML than risk stratification based on cytogenetics. Status of FLT3-ITD should be analyzed differently in AML patients according to morphologic profile. FLT3-ITD is a predictive and prognostic marker only in monocyte lineage patients. This result suggests an existence of distinct subset of monocyte lineage AML with leukemogenesis involving FLT3 activating pathway.     

异基因造血干细胞移植治疗骨髓增生异常综合征60例疗效分析

目的 评价异基因造血干细胞移植(silo-HSCT)治疗骨髓增生异常综合征(MDS)的疗效.方法 回顾性分析2001年8月-2009年2月在北京市道培医院接受allo-HSCT治疗的60例MDS患者.同胞相合移植采用马利兰+环磷酰胺/氟达拉滨预处理方案,非亲缘、单倍体移植采用马利兰+环磷酰胺/氟达拉滨+兔抗人胸腺细胞免疫球蛋白预处理方案.移植物抗宿主病(GVHD)预防采用环孢素A(CsA)、短程甲氨蝶呤(MTX)和霉酚酸酯(MMF)方案.采用Kaplan-Meier曲线计算无病生存率(DFS),率的比较采用Log-rank检验.结果 总体DFS为75.3%,复发率为20%;以WHO(2001年)分组显示DFS率在难治性贫血(RA)/难治性贫血伴环状铁粒幼细胞贫血(RARS)/5q-组为84.6%,难治性细胞减少伴有多系发育异常(RCMD)组为80.O%,难治性贫血伴有原始细胞过多(RAEB)-Ⅰ/Ⅱ组为81.O%,急性髓性白血病(AML)组为56.2%(P>0.05).以国际预后积分系统(IPSS)分组显示DFS在低危组为80.O%,中危-Ⅰ组为84.6%,中危-Ⅱ组为81.8%,高危组为65.4%(P>0.05).以移植前骨髓原始细胞百分比分组显示DFS在<5%组为87.O%,5%～20%组为65.5%,>20%组为75.0%(P>0.05).以移植类型分组显示DFS同胞相合组为79.2%,非血缘组为60.O%,单倍型组为76.9%(P>0.05),上述分组比较均未有统计学意义.结论 allo-HSCT治疗各种类型的MDS均获得较高的DFS,因此可作为MDS的一线治疗.非血缘移植以及单倍体移植治疗MDS疗效显著,因而在缺乏同胞相合供者时,可选择非血缘或单倍型供者.此外,除转化为明显的白血病患者,移植前的化疗不是必需的.但是评价allo-HSCT治疗MDS的影响因素尚需更大规模病例的临床研究.     

The impact of FLT3 mutations on treatment response and survival in Chinese de novo AML patients

Objective: Two distinct forms of FMS-like tyrosine kinase 3 (FLT3) mutations, internal tandem duplication (ITD) in the juxtamembrane domain and point mutation within the activation loop of the tyrosine kinase domain (TKD), have been identified in considerable number of patients with AML. This study was aimed to analyze the impacts of these mutations on clinical outcomes, and assess the efficacy of different therapeutic regimens (allo-HSCT, sorafenib, or conventional chemotherapy) for AML patients with FLT3 mutations after the standard induction therapy.

Materials and methods: We analyzed DNA samples from 158 consecutive de novo AML patients (18–60 years, excluding APL) with FLT3 mutations between July 2010 and October 2015.

Results: We found that AML patients with FLT3-TKD mutations have more favorable clinical outcomes than those with FLT3-ITD mutations. We also found that allo-HSCT therapy subgroup achieved longer OS and RFS than non-allo-HSCT therapy subgroup for FLT3-ITD positive patients (p?p?=?0.071). However, compared with the clinical outcomes in non-primary refractory patients, sorafenib did not show an obvious beneficial effect for the primary refractory patients. Further study on a large scale is still recommended.

Conclusions: FLT3-TKD-mutated AML patients have more favorable clinical outcomes than those with FLT3-ITD mutations. Allo-HSCT therapy subgroup achieved longer OS and RFS than non-allo-HSCT therapy subgroup for FLT3-ITD positive patients. Compared with the clinical outcomes in non-primary refractory patients, sorafenib did not show an obvious beneficial effect for the primary refractory patients.     

Place of HSCT in treatment of childhood AML

This short review focuses on the role of hematopoietic SCT (HSCT) in childhood AML. In first CR (CR1), some studies demonstrate superiority of allogeneic HSCT with HLA identical sibling donors over the continuation of chemotherapy and others did not. The studies differ in regard to the included risk categories of patients and the outcome niveau of the chemotherapy arm. The BFM98 study found no benefit in having a donor, in particular in terms of overall survival. Autologous HSCT in CR1 is not superior in any of the reviewed trials over the continuation of chemotherapy. In second CR, evidence for the function of allogeneic HSCT is small. However, published data and evidence-based reports recommend an unrelated or related transplantation in the situation of a renewed remission. Data on haploidentical HSCT and on cord blood HSCT are still lacking in the case of AML. Combined studies of larger study groups are warranted to broaden the data basis for rational decision.     

A fast and simple approach for the simultaneous detection of hematopoietic chimerism, NPM1, and FLT3-ITD mutations after allogeneic stem cell transplantation

Hematopoietic chimerism can be used as a tool for patient management after allogeneic hematopoietic stem cell transplantation (HSCT). An increase in the proportion of recipient cells after transplantation is strongly associated with relapse in chronic myeloid leukemia. However, in acute myeloid leukemia (AML) the significance of increasing mixed chimerism (MC) as a predictive marker for relapse is less clear. Several mutations frequently found in AML have been employed for minimal residual disease detection and relapse prediction. Therefore, a combined analysis of hematopoietic chimerism and of the molecular aberrations found in AML could be used to improve MC characterization. We developed a multiplex PCR for use in the simultaneous detection of hematopoietic chimerism and mutations in nucleophosmin (NPM1) and fms-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD). A total of 303 samples from 20 AML patients were analyzed after HSCT. The microsatellite markers used for hematopoietic chimerism detection were D1S80, D7S1517, D4S2366, THO1, and SE33. A total of 149 samples from 18 patients showed MC with a mean detection time of 9.7 months. From the 18 patients with MC, in 6 of the patients, no FLT3-ITD or NPM1 mutation was found at any time point tested, and these patients remained in complete hematological remission. In 12 patients with MC, FLT3-ITD and NPM1 mutations were found, and these patients showed signs of hematological relapse. Our combined analysis of NPM1/FLT3-ITD mutations and hematopoietic chimerism improved the characterization of patients with MC after HSCT. The present approach may be further expanded by combining additional mutations found in AML with hematopoietic chimerism detection.     

Effect of allogeneic hematopoietic stem cell transplantation from matched siblings or unrelated donors during the first complete remission in patients with cytogenetically normal acute myeloid leukemia

We retrospectively examined the impact of hematopoietic stem cell transplantation (HSCT) during the first complete remission (CR1) in 81 patients with cytogenetically normal acute myeloid leukemia (CN-AML). Eligible patients were divided into three subgroups: HSCT recipients with allogeneic sibling or matched unrelated donors (MUD) (allogeneic HSCT, n = 47), recipients of autologous HSCT (n = 12), and patients receiving chemotherapy alone (n = 22). We examined factors associated with overall survival (OS) in these patients, focusing particularly on the effect of allogeneic HSCT. Comparing to those receiving chemotherapy alone, patients in the allogeneic HSCT group had significantly better OS, which was independent of the presence of comorbidities. Furthermore, patients who received allogeneic sibling HSCT had the best OS and disease-free survival (DFS). Patients who received MUD HSCT also had significant advantage in DFS but not in OS, when compared with patients in the chemotherapy group. The study results suggest that patients with CN-AML in CR1 who are eligible for HSCT may have a survival benefit from HSCT, especially the allogeneic HSCT. We suggest that future studies employ molecular classification of AML to better define the benefits of HSCT during CR1 in patients with CN-AML.