Epidemiological evaluation and survival of children with acute myeloid leukemia

ObjectiveThis study aims to describe the epidemiological characteristics and survival rates of children with acute myeloid leukemia treated in hospitals in southern Brazil and compare them with international data.MethodsA multicenter cohort study was conducted with retrospective data collection of all new patients with acute myeloid leukemia under 18 treated at five referral centers in pediatric hematology-oncology in southern Brazil between January 2005 and December 2015.ResultsOf the 149 patients with acute myeloid leukemia, 63.0% (n = 94) were male. The median age at diagnosis was 10.5 years (range 0–18 years) and 40.3% (n = 60) had a white blood cell count below 50,000/mm². The most common Franco-American-British (FAB) subtype was M3 (n = 43, 28.9%). Nine (6.0%) patients had central nervous system disease. In M3 patients, overall survival (OS) was 69.2% and 3-year event-free survival was 67.7%; in non-M3 patients, these rates were 45.3% and 36.7%, respectively. In non-M3 patients, OS was significantly different between transplanted (61.8%) and non-transplanted (38.2%) patients (p = 0.031).ConclusionsThese results show a higher prevalence of the Franco-American-British M3 subtype than that reported in the international literature, as well as a decreased OS compared with that of developed countries. Further multicenter Brazilian studies with a larger sample size are encouraged to better understand the characteristics of acute myeloid leukemia, and to improve the treatment and prognosis in this population.     

Recent advances in management of acute myeloid leukemia (AML)

Acute myeloid leukemia (AML) is the most common childhood malignancy. AML has therapentically been difficult to treat. In 2001, the World Health Organization (WHO), in conjunction with the Society for Hematopathology and the European Association of Hematopathology, published a new classification for myeloid neoplasms. A number of chromosomal abnormalities are used to predict outcome and stratify therapeutic risk groups in children with AML. Recently, alterations in receptor tyrosine kinases, tyrosine phosphatases and in oncogenes such as RAS have been implicated in the pathogenesis of AML. This article aims to review the recent development in diagnosis, treatment and monitoring of AML. Better understanding of the molecular pathogenesis of AML has led to the development of target-specific therapies. Some of the new classes of drugs include monoclonal antibody directed against the CD33 antigen, farnesyltransferase inhibitors (FTI), and FMSlike tyrosine kinase 3 (FLT3) inhibitors. The role of allogenic SCT, particularly whether it should be done during first CR or reserved for second remission, remains the most controversial issue in pediatric AML. There is a need of collaboration with international pediatric cooperative oncology groups and definitive clinical trials in order to estabilish use of these newer molecules in pediatric populations.     

Development of acute lymphoblastic leukemia following treatment for acute myeloid leukemia in children with Down syndrome: A case report and retrospective review of Children's Oncology Group acute myeloid leukemia trials

Children with Down syndrome have a 150‐fold increased risk of developing acute myeloid leukemia (AML) and 20‐fold increased risk of developing acute lymphoblastic leukemia (ALL). Although the risk of developing AML and ALL is significantly increased in children with Down syndrome, the development of both malignancies in the same patient is very rare. We describe a patient with Down syndrome who developed ALL 6 years after being diagnosed with AML. We performed a literature review and Children's Oncology Group query and discovered eight published cases and five cases of ALL following AML in pediatric patients with Down syndrome, as well as six cases of ALL following AML in non‐Down syndrome patients. There was a similar cumulative incidence of ALL after treatment for AML in the Down syndrome and non‐Down syndrome populations. Overall survival in patients with Down syndrome who developed ALL after treatment for AML was comparable to overall survival for patients with Down syndrome with de novo ALL with an average follow‐up of 7 years after ALL diagnosis. Clinical data collected were used to discuss whether this phenomenon represents a secondary leukemia, second primary cancer, or mixed‐lineage leukemia.     

101例儿童急性髓细胞性白血病免疫表型与预后相关分析

目的探讨免疫表型对儿童急性髓细胞性白血病的预后价值。方法采用流式细胞术检测101例儿童急性髓细胞性白血病(AML)患儿相关免疫表型,分析免疫表型对完全缓解(CR)及无疾病生存期(DFS)的影响。结果CD34阴性组及CD34、HLA-DR同时阴性组一疗程CR率均明显高于非阴性组,差异有统计学意义(P=0.008,0.000);DFS的CD34阴性组,HLA-DR阴性组以及CD34和HLA-DR同时阴性组均明显高于非阴性组,差异有统计学意义(P=0.004,0.006,0.040),而CD14,CD15,CD7,CD19差异对CR和DFS均无统计学意义。结论免疫表型对评估AML患儿的预后有一定意义。     

儿童急性髓系白血病FLT3突变临床分析：单中心研究

目的：探讨FMS样酪氨酸激酶3(FLT3)基因的内部串联复制（ITD）及激酶结构域（TKD）点突变在儿童急性髓系白血病（AML）中的临床意义。方法：通过实时定量PCR法对116名初诊AML儿童进行骨髓FLT3/ITD及FLT3/TKD突变检测,分析FLT3/ITD及FLT3/TKD突变与AML临床特征、疗效之间的关系。结果：116名患儿中,伴有FLT3/ITD及FLT3/TKD突变分别为9例（7.8%）、13例（11.2%）。3例AML-M3(3/9,33.3%)及3例AML-M5(3/9,33.3%)患儿出现FLT3/ITD突变;FLT3/TKD突变以AML-M3最多见（10/13,76.9%）。伴FLT3/ITD突变患儿较不伴该突变的患儿初诊时具有更高的白细胞及骨髓幼稚细胞比例（P<0.01）。伴FLT3/ITD突变患儿3年总生存率明显低于不伴该突变患儿（38.9% vs 64.3%,P<0.05）。结论：FLT3/TKD突变多见于儿童AML-M3患者;伴FLT3/ITD突变患儿初诊时具有更高的白细胞及骨髓幼稚细胞比例,且预后更差。     

儿童急性髓系白血病的疗效及预后相关因素分析

目的评价除急性早幼粒细胞白血病(APL)外的儿童急性髓系白血病(AML)的疗效并探讨其预后相关因素。方法 2000年-2013年间诊断的非APL的AML患儿61例,采用统一的治疗方案,分析其临床特征、诱导缓解情况、远期疗效及预后影响因素。结果(1)61例患儿中位随访时间36(1.1~186.2)个月,5年无事件生存率(EFS)为56.5%±7.1%,5年总生存率(OS)为69.6%±6.4%。(2)61例患儿分为低、中、高危组,5年OS率分别为72.7%±10.8%、74.1%±8.5%、42.9%±18.7%,两两相比差异无显著性(P0.05)。(3)单因素分析显示,初诊时存在髓外浸润、免疫表型CD56阳性患儿的远期疗效较差(P值分别为0.03和0.04)。1疗程获得缓解(CR)的患儿获得更高的OS值(P=0.03)。(4)多因素分析显示,初诊时存在髓外浸润、免疫表型CD56阳性、1年内复发、1疗程未获得CR是影响5年EFS的危险因素。(5)初诊时存在髓外浸润、1疗程未获得CR为复发的主要危险因素。结论非APL的儿童AML初诊时存在髓外浸润、免疫表型CD56阳性患儿预后较差,获得CR的疗程数是影响预后和复发的危险因素,降低复发是提高远期生存情况的关键。高危组患儿长期生存情况明显低于低、中危组患儿,应加强高危组患儿的化疗强度或早期行造血干细胞移植。     

急性白血病患儿中性粒细胞减少合并感染诊治分析

中性粒细胞减少症合并感染是儿童急性白血病(A L)化疗的主要并发症之一,尽管有效的抗感染药物、粒细胞集落刺激因子(G C SF)及其他支持疗法,大大降低了死亡率,但仍严重危害患儿的生命犤1～2犦。临床上大约30%的患儿可发现明确的病原体,主要是细菌、真菌和病毒。但大部分患儿找不到病原体,因此以经验用药为主。现对我院小儿血液科急性白血病(A L)患儿中,发生中性粒细胞减少合并感染353例次的诊治问题进行分析探讨如下。1对象及方法1.1对象自2003年1月～2004年12月共收治A L105例,其中急性淋巴细胞性白血病(A LL)82例,急性非淋巴细胞性…     

儿童急性髓细胞白血病WT1基因表达及其临床意义

目的研究急性髓细胞白血病(AML)患儿WT1基因表达情况及其与临床预后的关系。方法采用实时荧光定量PCR方法检测45例非M3儿童AML的WT1表达水平,并回顾性分析其与AML预后的关系。结果骨髓幼稚细胞比例60%的AML患儿WT1表达水平高于幼稚细胞≤60%的患儿(P0.05)。M2病例组初诊时WT1表达量低于非M2病例组(P0.05)。完全缓解组患儿的WT1表达量显著低于初诊组和复发组(P0.01)。诱导化疗结束时WT1高表达组的2年无病生存率(DFS)低于WT1低表达组(P0.05)。诱导化疗结束时WT1下降程度≥1个数量级病例组的2年总生存率(OS)和DFS高于WT1下降程度1个数量级病例组(P0.05)。AML患儿骨髓复发2~3个月前WT1表达呈上升趋势。结论 WT1表达水平与儿童AML预后密切相关,动态监测WT1表达在指导儿童AML个体化治疗、预后评估和复发预测方面具有重要临床应用价值。     

儿童急性髓系白血病163例临床分析

目的分析重庆医科大学附属儿童医院初诊急性髓系白血病（AML）患儿的临床资料,为进一步完善治疗方案提供依据。方法除外急性早幼粒细胞白血病,2008年1月-2012年12月共收治AML患儿163例,分析其临床资料。结果（1）以男性和5～10岁组患儿较多见;中位初诊年龄为5岁4个月,其中有18例患儿初诊年龄≤1岁。（2）骨髓MICM分型检查：FAB分型中以M2亚型最多见;免疫分型除139例患儿单纯表达髓系分化抗原表达以外,21例同时伴有淋巴系抗原表达,3例为未表型;细胞遗传学中异常核型的检出率为66％,以复杂核型最多见;26例患儿检测到AML1-ETO融合基因。（3）本研究治疗率55．2％,总诱导缓解率为87．8％,无诱导缓解化疗相关死亡患儿。（4）90例接受诱导缓解化疗患儿中位生存时间为13个月,中位无复发生存时间为9个月,其中43例接受2个疗程以上根治性缓解后化疗患儿中位生存时间为20个月,中位无复发生存时间为14个月。结论我院AML患儿治疗率仅为52．5％。还需要进一步完善AML患儿临床危险度分组以指导治疗,以中大剂量阿糖胞苷为主的化疗可改善预后。     

儿童急性髓系白血病靶向治疗进展

急性髓系白血病(AML)约占儿童急性白血病的15%~20%,虽然在危险度分级、分层化疗以及支持治疗等手段下AML的总体生存率较前升高,但是传统治疗下的临床疗效仍然有限,且在提高初治缓解率及减少缓解后复发方面存在局限性。近年来,随着精准医疗的不断发展,靶向治疗机制即包括AML相关信号通路的异常激活以及表观遗传修饰等研究不断深入,分子靶向药物可针对于特定的受体及目的基因等发挥作用,从而增加疗效和改善AML患者预后。     

儿童急性髓系白血病9P21区基因甲基化的研究

目的 研究9P21 区的CDKN2A 和CDKN2B 基因甲基化在儿童急性髓系白血病(AML)中的发生率及其与临床特征及预后的相关性.方法 回顾性分析2010 年4 月至2012 年12 月被诊断为AML 的58 例患儿的临床资料.选取38 例健康志愿儿童为对照组,采集两组儿童的骨髓或外周血,常规提取基因组DNA;应用甲基化特异性- 多重连接酶依赖性探针扩增法(MS-MLPA)检测CDKN2A 和CDKN2B 基因甲基化情况.结果 进行检测的健康儿童未发现基因甲基化.58 例患儿中,44 例检测到甲基化探针.CDKN2A 基因甲基化涉及136 bp 和237 bp 探针;CDKN2B 基因甲基化涉及130 bp、210 bp、220 bp 和417 bp 探针.CDKN2A 基因甲基化率仅为5%,而CDKN2B 基因甲基化率为76%.部分探针甲基化与初诊时的性别、血红蛋白和血小板水平有关.结论 儿童AML 患者CDKN2B 基因甲基化率较高,而CDKN2A 基因甲基化率较低.     

儿童急性淋巴细胞白血病中性粒细胞缺乏伴发热单中心血流感染病原菌分析

目的 分析儿童急性淋巴细胞白血病(ALL)化疗后中性粒细胞缺乏伴发热(FN)血流感染的临床特点、危险因素和病原菌分布。方法 回顾性分析2007年1月1日至2016年12月31日上海交通大学附属儿童医院血液肿瘤科收治的ALL化疗后发生FN住院患儿的临床资料和血培养结果,分析菌株的分布及药敏特点。结果 纳入ALL患儿312例,FN1 548例次,共送检1 700例次血培养,血培养阳性率7.5%(127/1 700),血流感染发生率8.2%(127/1 548),病死率9.4%(12/127)。血流感染革兰阳性菌51.1%(65/127),革兰阴性菌47.2%(60/127),真菌1.5%(2/127)。革兰阴性菌血流感染与革兰阳性菌血流感染比较,ANC<0.1×10⁹·L^-1的患儿占比(P=0.041)和感染性休克发生率更高(P=0.002)。2012~2016年铜绿假单胞菌构成比较2007~2011年增加(χ²=4.712,P=0.030)。ALL的危险程度分层IR/HR(OR=2.560,P=0.045)和ANC<0.1×10⁹·L^-1(OR=0.754,P=0.025)是血流感染发生的独立危险因素。结论 ALL患儿发生FN时血流感染病原菌阳性率较高(8.2%),以革兰阳性菌感染为主。在严重粒细胞缺乏时以革兰阴性菌血流感染为主,铜绿假单胞菌感染有增加趋势,合并感染性休克是FN死亡的独立危险因素。     

儿童Pre-B急性淋巴细胞白血病和急性髓系白血病特异遗传亚型

目的总结儿童急性白血病(AL)特异遗传亚型的发生率和特征,为评估预后提供依据。方法对365例AL患儿进行骨髓染色体核型检测分析白血病细胞的遗传学特点,荧光原位杂交(FISH)检测特异基因及相应位点拷贝数变异。结果 175例前体B急性淋巴细胞白血病(Pre-B ALL)和54例急性髓系白血病(AML)存在特异亚型。在Pre-B ALL中,高超二倍体最常见(33%),t(12;21)/ETV6-RUNX1、t(4;11)/MLL重排、t(9;22)、t(1;19)和iAMP21占比分别为22%、5%、3%、7%和1%。在AML中,MLL重排最常见(18%),其中t(9;11)型占56%;BCR/ABL阳性1例,FISH证实是隐匿核型ins(22;9);t(8;21)、t(15;17)和inv(16)分别占12%、15%和8%。倍体水平显示ALL高超二倍体和AML超二倍体获得染色体方式为非随机性。值得注意的是特异亚型中的变异型和不同附加异常,如额外融合,del(9p),del(12p),dup(1q)和非整倍体等畸变。结论儿童Pre-B ALL和AML中特异遗传亚型的发生率与西方儿童相似,揭示遗传异质性可能有助于预后研究。     

Expression of myeloid differentiation antigens in acute nonlymphocytic leukemia: Increased concentration of CD33 antigen predicts poor outcome—A report from the childrens cancer study group

Ninety-eight cryopreserved specimens of acute nonlymphocytic leukemia (ANLL) cells obtained at initial diagnosis of children enrolled on the Childrens Cancer Study Group 251 protocol (CCG 251) were examined by indirect immunofluorescence using four monoclonal antibodies to myeloid differentiation antigens. The relationship between the level of differentiation of ANLL cells as determined by their antigen phenotype and the clinical outcome of treatment, including complete remission (CR) rate, survival, and event-free survival, was evaluated. Most leukemic specimens were determined to express the CD33 antigen (L4F3), a 67-kD protein. Because the level of differentiation of normal myeloid cells is reflected by the concentration of the CD33 antigen expressed, samples were categorized as CD33-bright (immature) versus CD33-dull (mature). Patients with CD33-bright leukemic blasts had a marginally inferior CR rate to those with CD33-dull blasts (P = 0.08). With respect to survival and event-free survival, there was a significantly inferior outcome in the CD33-bright patients (P = 0.04 and P = 0.06, respectively). Reactions of ANLL with anti-CD15 antibody (1G10), anti-CD36 antibody (5F1), or anti-CD17 antibody (T5A7) did not predict clinical outcome. This study indicates that patients whose ANLL blasts displayed the CD33 antigen in an amount associated with immature myeloid cells experienced a worse outcome than patients with ANLL blasts that expressed a phenotype associated with more mature cells. © 1992 Wiley-Liss, Inc.     

儿童急性髓系白血病M2型性染色体缺失的预后意义

目的 探讨儿童急性髓系白血病(AML)M2型性染色体缺失与预后的关系.方法 根据细胞遗传学结果将106例AML患儿分为正常核型组(A组,n=26)、不伴性染色体缺失的非正常核型组(B组,n=52)和伴性染色体缺失的非正常核型组(C组,n=28),比较各组患儿预后差异.结果 A、B、C组5年无事件生存率(EFS)分别为38.9%±11.2%、59.3%±7.3%和66.5%±10.5%,其中C组明显高于A组(P=0.035);A、B、C组5年总生存率(OS)分别为54.3%±13.5%、68.1%±7.7%和77.9%±9.8%,三组间比较差异无统计学意义(P>0.05).发生t(8;21)易位的AML患儿58例,5年EFS率为63.3%±7.3%,明显高于正常核型患儿(P=0.015);C组中28例伴性染色体缺失的AML患儿均伴有t(8;21)易位,与不伴性染色体缺失的t(8;21)易位患儿相比,5年EFS率差异无统计学意义(P>0.05).结论 儿童AML M2型中性染色体缺失是预后好的染色体核型,该类型大多同时伴有t(8;21)易位;在伴有t(8;21)易位的患儿中,性染色体缺失并没有显示出更好的预后,推测性染色体缺失的非正常核型预后好可能与伴有t(8;21)易位有关.     

达沙替尼治疗对急性髓系白血病儿童身高的影响

目的 探讨达沙替尼治疗对急性髓系白血病（AML）儿童身高的影响。方法 回顾性分析86例17岁以下AML儿童的临床资料,按照患儿的治疗方案分为常规化疗组和达沙替尼组：常规化疗组应用常规化疗药物而不使用酪氨酸激酶抑制剂,共57例;达沙替尼组应用常规化疗药物并加用达沙替尼治疗,共29例。对两组患儿在治疗开始时、治疗后的身高标准差积分（HtSDS）以及治疗后1年、治疗后2年HtSDS变化进行比较。结果 常规化疗组及达沙替尼组在治疗前HtSDS的比较差异无统计学意义（P > 0.05）。达沙替尼组在治疗前两年内HtSDS变化与常规化疗组保持一致。随访时达沙替尼组共有4人达到成年终身高,均显著低于遗传靶身高（P=0.044）。常规化疗组中成年终身高与遗传靶身高差异无统计学意义。达沙替尼组中青春期儿童治疗后与治疗前的HtSDS相比较差异有统计学意义（P=0.032）。结论 达沙替尼治疗可影响AML儿童的终身高,青春期开始后应用达沙替尼会存在生长障碍,但治疗短期内对身高影响不大。     

SIRT1在急性髓系白血病患儿骨髓活检组织中的表达及临床意义

目的 了解SIRTl 在急性髓系白血病（AML）患儿骨髓活检组织中的表达水平,并分析其与AML 预后的相关性。方法 回顾性分析2009 年7 月至2012 年4 月确诊为AML 并于初诊时行骨髓活检检查的54 例患儿的临床资料。采用免疫组织化学染色方法检测患儿骨髓活检组织中SIRTl 的表达;根据SIRT1 的表达情况将病例分为SIRT1 阴性组（n=10）和SIRT1 阳性组（n=44）,再根据SIRT1 表达的阳性程度进一步将SIRT1 阳性组分为（+）组（n=8）、（2+）组（n=7）和（3+）组（n=29）,比较各组患儿的预后。Cox 多因素回归分析患儿长期生存的危险因素。结果 SIRT1（3+）组病死率明显高于SIRT1 阴性组（PPPP=0.045,危险系数绝对值=2.071,95%CI：1.017~4.219）。结论 部分AML患儿骨髓活检组织存在SIRTl表达增高情况,且SIRTl高表达与不良预后相关。