LATE CARDIAC DAMAGE OF ANTHRACYCLINE THERAPY FOR ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDHOOD

Long-termleukemia survivors (46) underwent cardiac evaluation, including physical examination, ECG, exercise testing, and echocardiography. They were 2-17 years old at diagnosis and 5-23 years old aftertreatment. Thirty-four survivors received anthracyclines (AC) (mean 203 mg/m2), 12 of them had also alkylating agents (AA) and 12 had no AC. Exercise tolerance was bellow predicted valuesin 21 (48%) survivors and 21 survivors had ECG abnormalities, which were more frequent in those treated with AC. Concomitant AC with AA was correlated with prolonged isovolumic relaxation time (IVRT) and influenced significantly the volume of left atrium (p = .02). Sixteen (52%) survivors had IVRT 90 ms. There were no significant differences in other parameters of diastolic orsystolic function. Despite the lack of clinical symptoms in the survivors treated with lower doses of AC, subtile abnormalities in myocardial function were found, mainly manifest as abnormal diastolic function. Prolonged IVRT may be a sensitive indicator for early detection of AC cardiotoxicity.     

Late cardiac effects of anthracycline containing therapy for childhood acute lymphoblastic leukemia

BACKGROUND: At present about 80% of children with acute lymphoblastic leukemia (ALL) will be cured following treatment with multi-drug chemotherapy. A major concern for this growing number of survivors is the risk of late effects of treatment. The aim of this study was to determine whether signs of cardiomyopathy were present in patients treated in childhood with cumulative anthracycline doses of less than 300 mg/m(2). PROCEDURE: Evaluation of cardiac function in a cohort of 63 long-term survivors in first continuous remission following treatment of ALL with multi-drug chemotherapy including anthracyclines was performed using standard M-mode echocardiography and tissue doppler imaging (TDI). Associations between age at diagnosis, cumulative dose of anthracycline, sex, length of follow-up, and deviations from normal values in M-mode echocardiograms were evaluated using univariate and multivariate regression analysis. TDI data were compared to normal values using Wilcoxon matched-pairs signed-ranks test. RESULTS: By standard M-mode echocardiography the most significant findings were diastolic dilation of the left ventricle, thinner interventricular septum (IVS), decreased left ventricular mass (LVM) in females, follow-up dependent dilation of the left ventricle in systole and follow-up dependent decrease in ejection fraction (EF). TDI abnormalities included signs of early diastolic dysfunction and myocardial hypertrophy, and were also found in structures that appeared normal by M-mode echocardiography. CONCLUSIONS: This study adds to the growing evidence that even low to moderate doses of anthracyclines might lead to progressive cardiac dysfunction. It is important that children treated with anthracyclines receive life long follow-up for signs of cardiomyopathy.     

Prognostic factors in childhood acute lymphoblastic leukemia

Approximately 80% of children and adolsecents with acute lymphoblastic leukemia (ALL) can be cured. To reduce the rate of relapses, but also to limit treatment toxicity, risk-adapted treatment has been attempted after identifying the most specific prognostic factors. In addition to clinical factors such as age and WBC, or factors of the leukemic cell such as the immunphenotype and the cytogenetics, thein vivo response to therapy has evolved as the most important predictor for relapse. The lack of specificity of most prognostic factors stimulated the search for more relevant parameters. Detection of residual disease at defined timepoints by cytomorphology can provide specific prognostic information, which allows to define new risk groups. Detection of minimal residual disease (MRD) by identifying clone-specific T-cell receptor-(TCR) or immunglobuline (Ig) gene rearrangements is currently being evaluated to extend this approach of testing the individual’s sucsceptibility to therapy. The high sensitivity of the method when indicating fast clearance of leukemia might eventually spare some patients of inadequately toxic therapy. Persistent disease is an indication for treatment modification and intensification. If standardized tools are used for treatment response evaluation, logistics and quality controls are demanding but essential for the reliable conduct of such clinical studies.     

儿童急性T淋巴细胞白血病微小残留病检测的临床意义

目的：探讨急性T淋巴细胞白血病（T-ALL）患儿微小残留病（MRD）监测的临床指导价值。方法采用多参数流式细胞术对2006年1月1日-2008年12月31日在北京儿童医院治疗的60例T-ALL患儿在治疗不同时间点进行追踪监测,分析不同MRD水平患儿的临床特征及预后。结果诱导治疗第33 d MRD≥1×10-4组患儿易复发,P＝0.03;诱导治疗第33 d MRD＜1×10-4组患儿预计5年无事件生存率（EFS）为100％,而MRD≥1×10-4组患儿5年EFS为（62.5±7.1）％,两组之间差异有显著性（P＝0.018）。结论监测T-ALL患儿MRD水平在评估早期治疗反应、监测复发以及估计预后中具有重要临床价值。     

ALL-2005方案治疗儿童T系急性淋巴细胞白血病35例疗效总结

目的研究ALL-2005方案治疗儿童T系急性淋巴细胞白血病(T-ALL)的疗效。方法对2005年5月-2009年4月初发的35例T-ALL患儿采用ALL-2005方案进行分层治疗及疗效分析。结果 T-ALL患儿35例,男30例(86%),女5例(14%),发病时中位年龄8.3(2.0～15.6)岁。其中>10岁患儿14例,占40%。起病时外周血白细胞≥50×109/L者24例,占69%,起病时6例患儿有纵隔增宽。泼尼松治疗第8天时泼尼松试验反应好者22例(63%)。诱导治疗第35天有29例获完全缓解(83%),骨髓微小残留病(MRD)≤0.01%者共20例(67%)。治疗第55天时MRD≤0.01%共26例(87%)。4例复发,3例失访,6例死亡(包括3例复发和3例第1疗程未缓解而放弃治疗者)。随访至2011年6月31日,中位随访时间39(1～71)个月,5年无事件生存率为73.5%。结论 ALL-2005方案治疗儿童T-ALL疗效较好。     

Initial P-glycoprotein expression in childhood acute lymphoblastic leukemia: no evidence of prognostic impact in follow-up

Treatment results in childhood acute lymphoblastic leukemia (ALL) have improved remarkably during the past 20 years, but still 25% of children cannot be permanently cured. Drug resistance is a major cause of poor outcome. One of the most investigated resistance mechanisms is the P-glycoprotein (P-gp)-mediated multiple-drug resistance (MDR). The authors prospectively analyzed P-gp using flow cytometry with monoclonal antibody JSB1 in a population-based series of 103 children with ALL treated according to intensive Nordic ALL protocols. Increased P-gp expression was detected in 55 patients (53%). With a cutoff value of 1% P-gp-positive blasts in bone marrow, no difference was found in event-free survival (EFS) or overall survival between children with low vs. increased P-gp expression. The 4-year EFS in the whole series was 77%. Patients with T-ALL had higher P-gp levels than the others, 3.6% vs. 1.0% (p = .002). P-gp expression did not correlate with the white blood cell count, age, sex, or cytogenetics. The authors conclude that the level of P-gp expression cannot be used as a tool for treatment stratification in childhood ALL.     

Bim基因内含子缺失多态性在儿童急性淋巴细胞白血病治疗中的临床意义

目的探讨Bim基因内含子缺失多态性在儿童急性淋巴细胞白血病糖皮质激素治疗中的临床意义。方法提取入组110例缓解期儿童急性淋巴细胞白血病患儿骨髓液并提取基因组DNA,采用PCR方法特异性扩增基因组DNA检测,是否存在Bim基因内含子2序列缺失并行Sanger测序鉴定。分析Bim基因内含子缺失与泼尼松反应和远期预后之间的关系。结果 110例患儿中,共有17例存在Bim内含子2的部分序列缺失,占15.4%,其5年无事件生存率为68.0%(SE=0.122),与无序列缺失患儿(5年EFS为69.6%,SE=0.048)无明显差异(P=0.940);单因素分析提示泼尼松敏感试验与Bim缺失多态无相关性(P=0.451),与患儿年龄、性别、免疫表型、化疗第35天微小残留病(MRD)、诊断时外周血白细胞数也无显著统计学差异(P值分别为0.224、0.784、1.000、0.716、0.604),但是与儿童急性淋巴细胞白血病危险度分组相关(P=0.046)。结论Bim基因内含子缺失多态性与ALL患儿糖皮质激素耐药和远期预后无显著相关性。     

Prognostic cytogenetic markers in childhood acute lymphoblastic leukemia

Objective To evaluate children with acute lymphoblastic leukemia (ALL) showing resistance to immediate induction chemotherapy in relation to conventional and advanced cytogenetic analysis. Methods This work was conducted on 63 ALL children (40 males and 23 females) with age range 4.5 months–16 years (mean = 7.76 years). They included 37 cases attained true remission and 26 complicated by failure of remission, early relapse or death. They were subjected to history, clinical examination and investigations including CBC, BM examination, karyotyping, FISH for translocations and flowcytometry for immunophenotyping and minimal residual disease diagnosis. Results Cases aged < 5 years; male sex with organomegaly had better remission although statistically insignificant. Initially low HB < 8 gm/dl, high WBCs and platelet counts > 50.000/mm³ also showed better but non-significant remission rates. Most of the present cases were L₂ with better remission compared to other immunophenotypes. Forty informative karyotypes were subdivided into 15 hypodiploid, 10 pseudodiploid, 8 normal diploid and 7 hyperdiploid cases; the best remission rates were noticed among the most frequent ploidy patterns. Chromosomes 9, 11 and 22 were the most frequently involved by structural aberrations followed by chromosomes 5, 12 and 17. Resistance was noted with aberrations not encountered among remission group; deletions involving chromosomes 2p, 3q, 10p and 12q; translocations involving chromosome 5; trisomies of chromosomes 16 and 21; monosomies of 5 and X and inversions of 5 and 11. Conclusion Some cytogenetic and molecular characterizations of childhood ALL could add prognostic criteria for proper therapy allocation.     

The combined analysis of P-glycoprotein expression and activity predicts outcome in childhood acute lymphoblastic leukemia

The link between drug resistance and relapse was often suggested, but rarely demonstrated in long-range clinical studies. Since it is nowadays recommended to validate immunocytochemical results, the authors studied prospectively 52 acute lymphoblastic leukemia (ALL) patients with an immunocytochemical test and a functional flow cytometric test. The 4-year EFS and OS were 79.3% and 85.2%, respectively. Patients scoring positive in both tests had a significantly higher relapse rate and worse survival (log rank p = .007 and .047 for event-free survival and overall survival, respectively). Among the different prognostic variables evaluated, only the combination of P-gp expression and activity was a statistically significant parameter predicting relapse in childhood ALL.     

The late consequences of anthracycline treatment on left ventricular function after treatment for childhood cancer

The purpose of this study was to determine the incidence of changes in left ventricular function in patients in long-term remission after treatment with anthracyclines for a childhood malignancy. The authors examined 155 patients in disease remission who underwent treatment protocols utilising anthracyclines in childhood. The group comprised 90 males and 65 females aged 15±4.9 years (range 5–29 years, median 15 years). The age at the time of diagnosis and start of treatment was 8.6±4.9 years (range 1–18 years, median 8 years). The time of follow-up was 7.3±4 years (range 1–21 years, median 6.3 years). The patients were given a cumulative dose of doxorubicin or daunorubicin of 250±131 mg/m² (range 50–1200 mg/m², median 240 mg/m²). The values of ejection fraction below 55% and fractional shortening below 30% assessed by means of echocardiography were considered as pathological. The control group consisted of 41 volunteers. Pathological values of fractional shortening were found in 12 patients (8%). Only one patient (0.64%) showed the development of heart failure due to cardiomyopathy. The group of the patients after chemotherapy revealed significantly worse values of left ventricular endsystolic wall stress, mean velocity of circumferential fibre shortening, Tei index, and isovolumic relaxation period in comparison with the control group. We found a correlation between the given cumulative dose of anthracyclines and indicators of systolic function of the left ventricle, but not a relation to the time indicators (age at diagnosis, time of follow-up). Conclusion:in the mean period of 6 years after chemotherapy, subclinical cardiotoxicity was found in 11 patients (7%) and cardiomyopathy with heart failure in one patient. Further indicators of subclinical damage are elevation of afterload (end-systolic stress), impaired relaxation and increased value of the Doppler index of global left ventricular function. Further monitoring and evaluation of the relevant subclinical abnormalities over a longer period of time are needed.Abbreviations CD cumulative dose - DT deceleration time - E/A index of the diastolic filling of the left ventricle - EF ejection fraction - ESS end-systolic stress - FS fractional shortening - HR heart rate - IRT isovolumic relaxation time - LV left ventricle - LVPWDd end-diastolic diameter of the left ventricular posterior wall - LVPWex excursion of the left ventricular posterior wall - LVPWP percentage of the systolic thickening of the left ventricular posterior wall - MPI myocardial performance index - mVcf _c mean velocity of circumferential fibre shortening     

儿童急性淋巴细胞白血病184例分析

目的分析2001-2010年在本院住院的初发急性淋巴细胞白血病(ALL)患儿的病历资料,为儿童ALL的防治提供参考依据。方法回顾性分析184例初发ALL患儿的临床资料。结果初发ALL患儿年就诊例数由2001年的8例上升到2010年的28例,平均年增长率为13.3%。男女性别比例为1.75∶1。儿童初发ALL的年龄分布以2～7岁组最多,起病时临床表现各不相同,其中T-ALL 33例(17.9%),伴有髓系抗原表达2例;B-ALL 151例(82.1%),伴有髓系抗原表达11例。染色体异常47例(47/156),融合基因异常9例(9/20)。发病季节上差异无显著性。184例中92例接受治疗,化疗缓解率96.7%。化疗后合并感染率38.8%。结论本院初发儿童ALL的就诊病例数呈逐年上升趋势,加强儿童白血病的防治尤其重要。提高白血病患儿的治疗依从性,亦是目前应高度重视和亟待解决的问题。     

端粒酶活性与儿童急性淋巴细胞白血病相关性的研究

目的了解端粒酶在儿童急性淋巴细胞白血病中的表达情况。方法采用端粒重复序列扩增法（ＴＲＡＰ）检测了１４例儿童急性淋巴细胞白血病骨髓单个核细胞端粒酶活性水平，并与１０例正常健康儿童外周血和骨髓单个核细胞端粒酶活性相比较。结果白血病细胞端粒酶活性显著升高，可高达Ｋ５６２白血病细胞端粒酶活性的７５％～９８％，而正常外周血和骨髓单个核细胞具有适度低水平的酶活性，其相对活性为Ｋ５６２细胞的１．３％～５．７％。结论端粒酶的激活在急性淋巴细胞白血病的发生发展中可能具有重要作用。     

小儿急性淋巴细胞白血病微量残留病检测的临床研究

目的　探讨小儿急性淋巴细胞白血病 (ALL)微量残留病 (MRD)检测的临床意义 ,进一步了解ALL复发与缓解的生物学特点。方法　分析近 10年来有MRD检测资料的 77例初治ALL ,对其中 4 4例进行动态追踪检测MRD。主要采用聚合酶链反应 (PCR)方法 ,以免疫球蛋白重链和T细胞受体δ基因重排作为肿瘤标志。结果　初治标本PCR检测MRD阳性者和阴性者的复发率差异无显著性意义 (P >0 0 5 )。化疗 3个月时PCR检测转阴的病例复发率明显低于未转阴的病例 (P <0 0 5 ) ,且与临床分型无明显相关性。结论　MRD的动态检测可以作为小儿ALL判断预后的独立因素。PCR法动态监测MRD ,有助于完善白血病分型、判断预后和指导治疗。     

Cardiac failure 30 years after treatment containing anthracycline for childhood acute lymphoblastic leukemia

In 1977, a 5-year-old girl diagnosed with acute lymphoblastic leukemia was treated on Dana-Farber Cancer Institute Childhood Acute Lymphoblastic Leukemia Protocol 77-01, receiving a cumulative doxorubicin dose of 465 mg/m(2), cranial radiation, and other drugs. After being in continuous complete remission for 34 months, she developed heart failure and was treated with digoxin and furosemide. At 16 years of age, she was diagnosed and treated for dilated cardiomyopathy. Over the years, she continued to have bouts of heart failure, which became less responsive to treatment. At 36 years of age, she received a heart transplant. Six months later, she stopped taking her medications and suffered a sudden cardiac death.     

小儿急性淋细胞白血病P16蛋白表达的研究

目的 探讨Ｐ１６蛋白表达异常在小儿急性淋巴细胞白血病（ＡＬＬ）发病中的意义。方法 应用免疫细胞化学ＳＴ法检测了５２例初治ＡＬＬ、２０例正常对照小儿的Ｐ１６蛋白的表达。结果 初治ＡＬＬ中的Ｐ１６蛋白表达阳性率为４２％,明显低于正常对照组（９５％）（Ｐ〈０．０１）。正常对照Ｐ１６蛋白弱阳性表达占８０％。在ＡＬＬ阳性表达中,强阳性占７３％（１６／２２）,弱阳性占５％（１／２２）。Ｔ系与Ｂ系ＡＬＬ中Ｐ１     

MRD监测对儿童B系急性淋巴细胞性白血病疗效评估的意义

目的：研究监测微小残留白血病(MRD)在B系急性淋巴细胞白血病（ALL）患儿治疗中的作用。方法：回顾性研究了2001年9月1日至2005年4月31日,采用ALL-XH-99方案治疗的B系ALL患儿中进行MRD监测的患儿共124例。用四色多参数流式细胞仪监测ALL患儿治疗过程中不同时间点的MRD。结果：在124例进行过MRD监测的B系ALL患儿中,其中MRD<0.01%、0.01%~0.1%和>0.1%的分别有103例、13例和8例,其5年无复发生存率（RFS）分别为（88.9±3.9）%、（70.0±14.5）%和0%,而5年无事生存率（EFS）分别为（82.4±4.4）%、（21.2±18.0）%和0%,两者均P<0.01;将首次CR后半年内MRD检查分成阴性（<0.01％）和阳性两组,其5年RFS分别为（87.7±4.1）%和（58.3±14.2）%,（P<0.01）;5年EFS分别为（80.7±4.6）%和（25.6±13.8）%（P<0.01）;首次CR后半年以后MRD检查阴性和阳性两组的5年RFS分别为（92.0±3.6）%和（48.5±15.5）%（P<0.01）。多因素分析显示结果显示诱导缓解后MRD、泼尼松诱导窗口反应、第19天骨髓象是否达M-1级骨髓象和是否检出BCR-ABL或MLL-AF4融合基因对患儿治疗过程中是否发生复发有预后价值（P<0．05)。结论： 在B系ALL患儿治疗过程中,无论在诱导缓解达到CR时,还是在随后的治疗过程中,监测MRD水平对于评估ALL患儿疗效有重要意义。     

Follow-up of minimal residual disease in acute childhood lymphoblastic leukemia by WT1 gene expression in the peripheral blood: the Hungarian experience

The aim of the study was to investigate if monitoring WT1 gene expression in the peripheral blood is an appropriate approach to monitor the progression of childhood acute lymphoblastic leukemia (ALL). Forty-six patients have been enrolled into this study (24 ALL and 22 control, nonleukemic cases). The peripheral blood was tested for WT1 gene expression using a sensitive nested RT-PCR technique. The assay was sensitive enough to detect 10 2 leukemic cells among 10 6 normal leukocytes. In agreement with the literature 96% of childhood ALL (23/24) expressed WT1 independent of the prognostic factors of the disease. On the other hand, no WT1 gene expression was found in the peripheral blood of nonleukemic hematological diseases, except myelodysplasia. WT1 became negative in the peripheral blood of these patients at the end of the induction phase of the therapy in the majority of the cases (19/24), whereas clinical remission was achieved in all patients except one. WT1 gene expression changes in the peripheral blood was monthly monitored in 20 ALL patients for 1 year and in 16 cases during the second year (for a maximum of 21 months). Although continuous monitoring detected transient (1- to 3-month long) WT1 expression in the majority of the ALL cases (16/20), clinical relapse occurred in 2 cases only when the WT1 expression was maintained for 11-15 months. Follow up studies of the WT1 gene expression in the peripheral blood of WT1-positive childhood ALL may enable researchers to monitor MRD and detect a very low leukemic cell count (perhaps called "molecular relapse"). According to this study, the transient WT1 positivity for 1-3 months does not predict clinical relapse of childhood ALL, unlike a longer-lasting positivity.     

Superior treatment results in females with high-risk acute lymphoblastic leukemia in childhood

In this population-based study, 808 children aged 1-15 years from Denmark, Finland, Iceland, Norway and Sweden, were diagnosed between July 1981 and June 1986 as suffering from non-B-cell acute lymphoblastic leukemia (ALL). The total population was 4.5 million children. Remission was achieved in 770/808 of the patients (95%). No sex difference in the remission rate was observed. The event free survival (EFS) at 102 months was 0.47 for males and 0.62 for females (p less than 0.001). There was no difference in EFS between males and females with standard-risk (0.58 and 0.60) or intermediate-risk (0.47 and 0.60) ALL, respectively. The EFS for females with high-risk ALL (0.68) was superior to that of males with high-risk ALL (0.31). Cox multivariant analysis showed that white blood cell count, sex, age and thrombocyte count were significant prognostic factors in all children. The intensified treatment according to the prognostic factors used in this study led to equal EFS for females with ALL from all risk groups. Males with high-risk ALL, however, did not benefit from the intensified treatment.     

Antithrombin supplementation III in childhood acute lymphoblastic leukemia treated with L-asparaginase

The change of plasma antithrombin III (AT) levels after supplementation of AT concentrates was examined in ALL children with acquired AT deficiency following L-asparaginase (ASP) administration. The patients received AT concentrates of 34.5 ±7.6 U/kg. The increase of plasma AT activity and antigen was 2.07 ±0.62% and 0.70 ±0.16 mg/dL per unit AT infused per kilogram of body weight, respectively. The activity decreased to 62.0 ±7.7% of the peak values by 48 hours after supplementation. The administration of AT concentrates constantly increased the plasma AT activity in ALL children treated with ASP, which may minimize the acquired prothrombotic state.     

急性淋巴细胞白血病患儿糖皮质激素预试验的临床意义

目的 探讨儿童急性淋巴细胞白血病进行糖皮质激素预试验的临床意义以及与预后的关系.方法 对309例急性淋巴细胞白血病患儿应用糖皮质激素预试验治疗7d,根据第8天外周血幼稚细胞动态变化分为激素敏感组(PGR组)263例及激素不敏感组(PPR组)46例,分析两组患儿临床特征及治疗转归.结果 PGR组与PPR组初诊白细胞计数分别为30.97×109/L及86.30×109/L,PGR组低于PPR组(P＜0.01).B系白血病患儿激素敏感率高于T系患儿,分别为86.6％及60.0％ (P ＜0.05).初诊高危、中位、标危组对激素敏感率分别为51.4％、82.7％、93.7％,不同的初诊危险度对激素敏感性各不相同(P ＜0.0125);两组间染色体表达情况差异无统计学意义(P＞0.05);BCR-ABL融合基因阳性者更易对激素不敏感(P＜0.05),而MLL、TEL-AML1、E2A-PBX1融合基因阳性率两组间差异无统计学意义(P＞0.05).治疗第15天(D15)、第33天(D33)复查骨髓,PGR组缓解率为60.5％、94.6％,PPR组缓解率为32.6％、73.3％,PGR组均高于PPR组(P均＜0.01);D33、第12周(W12)检查微小残留病(MRD)水平,达10-4者PGR组为75.9％、85.0％,PPR组为44.7％、66.7％,两组间差异均有统计学意义(D33:P＜0.01,W12:P＜0.05).随访结果:达持续缓解(CCR)者PGR组215例,PPR组28例,PGR组CCR率明显高于PPR组(P＜0.01).结论 糖皮质激素预试验与多项临床特征及疗效相关,是评估儿童急性淋巴细胞白血病预后的一项重要指标.