急性淋巴细胞白血病患儿亚甲基四氢叶酸还原酶基因多态性与大剂量甲氨蝶呤不良反应的相关性

目的探讨急性淋巴细胞白血病(ALL)患儿亚甲基四氢叶酸还原酶(MTHFR)基因677位点多态性与大剂量甲氨蝶呤(HDMTX)体内排泄及不良反应的相关性。方法 2008年3月-2010年2月在本院儿科中心和血液内科住院的完全缓解并接受HDMTX治疗的40例ALL患儿,在接受HDMTX治疗前应用PCR-限制性酶切片段长度多态性(RFLP)技术检测MTHFR基因C677T多态性,在HDMTX静脉输注开始后24 h、48 h应用荧光偏振免疫法(FPIA)测定其血浆MTX水平,密切观察ALL患儿HDMTX化疗后的不良反应,对化疗不良反应进行分级。对MTHFR677的基因多态性与MTX不良反应及HDMTX 48 h的MTX水平(MTX-48 h)的相关性进行分析。结果在有HDMTX相关不良反应的ALL患儿中,肝损害和骨髓抑制发生率最高。MTHFR C677T有肝脏损害的基因型分布频率由低到高为CC型40.0%,TT型60.0%,CT型80.0%,CT基因型者肝脏损害发生的风险是CC基因型者的6倍(OR=6.00,95%CI:1.05～34.32,P=0.044);677CT+TT基因型者肝脏损害发生的风险是CC基因型者的4.13倍(OR=4.13,95%CI:1.02～16.67,P=0.047)。MTHFR C677T基因型与骨髓抑制无明显相关性。携有MTHFR突变基因型(CT+TT)患者的48 hMTX血药质量浓度明显高于携带MTHFR野生型基因CC者(P=0.006)。结论 MTHFR 677位基因型可作为ALL患儿HDMTX化疗不良反应和药物体内排泄的有效预测指标。     

Maintenance Treatment With Low‐Dose Mercaptopurine in Combination With Allopurinol in Children With Acute Lymphoblastic Leukemia and Mercaptopurine‐Induced Pancreatitis

Mercaptopurine (6‐mercaptopurine, 6MP) is a mainstay of curative therapy in childhood acute lymphoblastic leukemia (ALL), and contributes to its 90% overall survival rate. We present two patients with ALL who suffered with severe pancreatitis secondary to 6MP. Through the use of allopurinol in conjunction with reduced dose 6MP, we were able to continue 6MP without further pancreatitis. This report contributes to the small body of literature on 6MP associated pancreatitis in childhood ALL and describes a novel approach to continued use of 6MP during therapy.     

Association of -24CT, 1249GA,and 3972CT ABCC2 Gene Polymorphisms with Methotrexate Serum Levels and Toxic Side Effects in Children with Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia patients after being treated with methotrexate, have differences in methotrexate serum levels and toxic side effects. One of the main determinants of these toxic side effects is the host pharmacogenetics. The aim of this study was to evaluate the association of -24CT, 1249GA, and 3972CT ABCC2 gene polymorphisms with serum levels, and toxic side effects of methotrexate in childhood acute lymphoblastic leukemia. Applying polymerase chain reaction and restriction fragment length polymorphism techniques, the prevalence of -24CT, 1249GA, and 3972CT ABCC2 gene polymorphisms was evaluated in 65 acute lymphoblastic leukemia patients. The relationship between polymorphisms and methotrexate serum levels and toxicities was studied. A reverse significant relationship was detected between 3972T allele carriers and hepatotoxicity (P = 0.01, OR = 0.25, 95% CI = 0.09–0.72). Also, 1249A allele carriers had increased rate of gastrointestinal toxicity (P = 0.05, OR = 3.47, 95% CI = 1.04–11.57). No significant relationship was detected between -24CT polymorphism and methotrexate toxic side effects. There was no significant relationship between these three polymorphisms and methotrexate serum levels. Genotyping for 3972CT and 1249GA ABCC2 gene variants maybe useful in acute lymphoblastic leukemia to optimize methotrexate therapy and reducing the associated toxicity.     

大剂量甲氨蝶呤治疗急性淋巴细胞白血病

目的探讨大剂量甲氨蝶呤(HD-MTX)治疗急性淋巴细胞白血病(ALL)在基层医院的可行性。方法对8例ALL患儿进行56次HD-MTX治疗,MTX剂量3 g/m2,同时水化碱化4 d,滴注MTX 36 h后开始四氢叶酸钙解救,首剂30 mg/m2,以后15mg/m2,1次/6 h,共8次。并观察其不良反应及疗效。结果接受HD-MTX治疗8例中,出现骨髓抑制(26/56次)占46.4%,消化道反应(24/56次)占42.9%,肝功能损害(13/56次)占23.2%,黏膜损害(12/56次)占21.4%,感染(5/56次)占8.93%,皮疹(3/56次)占5.36%,心脏损害(2/56次)占3.57%,出现肺弥漫性间质性浸润影、头痛各1例。主要不良反应发生率与HD-MTX疗程前后差异无显著性。随访8例ALL,仅1例发生中枢神经系统白血病(CNSL),该例为高危儿,发生时间为骨髓缓解(CR)后12个月。结论在基层医院不具备MTX监测及层流室条件下,只要在化疗前准备工作完善,水化碱化合理,四氢叶酸钙解救及时,HD-MTX治疗仍是安全可行的。     

Growth in Children Treated for Acute Lymphoblastic Leukemia with and without Prophylactic Cranial Irradiation

ABSTRACT. Growth and weight gain were studied longitudinally over a period of four years in thirty-nine children treated for acute lymphoblastic leukemia. The children were divided into two groups according to treatment. Twenty-eight children were given prophylactic cranial irradiation and eleven children were treated without such irradiation. The duration of cytostatic treatment was three years in all cases. Average growth during the first two years was similar in the two groups, and the standard deviation scores (SDS) were below average. The rate of growth (in height) during the fourth year was significantly higher among those children who had not received cranial irradiation ( p <0.01). After four years the average attained height had declined 0.5 SD for children treated with cranial irradiation and 0.2 SD for children without such treatment. Weight velocity was significantly greater than the expected mean in the non-irradiated group during the first year and in the irradiated group during the fourth year of the study. Attained weight after four years had increased 0.4 SD more among those children who had not received irradiation. The results suggest that prophylactic cranial irradiation is responsible for the greater part of the prepubertal growth inhibition in these children.     

High Incidence of Hypertension in Children Presenting with Acute Lymphoblastic Leukemia

Although hypertension is a complication of acute lymphoblastic leukemia (ALL), its true incidence in this disease is unknown. In this study the blood pressure profiles in all children newly diagnosed with ALL were reviewed over an 18-month period. Fourteen (46%) from a total of 30 patients were found to be hypertensive at presentation (n= 8) or during induction chemotherapy (n= 6). A patient with significant hypertension developed generalized convulsions; the rest were asymptomatic. Six patients were managed with antihypertensive drugs. Four patients with hypertension had renal enlargement on the initial ultrasound scan, which returned to normal when hematologic remission was achieved. One patient without hypertension had bilateral renal enlargement, but this persisted despite achieving remission. All patients with hypertension were nomotelwive at follow-up 2 to 18 months after induction chemotherapy. The presence of hypertension before therapy and its association with renal enlargement suggest that the leukmic process is an important etiologic factor. In all cases therapy aggravated or unmasked the elevation in blood pressure. Considering the high incidence of susceptible patients, increased awareness and prompt management may avoid possible life-threatening complications.     

Subnormal Growth During Puberty in Children Treated for Acute Lymphoblastic Leukemia

Growth was studied longitudinally in 19 children who were long-term survivors after acute lymphoblastic leukemia (ALL). Of the children, 13 were girls; 6 were boys. They had all undergone a 3-year cytostatic treatment period which included vincristine, adriamycin, asparaginase, methotrexate, purinethol, and prednisone. Prophylactic cerebral irradiation (20-24 Gy) had been given to all children; 4 of them had also been given irradiation to the spine (10 Gy). The pattern of growth was nearly identical in girls and boys. Growth in relation to the therapy was almost normal, whereas growth during puberty was subnormal and final height was 1.3 SD less than expected at onset of disease. The growth pattern was the same for children with cerebrospinal irradiation as for those with cerebral irradiation. In view of the present results and previous studies on growth hormone (GH) secretion after cerebral irradiation, we suggest that treatment with luteinizing hormone releasing hormone (LHRH) or GH could be considered at puberty for children who have been treated for ALL, including cerebral irradiation, and who have a poor prognosis for final height.     

Influence of Treatment Modalities on Prepubertal Growth in Children with Acute Lymphoblastic Leukemia

The statural growth of 85 prepubertal children treated for acute lymphoblastic leukemia was evaluated in a longitudinal study over 4.5 years. Patients were divided into three groups according to central nervous system prophylaxis: 37 patients received cranial irradiation with a dose of 24 Gy, 15 received a dose of 18 Gy, and 33 were not irradiated. According to the risk of leukemia, patients were divided into normal-risk (n = 74) and high-risk (n = 11) groups. The duration of treatment was 2 years, during which all patients showed growth retardation. The relative standard deviation score for height declined from 0 to -0.7 for the irradiated patients and from 0 to -0.2 for the non-irradiated group (P = 0.0001). There was no difference in growth pattern between cranial irradiation with 18 versus 24 Gy and chemotherapeutic treatment according to high-risk versus normal-risk protocols. However, a negative synergistic effect of more intensive chemotherapy and cranial irradiation on growth was demonstrated.     

大剂量甲氨蝶呤治疗急性淋巴细胞白血病的不良反应

目的研究大剂量甲氨蝶呤(HD-MTX)加四氢叶酸钙(CF)解救方案治疗儿童急性淋巴细胞白血病(ALL)的不良反应。方法82例ALL患儿进行139例次的HD-MTX加CF治疗。根据44 h MTX血药质量浓度分为A组(44 h MTX浓度≤1.0 mmol/L),B组(44 h MTX浓度>1.0 mmol/L)。对用药前后两组患儿不良反应观察,并进行对照研究。结果骨髓抑制、肝功能损害、胃肠道反应、感染发生率两组比较无显著性差异。但随着血药质量浓度增加,皮肤黏膜损害、心电图异常和心肌酶谱异常、神经系统症状发生率均显著增加,两组比较有显著性差异。结论HD-MTX加CF治疗儿童白血病时,不良反应较为常见,个体差异较大,应加强个体化治疗。     

长期无病生存急性淋巴细胞白血病患儿60例智力及生长发育情况分析

目的了解ALL患儿经长期正规序贯化疗对智力及生长发育的影响。方法对本院经一系列正规序贯化疗后获得长期无病生存的60例ALL患儿进行智商、身高、体质量、血清胰岛素生长因子-1(IGF-1)、骨龄、雌激素(E2)、睾酮(T)、第二性征发育情况检测,以调查时间不同分为A、B两组,所得结果分别与健康儿童上述各项指标进行比较分析。应用SPSS 17.0软件进行统计学分析。结果 A组30例患儿平均智商为107.0,B组30例患儿的平均智商为109.3,结果显示60例ALL患儿的智商与健康儿童比较差异无统计学意义。60例ALL患儿的身高、体质量均在同龄儿的x珋±2 s范围之内,B组30例患儿血清IGF-1水平在同龄儿的x珋±2 s范围之内。60例ALL患儿E2、T、第二性征发育情况、骨龄均与健康儿童基本一致。结论 ALL患儿经长期正规序贯化疗对智力及生长发育无明显影响。     

Varicella Vaccine in Children with Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma

To determine the safety and efficacy of varicella vaccine, 17 children with acute lymphoblastic leukemia (ALL) and 2 children with non-Hodgkin lymphoma (NHL) receiving chemotherapy in remission were immunized with live attenuated varicella vaccine (Oka strain). Rash occurred in 7 children 7-53 days (median 24 days) after vaccination. There were 10-80 (median 20) erythematous vesicles and low-grade fever. All children required no specific treatment. There was no spread of varicella to their susceptible siblings. The control group comprised 92 ALL and 25 NHL patients receiving chemotherapy in remission who were nonvaccinated and susceptible to varicella.

Over a risk duration of 80 person-years, one child of the vaccinated group developed varicella of mild degree, whereas in a risk duration of 120 person-years, 14 g the control group developed varicella. One patient died, though prompt antiviral therapy, especially acyclovir, was given to all of them. Herpes zoster of mild degree was observed in one child of the vaccinated group 65 days after vaccination. Two children of the control group deueloped disseminated herpes zoster. With acyclovir therapy, there was no mortalily. The incidence of varicella in the vaccinated group was less than that of the control group. The diffence is statistically significant (p =.0222), and the side effects of the vaccine were acceptable. Thus we conclude that the vaccine can be safely used in children with ALL or NHL under chemotherapy and can effectively protect such children from varicella.     

儿童急性淋巴细胞白血病骨骼并发症研究进展

ALL是儿童最常见的恶性肿瘤,应用目前的联合化疗方法,5 a生存率超过80%.骨骼并发症可发生于ALL诊断时、治疗过程中和治疗结束后,影响ALL的治疗和生存.骨坏死(ON)是儿童ALL治疗过程中最严重的并发症之一,可影响高达1/3的接受治疗的儿童.ON的危险因素包括糖皮质激素的使用、诊断时年龄及放疗等.双膦酸盐治疗可减轻患者疼痛,减少止痛药用量及改善骨关节功能.间充质干细胞可提高手术治疗的疗效.     

急性淋巴细胞白血病患儿血清瘦素及铁蛋白检测的意义

目的研究急性淋巴细胞白血病(ALL)患儿血清瘦素(leptin)和铁蛋白(SF)水平变化,探讨血清瘦素及SF与ALL的关系。方法采用酶联免疫分析法分别检测22例初治、26例缓解期ALL患儿及25例健康儿童血清瘦素水平,同时采用双抗体夹心酶联免疫分析法检测血清SF水平。结果ALL初治组血清瘦素水平显著低于正常对照组(P<0.01),经化疗缓解半年后,其血清瘦素浓度上升至正常水平;ALL初治组血清SF水平显著高于正常对照组(P<0.01),缓解后其血清瘦素浓度降至正常水平。结论血清瘦素和SF可作为判断ALL治疗效果的有效指标之一。     

Transient Encephalopathy Following a Single Exposure of High-Dose Methotrexate in a Child with Acute Lymphoblastic Leukemia

An episode of transient encephalopathy after the first course of intravenous high-dose methotrexate (HD-MTX; 1000 mg/m2) was observed in a 4-year-old girl with acute lymphoblastic leukemia. The neurological abnormalities took place 5 days after HD-MTX therapy. She experienced complex partial seizure and left hemiparesis, which resolved spontaneously in 5 days. Cranial computed tomographic scan and magnetic resonance imaging showed multiple low-density lesions in bilateral hemispheres. It is well appreciated that neurotoxicity from MTX follows prolonged exposures, often accompanying or following radiation therapy. To our knowledge, however, there have been no reports that such neurological complications developed following a single exposure of HD-MTX in patients with ALL. Follow-up electroencephalograms showed that she had periodic lateralized epileptiform discharges (PLEDS), suggesting functional deafferentation of cortical neurons following HD-MTX. Moreover, the serum and CSFMTX levels following a second low-dose course and her clinical course suggested that she had presumably central nervous system leukemia at the time of HD-MTX therapy, which might have been related to neurological complications. The pathogenesis of MTX-induced neurotoxicity is discussed.     

急性淋巴细胞白血病患儿长期疗效分析

目的分析70例ALL患儿分型治疗的长期疗效和远期不良反应,以寻求提高患儿长期高质量无病生存的方法。方法随访并分析2000年1月-2009年12月在本院儿科血液/肿瘤病房诊断并坚持治疗的70例ALL患儿情况。临床分型:标危型、中危型、高危型和ALL-L3型患儿分别为42、12、7例和9例。采用Kaplan-Meier方法进行长期生存情况分析。结果 5 a无事件生存率在标危组、中危组和ALL-L3组分别为(93.87±4.22)%、(85.33±6.45)%和(88.89±7.48)%。高危型患儿目前无病存活率为42.86%(3/7例)。复发6例(8.57%),其中死亡4例,另有5例无复发死亡,总病死率12.86%。长期不良反应观察未发现二次肿瘤及蒽环类心肌病发生,4例(5.71%)患儿生长受限,1例患儿发生单侧股骨头无菌性坏死。结论分型治疗可提高ALL患儿长期生存率,改善ALL患儿生存的质量。     

Cell-Mediated Cytotoxicity in Children During and after Therapy for Acute Lymphoblastic Leukemia

Cell-mediated cytotoxicity is considered to play a major role in immune defense and in particular in the killing of virus-infected and neoplastic cells. It appears to have some interesting implications when considering the infectious risk of acute lymphoblastic leukemia (ALL) children during immunosuppressive chemotherapy and the role of self-defense against minimal residual disease. We have studied natural killer (NK) activity and lymphokine-activated killer (LAK) activity in children during and after treatment for ALL. We observed that peripheral blood mononuclear cells in 22 children undergoing maintenance chemotherapy displayed significantly depressed NK activity compared with normal controls even when the proportion of NK cells was normal. LAK activity was also considered in 43 ALL children during and after maintenance chemotherapy. We observed that LAK activity was persistently comparable with that of normal controls. It seems definite that NK activity impairment is transient and is completely restored in ALL children a few months after chemotherapy has been successfully completed. The evidence that LAK activity is not impaired in ALL children may have some implications in view of a possible immunomodulatory approach in the presence of refractory disease.     

Thrombosis in Children with Acute Lymphoblastic Leukemia Treated at a Tertiary Care Center in Lebanon: Revisiting the Role of Predictive Models

The incidence of symptomatic venous thromboembolism (VTE) in children receiving therapy for acute lymphoblastic leukemia (ALL) varies widely and is protocol dependent. The authors herein report the incidence and potential risk factors for VTE in children with ALL while being treated on a uniform protocol at a single tertiary care center in Lebanon. The authors also examine necessary modifications in a recently published model before it could predict VTE in their patients.     

儿童高危型急性淋巴细胞白血病的危险因素及疗效

目的 探讨儿童高危ALL的危险因素及疗效,改善ALL患儿的预后.方法 回顾性分析本院2004年10月-2007年12月初诊ALL患儿的临床资料,按2004年全国小儿血液病会议通过的儿童ALL诊疗建议,具有危险因素的41例患儿进入研究.发病年龄8~12个月或10~14岁者共21例,白细胞≥50×109 L-1者20例(48.78%),初发时伴髓外浸润15例(36.59%),T淋巴细胞性白血病10例(24.39%),有不利的细胞遗传学改变5例(12.20%),窗口治疗不敏感12例(29.27%),2个疗程未获缓解1例(2.44%).以2006年1月为界,此前应用新华-99方案化疗,此后用上海儿童白血病协作组2005方案(ALL-2005方案)进行化疗.应用SPSS 13.0软件进行统计学分析.结果 随访至2010年6月,中位随访时间32.08个月(2~68个月).40例经1个疗程诱导后缓解,缓解率97.56%;10例(24.39%)复发,3例(7.32%)在治疗过程中死于感染.预期30个月无事件生存率(EFS)和总生存率(OS)分别为69.60%和73.30%.窗口治疗不敏感和诱导6周未获缓解2个危险因素作为单变量对EFS和OS影响有明显差异.结论 评判ALL的危险因素对选择治疗方案和预后判断均非常重要.强烈的联合化疗、造血干细胞移植作为补充手段治疗儿童高危白血病,能够获得较好的疗效.