Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia

Context  Early response to multiagent chemotherapy, including mercaptopurine, as measured by minimal residual disease is an important prognostic factor for children with acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (TPMT) is involved in the metabolism of mercaptopurine and subject to genetic polymorphism, with heterozygous individuals having intermediate and homozygous mutant individuals having very low TPMT activity. Objective  To assess the association of TPMT genotype with minimal residual disease load before and after treatment with mercaptopurine in the early treatment course of childhood ALL. Design, Setting, and Patients  TPMT genotyping of childhood ALL patients (n = 814) in Germany consecutively enrolled in the ALL-BFM (Berlin-Frankfurt-Münster) 2000 study from October 1999 to September 2002. Minimal residual disease was analyzed on treatment days 33 and 78 for risk-adapted treatment stratification. A 4-week cycle of mercaptopurine was administered between these 2 minimal residual disease measurements. Patients (n = 4) homozygous for a mutant TPMT allele, and consequently deficient in TPMT activity, were treated with reduced doses of mercaptopurine and, therefore, not included in the analyses. Main Outcome Measures  Minimal residual disease load before (day 33) and after (day 78) mercaptopurine treatment. Loads smaller than 10^–4 were defined as negative. Results  Patients (n = 55) heterozygous for allelic variants of TPMT conferring lower enzyme activity had a significantly lower rate of minimal residual disease positivity (9.1%) compared with patients (n = 755) with homozygous wild-type alleles (22.8%) on day 78 (P = .02). This translated into a 2.9-fold reduction in risk for patients with wild-type heterozygous alleles (relative risk, 0.34; 95% confidence interval, 0.13-0.86). Conclusions  TPMT genotype has a substantial impact on minimal residual disease after administration of mercaptopurine in the early course of childhood ALL, most likely through modulation of mercaptopurine dose intensity. Our findings support a role for minimal residual disease analyses in the assessment of genotype-phenotype associations in multiagent chemotherapeutic trials.      

Concordant childhood acute lymphoblastic leukemia in monozygotic twins

Two 4-year-old monozygotic Chinese, female twins developed concordant childhood acute lymphoblastic leukemia (ALL) within an interval of about 2 weeks. Based on morphology and cytochemistry findings of the bone marrow blast cells, a diagnosis of ALL, L1 was made. Immunophenotyping showed the blast cells of both twins expressed similar antigens, i.e. HLA-DR, CD10, CD13, CD19, CD22 and CD34. Identical blood group, same HLA (human leucocyte antigen) genotype, sex and similar appearance suggest that the twins are monozygotic. Since the bone marrow leukemic cells of both twins were identical in morphology and expressed the same antigens with almost similar percentages of positivity, it is likely that the blast cells were derived from the same single clone. Based on the single clone hypothesis, the leukemogenic event must have arisen in utero in one twin and the cells from the abnormal clone then spread to the other twin via shared placental anastomoses.     

Bone marrow Th2 cytokine expression as predictor for relapse in childhood acute lymphoblastic leukemia (ALL)

The immunological environment of leukemic blasts in the bone marrow might play a decisive role in determining an individual's risk for relapse. In order to identify potential predictors of relapse and to elucidate the mechanisms of immune control of leukemic blasts we examined the expression of cytokines, costimulatory molecules and members of the TNF family in leukemic marrow samples in a prospective study. Samples from 49 consecutive pediatric patients with B cell precursor acute lymphocytic leukemia (BCP ALL) were analyzed by semiquantitative RT-PCR. We identified interleukin (IL)-10 expression as a significant adverse prognostic indicator in childhood BCP-ALL. The event free survival (EFS) of patients expressing IL-10 mRNA in high quantity was significantly lower compared with patients expressing low IL-10 mRNA. Taqman RT-PCR of sorted cell populations showed that IL-10 mRNA was synthetized almost exclusively by NK or T cells. In addition, we found an increased expression of IL-1, IL-4, CD86 and VEGF mRNA in patients with late relapses. Possibly, ALL cells mediate a Th2 shift through increased expression of CD86 and thereby influence the individual relapse risk. These findings emphasize the role of the immune system for the outcome of childhood ALL.     

儿童急性淋巴细胞白血病危险因素的病例对照分析

目的:探索儿童急性淋巴细胞性白血病(ALL)发生的危险因素,为该地区儿童ALL的防治提供依据。方法:采用病例对照的流行病学研究方法,对233例ALL患者及380例健康对照进行问卷调查,资料处理采用EPIDATA3.02录入,SPSS13.0统计分析,通过Logistic回归模型进行单因素和多因素分析,计算比值比(OR),估计各危险因素与儿童ALL的关联强度。结果:所调查的因素中共筛选出8项与ALL发病有关的危险因素,其中5项(是否与父母共同居住、是否早产、儿童杀虫剂接触史、儿童父母亲是否吸烟、家庭是否装修)在多因素回归仍有显著意义。结论:儿童急性淋巴细胞性白血病的发生是多种因素共同作用的结果,在当地针对上述因素进行预防可降低儿童ALL发生的危险性。     

Rational use of methotrexate in maintenance therapy of childhood acute lymphoblastic leukemia.

This study was undertaken to research the pharmacokinetics and bioavailability of methotrexate (MTX). Plasma concentrations were measured by fluorescent spectrometry in 20 normal SD rats, and 28 measurements were done in children with acute lymphoblastic leukemia (ALL). Both rats and children were divided into four groups. Either 20 mg/m2 or 40 mg/m2 of MTX was given IV or PO in each group. The plasma MTX concentrations were measured within 8 hours after administration. The concentration versus time curves were fitted by MCPKP program for pharmacokinetics (PK) and the parameters calculated. After PO administration, the peak concentration, duration of therapeutic concentration and bioavailability were much lower than that after IV administration. The differences were more obvious at 40 mg/m2 dosage. The higher the PO dosage, the lower the bioavailability. Absorption of PO MTX in children with ALL varied widely and uniform concentration was not expected even after equal dosage. Drug concentration was not necessarily increased with dosage. It is our conclusion that drug concentrations and PK parameters should be measured in patients receiving PO MTX therapy.

     

动态观察端粒酶活性在儿童急性淋巴细胞白血病预后判断中的意义

目的 :研究儿童急性淋巴细胞白血病 (ALL)的治疗及其相关预后因素。　方法 :以多药联合化疗方案进行诱导缓解和缓解后治疗 ,以诱导治疗第 1 4天的骨髓原始淋巴细胞比例作为治疗反应敏感性指标 ,以端粒重复序列扩增 银染色技术检测端粒酶活性作为微小残留白血病指标。　结果 :90 % (1 9/ 2 1 )的儿童ALL获完全缓解(CR)。在中位随访时间 5 5 (1 2～ 1 2 0 )个月内 ,6例复发 ,7例已连续完全缓解 (CCR) 2 4～ 5 4个月 ,现仍在连续治疗中 ;6例已停止治疗 1 8～ 6 0个月。全组患儿 5年无复发生存率为 6 5 .5 %。诱导治疗第 1 4天骨髓检查分级为M1(原始细胞为 <5 % )、M2 (原始细胞 5 %～ 2 5 % )和M3 (原始细胞 >2 5 % )型者分别为 6 7%、1 4 %和 1 9%。 1 4例M1 型ALL的 5年无复发生存率明显高于 7例M2 和M3 型 (分别为 84 .6 %和 1 5 .8% ,P <0 .0 1 )。在CR后端粒酶持续阳性或在治疗期间由阴性转为阳性的ALL复发率明显增加。　结论 :诱导治疗第 1 4天骨髓检查结果是判断ALL长期存活的重要预后因素 ;不同治疗阶段检测骨髓细胞端粒酶活性可作为微小残留白血病指标     

Serum lactate dehydrogenase as a prognostic marker of childhood acute lymphoblastic leukemia

The estimation of serum lactate dehydrogenase (LDH) is easy, readily available and economic. We can assume the prognosis of childhood acute lymphoblastic leukemia (ALL) through this measurement. This case control prospective study was aimed to evaluate that the level of serum LDH has the prognostic marker of childhood ALL. The study was carried out in the Paediatric Haematology and Oncology unit, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, during the period from January to December 2006 on 69 subjects with age ranging from birth to 15 years irrespective of sex. The study subjects were grouped into case (ALL-44) and control (healthy-25). Serum LDH level were performed in ALL patients on admission, day 14 and day 29 of induction and in healthy control when came for check up and found healthy. Haematological parameters were performed in ALL patients and in healthy control along with the measurement of serum LDH. On admission the level of serum LDH was significantly raised in ALL patients than healthy control (p<0.001). After induction, serum LDH level were significantly decreased at day 14 and day 29 of induction from admission (p<0.001). There was significant rise of platelet count were observed at day 29 of induction from admission (p<0.001). A significant decrease of peripheral and bone marrow blast cell percentages were observed at day 29 of induction from admission (p<0.001). The total WBC count was significantly decreased along with serum LDH at day 14 and day 29 of induction from admission (p<0.001). So, the measurement of serum LDH can be accepted as a good and reliable prognostic marker of childhood acute lymphoblastic leukemia.     

米托蒽醌为主的联合方案初治儿童急性淋巴细胞性白血病的疗效分析

急性白血病是儿童最常见的恶性肿瘤性疾病,其中急性淋巴细胞性白血病(急淋)占急性白血病70％左右,联合化疗仍是目前治疗儿童急淋最主要的治疗方法,常采用以柔红霉素(DNR)为主的联合化疗方案,但DNR心脏毒性大,白血病复发率偏高,米托蒽醌(MTZ)作为一种全合成的葸醌类化疗药物,对白血病细胞的作用机制类似于葸环类的DNR,但其细胞毒作用更强、而心脏毒性较DNR小,以MTZ为主的联合化疗方案既往多用于难治复发性白血病,近年来报道将其应用于成人初治急性白血病的治疗取得较好的效果,但在儿童初治急性白血病治疗中应用甚少。我院儿科从1997年7月～2003年4月,应用MTZ为主的联合化疗方案初治儿童急性淋巴细胞性白血病76例,与目前通用的DNR为主方案相比,获得更好的临床效果,现报告如下。     

培门冬酶与左旋门冬酰胺酶在儿童急性淋巴细胞白血病诱导化疗中的毒副作用和疗效分析

目的比较培门冬酶与左旋门冬酰胺酶在儿童急性淋巴细胞白血病诱导化疗中的毒副作用和临床疗效。方法将2010年10月-2012年1月我院100例儿童急性淋巴细胞白血病患者随机分成两组各50例,对照组使用培门冬酶治疗,观察组采用左旋门冬酰胺酶治疗,治疗结束后比较两组患者的毒副作用和临床疗效。结果两组完全缓解率、总有效率、不良反应情况无统计学差异（P〉0.05）;观察组用药次数和住院时间明显多于对照组,差异有统计学意义（P〈0.05）。结论培门冬酶与左旋门冬酰胺酶诱导化疗儿童急性淋巴细胞白血病均有较好疗效,但培门冬酶用药次数和住院时间明显缩短,需在临床应用时加以注意。     

Malnutrition, measles, mortality, and the humanitarian response during a famine in Ehiopia

CONTEXT: The World Food Programme estimated that 10 million people were at risk of starvation in Ethiopia in 2000 but later reported that a famine had been averted. However, no population-based data on mortality or nutrition existed for Gode district, at the epicenter of the famine in the Somali region of Ethiopia. OBJECTIVES: To estimate mortality rates, determine the major causes of death, and estimate the prevalence of malnutrition among children and adults for the population of Gode district. DESIGN AND SETTING: Two-stage cluster survey conducted from July 27 through August 1, 2000, which included anthropometric measures and 8-month retrospective mortality data collection. PARTICIPANTS: A total of 595 households comprising 4032 people living in Gode district of Ethiopia. MAIN OUTCOME MEASURES: Crude mortality rates and mortality rates for children younger than 5 years, causes of death, weight for height of less than -2 z scores among children aged 6 months to 5 years, and body mass index of less than 18.5 kg/m(2) among adults and older persons. RESULTS: Of the 595 households, 346 (58.2%) were displaced from their usual places of residence. From December 1999 through July 2000, a total of 293 deaths occurred in the sample population; 159 (54.3%) deaths were among children younger than 5 years and 72 (24.6%) were among children aged 5 to 14 years. The crude mortality rate was 3.2/10 000 per day (95% confidence interval [CI], 2.4-3.8/10 000 per day), which is 3 times the cutoff used to define an emergency. The mortality rate for children younger than 5 years was 6.8/10 000 per day (95% CI, 5.4-8.2/10 000 per day). Approximately 77% of deaths occurred before major relief interventions began in April/May 2000. Wasting contributed to 72.3% of all deaths among children younger than 5 years. Measles alone or in combination with wasting accounted for 35 (22.0%) of 159 deaths among children younger than 5 years and for 12 (16.7%) of 72 deaths among children aged 5 to 14 years. The prevalence rate for wasting (weight for height of <-2 z score) among children aged 6 months to 5 years was 29.1% (95% CI, 24.7%-33.4%). Using a method to adjust body mass index for body shape, the prevalence of undernutrition (body mass index <18.5 kg/m(2)) among adults aged 18 to 59 years was 22.7% (95% CI, 17.9%-27.5%). CONCLUSIONS: To prevent unnecessary deaths, the humanitarian response to famine needs to be rapid, well coordinated, and based on sound epidemiological evidence. Public health interventions, such as mass measles vaccination campaigns with coverage extended to children aged 12 to 15 years should be implemented as the first priority. The prevalence of wasting and undernutrition among children and adults, respectively, should be assessed in all prolonged, severe famines.     

Survival variability by race and ethnicity in childhood acute lymphoblastic leukemia

Context  The role of race/ethnicity in survival of children with acute lymphoblastic leukemia (ALL) is unclear, with some studies reporting poorer survival among minority children and others reporting equivalent survival across race/ethnicity in the modern, risk-stratified treatment era. Objective  To investigate the relation between race/ethnicity and survival in a large, population-based analysis of incident ALL cases in the United States. Design, Population, and Setting  This study included 4952 individuals diagnosed with ALL between 1973 and 1999 at age 19 years or younger. ALL cases were identified from 9 population-based registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Main Outcome Measures  Survival probabilities were compared among white, black, Hispanic, Asian/Pacific Islander, and American Indian/Alaskan Native children. Kaplan-Meier curves and proportional hazard ratios from Cox regression analysis were calculated, accounting for treatment era (1973-1982, 1983-1989, and 1990-1999), age at diagnosis (<1, 1-9, and 10-19 years), and sex. Results  Although overall 5-year survival probabilities improved with each successive treatment era, differences according to race/ethnicity persisted. For 1990-1999, 5-year survival was 84% for white children, 81% for Asian/Pacific Islander children, 75% for black children, and 72% for both American Indian/Alaskan Native children and Hispanic children. The largest difference by race/ethnicity was observed among children diagnosed between ages 1 and 9 years. Compared with white children, after adjusting for treatment era, age at diagnosis, and sex, children of black, Hispanic, and American Indian/Alaskan Native descent had hazard ratios of 1.50 (95% CI, 1.0-2.2; P = .03), 1.83 (95% CI, 1.4-2.4; P<.001), and 1.90 (95% CI, 0.8-4.6; P = .16). Conclusions  Black, Hispanic, and American Indian/Alaskan Native children with ALL have worse survival than white and Asian/Pacific Islander children, even in the contemporary treatment era. Future work must delineate the social and biological factors, including any differences in pharmacokinetics associated with chemotherapeutic agents, that account for disparities in outcome.      

定期骨髓象观察指导急性淋巴细胞白血病诱导缓解治疗

目的评价定期骨髓象检查对急淋诱导化疗的指导意义。方法对引例初治成人急淋患音，于诱导化疗首疗程期间定时作骨髓象观察，用这两个时限的骨髓白血病细胞比率及／或白血病细胞减少指数指导化疗。结果本组完全缓解（CR）率82.4%（42/51），其中首疗程CR率60.8%（31／51）。结论诱导化疗期定时骨髓象观察指导化疗有助于提高急淋CR率及首疗程CR率。     

急性淋巴细胞白血病治疗后并发脑白质病1例

1 临床资料患者,男,22岁.2009年7月24日以"急性淋巴细胞白血病"入院.给予VDLP(长春新碱+柔红霉素+门冬酰胺酶+强的松)方案化疗1疗程,行骨髓穿刺达到血液学完全缓解(complete remission,CR),之后给予原方案巩固1疗程,并给予大剂量甲氨蝶呤(HD-MTX)、EA、VDCP等方案化疗5疗程,其中HD-MTX共计3疗程,MTX总量12 g.     

儿童急性淋巴细胞白血病beclin-1的表达及意义

目的:探讨自噬基因beclin-1在儿童急性淋巴细胞白血病(ALL)患者外周血白细胞的表达及意义。方法:选取儿童急性淋巴细胞白血病患者39例,体检正常儿童40例作为对照,收集患者及正常对照外周血标本,分离白细胞,用免疫组化和免疫印迹法检测beclin-1表达,分析比较患者与对照组beclin-1蛋白表达差异。结果:ALL患儿外周血白细胞beclin-1表达阳性率48.7%(19/39),低于正常对照组82.5%(33/40)(P<0.005),Western blot显示患儿阳性标本表达量亦低于对照阳性标本。标危组表达率(59.3%)高于高危组(25.0%),B-ALL与T-ALL的beclin-1表达率差异无显著性(P<0.05)。结论:beclin-1表达率及表达量在ALL患儿外周血白细胞中明显低于正常对照;beclin-1表达率与诊断时免疫学分型无明显关系,标危组表达率高于高危组。beclin-1可能与儿童ALL发生发展相关。