Discontinuing chemoimmunotherapy in childhood acute lymphoblastic leukemia

We examined the results of discontinuing therapy in Japanese children with acute lymphoblastic leukemia. Of the 209 patients in chemoimmunotherapy study, 120 (57.4%) had all chemotherapy stopped after 3 years of complete remission, and 72 (34.4%) reached the point of discontinuing immunotherapy after 5 years of complete remission. Of the 120 children removed from chemotherapy, 14 (11.7%) have relapsed, mainly in the extramedullary sites (5 testis, 5 bone marrow, 3 central nervous system, 1 bone); relapses occurred 1-23 months after cessation of chemotherapy (median 11 months). Boys had a higher post-chemotherapy relapse rate than girls (0.21 vs. 0.08, P less than 0.05). None of the 72 children removed from immunotherapy have yet relapsed. Long-term remission and possibly cure can be expected in approximately one half of newly-diagnosed Japanese patients. Moreover, the active immunotherapy could be of benefit to elimination of bone marrow relapses after cessation of chemotherapy in children with acute lymphoblastic leukemia.     

儿童急性淋巴细胞白血病细胞遗传学特征分析

目的 分析儿童急性淋巴细胞白血病(ALL)细胞遗传学变化的特点.方法 以2009年1月至2011年11月确诊的90例初发ALL患儿为研究对象,采用染色体核型分析及荧光原位杂交(FISH)技术检测患者骨髓白血病细胞的细胞遗传学和分子生物学变化.结果 ①染色体核型分析:有分裂象者66例,其中异常者35例(53.0%);无分裂象者24例.②FISH检测:对31例染色体核型正常和24例无分裂象的患者进行FISH检测,异常者分别为7例(占22.6%)和14例(58.3%),其中无分裂象患者异常检出率与有分裂象者核型分析异常检出率差异无统计学意义(P=0.655);55例患儿中TEL-AML1融合基因阳性16例(29.1%),MLL重排3例(5.5%),bcr-abl融合基因阳性2例(3.6%).③90例患儿通过两种检则方法 共检出细胞遗传学异常56例(占62.2%).结论 儿童ALL易出现细胞遗传学改变;对于有足够分裂象的患者,常规染色体核型分析仍是可靠的方法,对分裂象质量低或无分裂象的儿童ALL患者,FISH检测异常克隆能提高细胞遗传学异常检出率.     

儿童急性淋巴细胞白血病复发的研究进展

儿童急性淋巴细胞白血病(ALL)的治愈率不断提升,而复发成为ALL诊疗的瓶颈。本文从发病机理、危险分层、治疗进展三方面回顾分析了近十年关于儿童急性淋巴细胞白血病复发的文献。发现部分基因组异常和耐药性相关,成为ALL复发的主要原因之一。早期复发较晚期复发预后要差,且检测微小残留白血病对复发有独立预测作用。治疗手段从化疗和造血干细胞移植发展到分子靶向治疗、细胞治疗和免疫治疗新的层次。所以,正确认识ALL复发的发病机理、依据危险程度分层次进行综合治疗是ALL复发目前诊疗的趋势。     

起病时有肾脏增大的儿童急性淋巴细胞白血病的临床资料分析

目的总结起病时有肾脏增大表现患儿的急性淋巴细胞白血病（ALL）临床特点,并与起病时无肾脏增大表现的患儿进行临床资料及预后比较。 方法回顾性分析2010年至2019年北京大学第一医院儿科血液肿瘤专业病房（以下简称“我科”）收治的未经过任何治疗的初诊ALL患儿的临床资料及随访结果,将所有患儿根据初诊时治疗前的超声肾脏测量值分为初诊时有肾脏增大（肾脏超声长径≥同年龄儿童2倍标准差,肾脏增大起病组）及无肾脏增大表现（非肾脏增大起病组）2组并进行比较。 结果自2010年至2019年,我科收治确诊的初治ALL患儿规律治疗共69例,诊断时中位年龄4岁,起病时有肾脏增大共14例（20%）,其中,单侧肾脏增大3例,双侧肾脏增大11例。中位随访时间112个月。与非肾脏增大起病组相比,肾脏增大起病组患儿年龄偏小［（79.9±48.0）月龄vs（37.1±21.9）月龄,P＜0.05］;2组在性别构成、起病距确诊的时间、危险度分层、起病时髓外白血病侵犯情况、形态学完全缓解时间、无事件生存（EFS）时间方面,差异均无统计学意义（P＞0.05）。尽管2组患儿的肌酐及尿素水平差异无统计学意义（P＞0.05）,但考虑到2组患儿的年龄差异,认为肾脏增大起病组患儿的肾功能差于非肾脏增大起病组,但肾功能异常在治疗后均可恢复。E2A-PBX1融合基因阳性率在肾脏增大起病组患儿中占比高于非肾脏增大起病组（28.57% vs 5.36%,P＜0.05）。 结论初诊ALL患儿中起病时有肾脏增大表现的患儿比例高于既往文献报道,提示该现象较为普遍,起病时有肾脏增大的患儿年龄偏小。随着分层治疗的进一步优化,肾脏增大的患儿总体预后与起病时无肾脏增大的患儿相同,然而仍然要注意在初期治疗过程中注意肾功能的保护。     

儿童急性淋巴细胞白血病骨髓细胞增殖活力与预后观察研究

目的 检测儿童急性淋巴细胞白血病细胞增殖性抗原表达情况,观察其与预后的关系。方法 用流式细胞仪结合仪细胞增殖性抗原ＣＤ７１,Ｋｉ－６７和增殖细胞核抗原（ＰＣＮＡ）检测１２名正常儿童和３５例急性淋巴细胞白血病（ＡＬＬ）患儿骨髓细胞的表达率、观察８治疗前后增殖指数（ＬＩ）的变化及其与预后的关系。     

Association of muscle strength and bone mineral density in adult survivors of childhood acute lymphoblastic leukemia

Joyce ED, Nolan VG, Ness KK, Ferry RJ Jr, Robison LL, Pui C-H, Hudson MM, Kaste SC. Association of muscle strength and bone mineral density in adult survivors of childhood acute lymphoblastic leukemia.

Objectives

To investigate the association between bone mineral density (BMD) and muscle strength in survivors of childhood acute lymphoblastic leukemia (ALL), a population at increased risk for both decreased BMD and muscle strength from cancer and its treatment.

Design

Cohort data from the St Jude Lifetime Cohort (SJLIFE) study.

Setting

Department of Cancer Control at St Jude Children's Research Hospital.

Participants

Subjects were adults enrolled in St Jude Lifetime Cohort study and treated for childhood ALL between 1962 and 1999. As part of a comprehensive evaluation, participants had dual energy x-ray absorptiometry (DEXA) scans and muscle strength testing. The participants consisted of 261 women and 232 men who were 20.4 to 49.8 years old (median, 35.7y), and 12.7 to 46.5 years from diagnosis of childhood ALL (median, 27.2y).

Interventions

Not applicable.

Main Outcome Measures

BMD was determined by DEXA scan. Muscle strength of upper and lower extremities was assessed with physical performance testing.

Results

After adjusting for covariates, we found significant (P<0.005) associations between BMD and muscle strength in lower extremities (R² range, 0.33–0.40) and strong, significant associations in upper extremities (left-side R²=0.558; right-side R²=0.560).

Conclusions

Muscle strength was associated with BMD in the extremities of long-term survivors of childhood ALL, a finding suggesting that muscle strengthening interventions may improve bone health in them.     

儿童急性淋巴细胞白血病分子标志及临床应用的研究进展

儿童急性淋巴细胞白血病（ALL）的现代分型策略及治疗模式是，首先在初诊时，将形态学-免疫学-细胞遗传学-分子生物学（即MICM）检测结果与一些临床指征相结合，将患儿初步划分为高危、中危和低危三级危险度。在此基础上，进行基本相同的早期治疗（包括泼尼松试验治疗和诱导缓解治疗）。     

miRNA表达与儿童急性淋巴细胞白血病预后及复发的相关性研究

目的 筛选儿童急性淋巴细胞白血病(ALL)相关的microRNA(miRNA),研究miRNA的表达与ALL复发以及预后是否相关,寻找判断复发以及预后的新指标.方法 采用基因芯片技术分析49例初诊ALL患儿和作为对照组的12例原发免疫性血小板减少症(ITP)患儿的miRNA表达谱,实时定量RT-PCR方法验证异常的miRNA表达.分析miRNA表达与预后相关指标、泼尼松早期反应以及1年内是否复发的相关性.结果 miRNA表达谱在儿童ALL中有特异的表达模式,且与泼尼松治疗反应和早期复发存在相关关系;8个特异表达水平的miRNA(miR-18a、miR-532、miR-218、miR-625、miR-193a、miR-638、miR-550和miR-633)能幕本区分泼尼松治疗试验敏感与不敏感的患者.而早期复发的患儿无论初诊时临床分型属高危或非高危,均有一些相同特征的miRNA异常表达,其中miR-7、miR-216和let-7i表达上调,miR-486、miR-191、miR-150、miR-487和miR-342表达下调.结论 在儿童ALL中异常的miRNA表达谱提示miRNA在白血病发生中起重要作用,其表达信息可能为更准确地评估儿童ALL的预后、更合理的分型治疗以及复发前进行临床早期干预提供依据.

Abstract：

Objective To screen childhood ALL related microRNAs ( miRNAs), analyze association of miRNAs expression profiles with prognosis and relapse in childhood acute lymphoblastic leukemia (ALL) and explore new indicator for predicting relapse and prognosis. Methods miRNAs expression profile was analyzed by gene chip in 49 newly diagnosed childhood ALL and 12 primary immune thrombocytopenia (ITP) cases( as control group). Abnormal expression of miRNAs was verified by qRT-PCR. The correlation of miRNAs expression pattern with indicators predicting early prednisone response and relapse within a year was analyzed. Results Specific expression of miRNAs profiles associated with prednisone response and early relapse in childhood ALL was identified. Eight miRNAs ( miR-18a, miR-532, miR-218, miR-625, miR-193a, miR-638, miR-550 and miR-633 ) could distinguish prednisone sensitive from insensitive. The early relapse of newly diagnosed patients with either high-risk or non-high-risk clinical types had some characteristics of abnormal expression of miRNAs, including miR-7, miR-216 and let-7i upregulated, while miR-486, miR-191, miR-150,miR-487 and miR-342 downregulated. Conclusions The initial screening reveals miRNAs differentially expressed from normal in ALL suggesting the potential roles of them in leukemogenesis. MiRNAs expression signatures may be useful for predicting prognosis and relapse in childhood ALL and directing personalized treatment.     

血药浓度监测在大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病中的应用

目的探讨大剂量甲氨蝶呤（MTX）治疗儿童急性淋巴细胞白血病（ALL）中排泄延迟与MTX剂量的关系。方法 30例103例次ALL患儿采用大剂量MTX治疗〔按MTX剂量分为A组（2～3 g/m2）组和B组（3.1～5 g/m2）组〕,后1、24、36、42、48、54、96 h进行药物浓度检测,根据血药浓度调整四氢叶酸钙（CF）解救次数及剂量,比较其不同时段血药浓度的分布及排泄延迟的发生率、不良反应及CF的用量。结果①B组较A组MTX稳态血药浓度（24 h血药浓度）高,两组在24 h内浓度下降幅度明显,而24 h以后个体差异很大。两组1 h及24 h血药浓度差异有统计学意义（P〈0.05）,36～96 h差异无统计学意义（P〉0.05）;②103例次血浆MTX浓度监测显示,61.2%的患儿48 h血浆MTX浓度〈0.25μmol/L,75.8%的患儿〈0.5μmol/L,仅12.6%的患儿≥1μmol/L;约65.8%的患儿CF解救次数不超过3次,需解救6～8次的为11.9%,1.5%的患儿需解救超过8次;③有排泄延迟的患儿骨髓抑制、消化道症状、黏膜损害及感染较无排泄延迟时增加（P〈0.05）,CF解救剂量明显增加（P〈0.05）。A组和B组排泄延迟发生率分别为4%和20.8%,两组比较差异有统计学意义（P〈0.05）。结论在血药浓度监测下使用大剂量MTX安全可行。大剂量较低剂量稳态血药浓度高,但更易出现排泄延迟。大剂量MTX排泄延迟情况下不良反应增加,CF用量增加。MTX个体化用药可以减少排泄延迟的发生。     

Expression profiling of ATP-binding cassette transporters in childhood T-cell acute lymphoblastic leukemia

A major issue in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) is resistance to chemotherapeutic drugs. Multidrug resistance can be caused by ATP-binding cassette (ABC) transporters. The majority of these proteins have not yet been examined in T-ALL. Using a newly developed microarray for the simultaneous quantification of 38 ABC transporter genes, we observed a consistent overexpression of ABCA2/ABCA3 in clinical samples of ALL. Therefore, we analyzed the association of these two genes with drug resistance. Treatment of CCRF-CEM and Jurkat cells with methotrexate, vinblastine, or doxorubicin led to an induction of ABCA3 expression, whereas a significant increase of ABCA2 expression was only observed in Jurkat cells. To study the causal relationship of ABCA2/A3 overexpression with drug resistance, we applied RNA interference (RNAi) technology. RNAi specific for ABCA2 or ABCA3 led to a partial decrease of expression in these two ABC transporters. Upon cotreatment of RNAi for ABCA2 with methotrexate and vinblastine, a partial decrease of ABCA2 expression as well as a simultaneous increase of ABCA3 expression was observed. Vice versa, ABCA3 RNAi plus drugs decreased ABCA3 and increased ABCA2 expression. This indicates that down-regulation of one ABC transporter was compensated by the up-regulation of the other. Application of RNAi for both ABCA2 and ABCA3 resulted in a more efficient reduction of the expression of both transporters. As a consequence, a significant sensitization of cells to cytostatic drugs was achieved. In conclusion, ABCA2 and ABCA3 are expressed in many T-ALL and contribute to drug resistance.     

225例儿童急性淋巴细胞白血病临床疗效的回顾性分析

目的 回顾性分析初治儿童急性淋巴细胞白血病(ALL)化疗疗效.方法 将入选的225例儿童ALL患者(2003年1月至2006年12月)根据细胞形态学、免疫学、细胞遗传学和分子遗传学(MICM)进行危险分组.标危组患者按传统方案治疗;高危组患者的治疗采用大剂量甲氨蝶呤(每次5 g/m2),并早期加用中剂量阿糖胞苷(每次1 g/m2,每12 h 1次,共3 d)强化.维持治疗采用MM+VP(甲氨蝶呤、6-巯基嘌呤、长春新碱、泼尼松).结果 ①225例患儿3、5年总体生存(OS)率分别为79.0%、72.6%.②标危组3年预期0s率(87.6%)显著高于高危组(66.1%)(P=0.002).结论 ①早期采用中剂量阿糖胞苷强化治疗和大剂量甲氨蝶呤进行庇护所治疗,可显著提高高危患儿的疗效,明显提高儿童ALL的长期无病生存率.②高危组采用早期强化疗,加大甲氨蝶呤剂量后中枢神经系统白血病发生率减低.③标危组患儿进行定期强化和增加再诱导次数可显著提高长期生存率.     

儿童B-急性淋巴细胞白血病治疗中微量残留病动态监测及其意义

目的评价微量残留病(MRD)监测在儿童B-急性淋巴细胞白血病(B-ALL)治疗中的预后价值。方法2001年9月1日至2004年10月31日采用ALL-XH-99方案行MRD标记筛选并监测的B-ALL患儿102例。用四色多参数流式细胞仪监测诱导治疗结束完全缓解(CR)时、髓外白血病预防性治疗前、早期强化前、维持治疗中定期强化前、维持治疗1年及2年时患儿。MRD 。结果①行筛选并监测的102例B-ALL患儿中,对诱导治疗结束获CR的86例患儿进行了MRD监测。其中MRD ≥10~(-4)的患儿20例,占23．30％;MRD<10~(-4)的患儿66例,占76．70％,其39个月无事件生存率分别为 0．00％和(83．00±9．90)％,差异有统计学意义(P<0．01)。②单因素分析显示患儿的性别、起病时年龄、白细胞计数及染色体倍体数与CR时MRD水平无关(P>0．05);而Ph染色体、诱导治疗第19天骨髓幼稚淋巴细胞比例、CR时间、ALL-XH-99危险度分类标准与其相关(P<0．05)。③多因素分析显示 CR时MRD水平具有独立的预后价值(比例风险为5．381,95％可信区间为0．004-0．624,P<0．05)。结论诱导治疗结束CR时MRD水平可用于评估早期治疗反应,是儿童B-ALL治疗中重要的预后因素之一。     

儿童T系急性淋巴细胞白血病的临床研究

目的 研究T系急性淋巴细胞白血病(ALL)患儿的临床与预后特征.方法 对1999年1月至2005年4月采用ALL-XH-99方案治疗的305例ALL患儿进行细胞形态学、免疫学、细胞遗传学和分子遗传学分型,并按型分层治疗.结果 在305例ALL患儿中T系ALL患儿43例,其中男34例(79.1%),平均年龄7.8(2.2～16.4)岁,大于10岁的患儿29例(67.4%),中危和高危组患儿分别为11例和32例,WBC≥50×109/L 27例(62.8%),骨髓形态学分型L2 32例,22例患儿出现纵隔增宽.与B系ALL患儿比较,T系ALL患儿在骨髓形态学分型L2比例、大于10岁患儿的比例和WBC≥50×109/L的比例差异均有统计学意义(P<0.05).在诱导缓解治疗中,T系ALL患儿泼尼松窗口试验反应好和第19天骨髓未达缓解的比例分别为62.9%和57.9%,与B系ALL患儿比较,差异均有统计学意义(P值均<0.01).有14例T系ALL患儿复发,完全缓解至复发时间为(1.2±1.5)年.T系ALL患儿的8年无事件生存(EFS)率、无复发生存(RFS)率和总生存(OS)率分别为(40.2±10.1)%、(51.4±11.6)%和(49.8±9.9)%,而B系ALL患儿的8年EFS率、RFS率和OS率分别为(72.1±3.0)%、(83.2±2.7)%和(76.6±2.9)%(P值均<0.01).结论 T系ALL患儿在年龄、白细胞计数和骨髓形态学分型上和B系ALL患儿存在差异,早期治疗反应以及远期疗效较B系ALL患儿差.     

黄芪注射液对急性淋巴细胞白血病患儿诱导缓解化疗期间感染的影响

目的分析黄芪注射液对急性淋巴细胞白血病(ALL)患儿诱导缓解化疗期间感染的影响。方法选取ALL患儿100例,将其随机分为观察组和对照组各50例,2组患儿均应用诱导缓解化疗方案治疗,观察组患儿同时加用黄芪注射液静脉滴注,对2组患儿化疗期间的医院感染发生率、发生部位及化疗前、后外周血白细胞(WBC)和中性粒细胞(NE)计数进行观察和比较。结果观察组患儿化疗期间感染的总发生率显著低于对照组,观察组中各危险度分型患儿的感染发生率亦显著低于对照组中的同种分型患儿(χ~2=13.000、4.250、3.895、5.106,P0.05),观察组患儿化疗期间呼吸道、泌尿道、皮肤软组织感染的发生率显著高于对照组(χ~2=11.602、4.960、6.112,P0.05),化疗后观察组中各危险度分型患儿的外周血NE计数均显著高于对照组中的同种分型患儿(t=5.265、3.795、4.286,P0.05)。结论在ALL患儿的诱导缓解化疗期间,加用黄芪注射液能够缓解患儿的骨髓抑制,降低ALL患儿的感染发生率。     

Endocrinologic function following cranial irradiation in acute lymphoblastic leukemia in childhood]

Endocrinological function was evaluated in 31 children after successful treatment of acute lymphoblastic leukaemia. All patients had received combination chemotherapy and 12-24Gy of cranial irradiation according to the German therapy protocols BFM-81, BFM-83 and BFM-86. Height, weight, bone age and pubertal development, as well as hypothalamic-pituitary function were measured. Long-term linear growth was unaffected in all patients. However, 9 patients showed subnormal serum growth hormone levels in response to pharmacological stimulation of the pituitary. All patients had normal levels of T3 and T4, but one patient showed an increased response of thyrotropin to thyrotropin releasing hormone. All prepubertal and postpubertal children demonstrated appropriate secretion of follicle-stimulation hormone (FSH) and luteinizing hormone (LH) after stimulation with LH-releasing hormone (LH-RH). 3 pubertal girls showed adequate oestradiol levels, but abnormally high levels of gonadotropins in response to LH-RH. Sexual development was normal in two of them, but the third had a late menarche and irregular menses. The significance of these findings is discussed in the context of recommendations possibly to further reduce or completely delete prophylactic cranial irradiation.