严重不耐受巯嘌呤的急性淋巴细胞白血病患儿的临床特征

目的 分析严重不耐受巯嘌呤(6-MP)的ALL患儿的临床特征,并根据随访结果进一步了解这些患儿停化疗后不良反应的恢复情况.方法 选取2004年10月至2007年9月规范应用北京儿童医院-2003-急性淋巴细胞白血病(BCH-2003-ALL)化疗方案的ALL儿童,且处于6-MP维持化疗期间.按NCI-CTC V2.0评价6-MP的不良反应,详细记录出现3～4度不良反应(严重不耐受6-MP)患儿的临床资料和治疗情况,随访至2011年3月31日.结果 61例ALL患儿于服用标准剂量6-MP的2～4周出现3～4度不良反应,其中3～4度骨髓不良反应48例(78.7％),包括单纯骨髓不良反应39例(63.9％),同时伴有肝脏不良反应9例.单纯3～4度肝脏不良反应12例(19.7％),1例(1.6％)皮肤3度不良反应.严重不耐受6-MP的不良反应类型与ALL患儿年龄、性别、初诊时白细胞数及中枢侵犯均无明显关系(P=0.605,0.053,0.342,0.983),而与免疫类型和临床危险度密切相关(P =0.039,0.006).61例ALL患儿随访时间18～77个月(中位随访53个月),5例于治疗18～41个月后复发,其中6-MP维持治疗中复发4例,1例为停化疗5个月后,其余56例患儿均已停化疗,中位停药时间20个月(4.5 ～47.0个月),存活至今.除1例停药后1年仍轻度贫血,骨髓红细胞系增生不良,其余患儿骨髓不良反应恢复时间12～48周(平均15周),肝功能恢复时间4～25周(平均8周).免疫功能恢复时间6～12个月,1例皮肤不良反应患儿,停化疗后皮疹4周消失.结论 严重不耐受6-MP的ALL患儿近期随访结果表明,骨髓毒性和肝脏毒性是可逆的.这些患儿停化疗后预后良好,均未发现严重的脏器功能不良.但临床需要继续随访这些患儿,进一步了解与6-MP可能相关的第二肿瘤等远期不良反应,以明确严重不耐受6-MP的ALL患儿的远期预后.     

NUDT15基因型对儿童急性淋巴细胞白血病6-MP个体化治疗的影响

6-巯基嘌呤（6-MP）是急性淋巴细胞白血病（ALL）维持治疗阶段的重要药物，其副作用包括肝毒性和骨髓抑制，不同个体对6-MP的耐受差异较大，6-MP治疗需个体化。巯嘌呤甲基转移酶（TPMT）活性缺乏与6-MP不耐受具有相关性。但亚洲患者TPMT等位基因的突变频率较低。近来发现存在NUDT15基因突变的ALL患者6-MP耐受剂量低于常规剂量。该文就NUDT15基因型对ALL患儿6-MP个体化治疗的影响进行综述。     

6-巯基嘌呤致急性淋巴细胞白血病患儿不良反应及其与TPMT基因多态性的关系

目的 分析6-巯基嘌呤（6-MP）维持治疗急性淋巴细胞白血病（ALL）患儿不良反应的发生情况,探讨巯嘌呤甲基转移酶（TPMT）基因多态性与6-MP毒副作用的关系。方法 提取46例ALL患儿骨髓细胞总RNA并逆转录成cDNA。应用变性梯度凝胶电泳（DGGE）结合DNA测序,对ALL患儿TPMT*S和*3C基因型进行检测。采用美国国立癌症研究所第3版常规毒性判定标准（NCI CTC 3.0）行药物毒性分级,分析TPMT基因多态性与6-MP不良反应发生的关系。结果 在维持治疗阶段,22%（10/46）患儿因6-MP所致严重不良反应停药,不良反应主要表现为骨髓抑制、肝脏毒性和胃肠道反应。2例TPMT*3C突变基因型（AG+GG）患儿均出现重度不良反应,其中1例纯和突变患儿出现与6-MP剂量相关的骨髓抑制和肝脏毒性。TPMT*1S各基因型与6-MP所致的重度骨髓抑制及肝脏毒性无明显相关性（P>0.05）。结论 TPMT*3C多态性可能与6-MP所致严重不良反应发生有关。     

NDUT15 基因多态性与巯基嘌呤诱导的白细胞减少症的相关性

目的探讨我国东部地区汉族人群中NDUT15基因SNP位点(rs116855232)的多态性与儿童急性淋巴细胞白血病(ALL)化疗药物巯基嘌呤(6-MP)引起的白细胞减少症的相关性。方法选取133例确诊为ALL并接受正规治疗的患儿作为研究对象,根据化疗后白细胞减少程度分为白细胞减少组(WBC≤2.0×10~9/L)及对照组(WBC2.0×10~9/L)。利用限制性片段长度多态性分析(PCR-RFLP)检测该SNP位点的多态性分布;并收集治疗初期以及维持治疗阶段患儿的临床资料。结果 133例ALL患儿中TT基因型4例,CT型31例,CC型98例。在治疗初期及维持治疗阶段白细胞减少组及对照组基因型频率分布差异有统计学意义(P均0.05)。在维持及加强治疗阶段TT基因型患儿6-MP用量显著低于其他基因型(P0.05)。结论 NDUT15基因多态性与6-MP药物诱导的白细胞减少症相关,相对于其他基因型,TT基因型患儿的6-MP用量应减少,以避免并发症发生。     

6-巯基嘌呤减量治疗3例急性白血病患儿基因突变分析及临床表现

目的：分析6-巯基嘌呤（6-MP）减量化疗的急性白血病（AL）患儿维持治疗阶段临床资料及其巯嘌呤甲基转移酶（TPMT）、次黄嘌呤鸟嘌呤磷酸核糖转移酶（HGPRT）基因突变情况,探讨其基因型和临床表型的相关性。方法分别提取3例AL患儿骨髓液及77例对照组儿童外周血总RNA并逆转录成cDNA,PCR特异性扩增TPMT和HGPRT基因蛋白质编码区序列并测序。采用美国国立癌症研究所第3版常规毒性判定标准（NCI CTC 3．0）对维持治疗阶段药物不良反应进行评价和分级,应用国家食品药品监督管理局（SFDA）推荐的药物不良反应关联性评价标准评价6-MP与不良反应发生的相关性。结果1例AL患儿为TPMT＊3C（Try240Cys）纯合突变基因型,减少6-MP剂量至常规剂量1/3～2/3可使骨髓抑制及肝脏毒性等重度不良反应转为轻度。对照组发现2例TPMT＊3 C杂合突变,该位点在人群中的等位基因频率为1.3％。以上两组均未发现HGPRT基因突变。结论 TPMT＊3 C纯合突变患儿可出现与6-MP剂量相关的不耐受现象,中断或减量治疗能够减少维持期间严重药物不良反应的发生。提示TPMT＊3 C基因型的检出可能有利于提高6-MP用药的安全性。     

中剂量阿糖胞苷早期强化治疗急性淋巴细胞性白血病64例

目的研究中剂量阿糖胞苷早期强化治疗急性淋巴细胞白血病(ALL)的诊疗,探索提高儿童ALL长期生存的方法。方法应用标准的首次诱导缓解化疗方案治疗后,采用中剂量阿糖胞苷(Arac)1 g/(m2·次),1次/12 h×6次,配合柔红霉素(DNR)或米托蒽醌(MTZ)方案早期强化治疗,2～3个疗程进入维持治疗。采用Kaplan—Meter方法评估患儿无事件生存(EFS)率结果本组ALL完全缓解率(CR)为93.8%,标危(SR)ALL为100%,高危(HR)ALL为83 3%,5年EFS率达72 3%,SR-ALL患儿5年EFS率达84.2%,6例(10%)复发,治疗相关死亡2例(3.3%)。结论采用中剂量Arac方案早期强化治疗,降低化疗相关死亡,提高ALL患儿5年EFS率。     

巯嘌呤甲基转移酶基因多态性位点与白血病巯嘌呤耐受性的关系

目的 分析巯嘌呤甲基转移酶(thiopurine methyltransferase,TPMT)基因型对急性白血病(AL)患儿巯嘌呤(6-mercaptopurime,6-MP)耐受性的影响,提高患儿对巯嘌呤类药物治疗的有效性和安全性。方法 应用以聚合酶链反应(PCR)为基础的2种方法并结合DNA直接测序,检测250例健康成人和280例AL患儿TPMT基因第5外显子G238C、第7外显子G460A和第10外显子A719G的3个多态性位点。详细记录160例患儿6-MP全量治疗时间、减少剂量时间和未治疗时间。结果 280例AL患儿中,10例为TPMT第10外显子A719G杂合变异,变异率为3．6％,未发现纯合变异,变异的等位基因均为TPMT*3C。AL患儿TPMT基闪变异的频率和类型与健康成人差异无显著性。在观察的160例患儿中,有28%的患儿未接受6-MP标准剂量、全疗程治疗。其中TPMT野生型者39例,占野生型患儿的26%,杂合型者6例,占杂合型患儿的60％(P=0．03)。而且,6／10例TPMT杂合型者和30／150例野生型者减少6-MP的剂量(P=0．009)。结论 TPMT基因的多态性位点与AL患儿6-MP的耐受性有关。TPMT杂合型患儿中不耐受6-MP的比例明显高于TPMT野生型者,必须中断治疗或减少剂量以避免较大毒性反应的发生：提示检测TPMT基因型有利于提高巯嘌呤类药物的有效性和安全性。     

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目的通过对中枢神经系统白血病(CNSL)的防治,预防和降低白血病的髓外复发机会,提高儿童急性淋巴细胞性白血病(ALL)的长期生存。方法1999～2003年上海市新华医院对277例儿童ALL的诱导治疗期4～5次鞘内三联注射(甲氨蝶呤、阿糖胞苷、地塞米松),巩固期后采用大剂量甲氨蝶呤(HD-MTX)24h静脉连续滴注,进入维持后,每3个月1次,总共8～9次,以后改为鞘内注射3个月1次,直至化疗结束,对于超高危ALL患儿(白细胞计数>100×109/L、Ph1染色体阳性)采用头颅照射加鞘内注射。结果277例ALL患儿发生CNSL9例,发生率为3.2%,9例CNSL中4例骨髓复发,5例存活,中位生存时间22.2个月。结论CNSL的防治方法,明显降低了CNSL的发生率,使ALL患儿生存机会提高。发生CNSL的不利因素有高白细胞血症、T细胞性ALL、Ph1阳性染色体改变等。     

bcr/abl融合基因阳性急性淋巴细胞白血病的临床特点

目的总结bcr/abl融合基因阳性急性淋巴细胞白血病(ALL)患儿临床特点,探讨其治疗及预后的相关因素。方法对经巢式逆转录聚合酶链反应(RT-PCR)方法检测bcr/abl融合基因阳性ALL患儿临床表现、治疗、预后进行回顾性分析。结果bcr/abl融合基因阳性ALL患儿20例。中位年龄9岁,普通B细胞型ALL 19例(95%);治疗d33骨髓完全缓解率为66.7%,16例中7例复发(45%),持续缓解时间2年以上6例;5例接受造血干细胞移植(HSCT),均骨髓复发;6例存活患者中均为单纯化疗,bcr/abl融合基因已转阴。1例T细胞表型患儿于化疗缓解3个月骨髓复发,接受移植术后1个月骨髓再次复发。结论bcr/abl融合基因阳性ALL患儿化疗效果差,难缓解,复发率高,预后差,T细胞表型预后更差。部分对化疗敏感的患儿bcr/abl融合基因持续阴性。异基因HSCT复发率也较高。     

全反式维甲酸与砷剂联合化疗治疗初诊儿童急性早幼粒细胞白血病6例临床观察

目的 探讨全反式维甲酸(ATRA)与砷荆联合化疗对儿童初诊急性早幼粒细胞白血病(APL)的疗效和不良反应.方法 1994年10月至2006年5月在西安市儿童医院共收治儿童APL 6例,男2例,女4例.诱导缓解期例1用ATRA联合化疗,例2用DAE[(D柔红霉素(DNR);A阿糖胞苷(Ara-C);E足叶乙甙(Vp16)]方案无效,换用ATRA和三氧化二砷(As2O3)治疗.例3～6用ATRA、As2O3联合化疗.巩固治疗例1用DA方案,例2用As2O3,例3～6用DAE方案.维持治疗例1、2用青黄散、化疗、6-巯基嘌呤(6-MP)和甲氨蝶呤(MTX)各1个月交替用药.例3～6用大剂量阿糖胞苷(HD-Ara-c)4～6个疗程,其间间隙用DA、HA(H高三尖杉酯碱)方案.共8～10个疗程以后,再交替用As2O3、6-MP MTX、ATRA各1个月,总疗程3年.结果 例1诱导缓解期第45天获完全缓解(CR),余5例均在第30天达CR,期间无严重出血及骨髓抑制,不良反应有恶心、腹痛、皮疹、心电图异常.随访11～152个月,均为持续完全缓解,例2～6获分子生物学缓解.3例分别停药116、16、14个月.血砷测定均未达到中毒浓度.结论 砷剂联合 ATRA、化疗适合初诊儿童APL的治疗,总体预后良好.     

6-Mercaptopurine Cumulative Dose: A Critical Factor of Maintenance Therapy in Average Risk Childhood Acute Lymphoblastic Leukemia

A multivariate survival analysis including gender, age, log white blood cell (WBC) count, liver and spleen size at diagnosis, mean log WBC count during maintenance therapy, and the prescribed cumulative doses of 6-mercaptopurine (6-MP), methotrexate (MTX), vincristine (VCR), and prednisom (PDN) during maintenance therapy was performed on 53 children with average-risk acute lymphoblastic leukemia (ALL). The 6-MP cumulative dose prescribed during maintenance therapy resulted in the most important statistically significant independent prognostic factor. Patients who received less than the median cumulative dose of 6-MP (86% of planned protocol dose) fared significantly worse than the other patients, regardless of WBC count at diagnosis, gender, age, and other factors studied. Therefore, 6-MP cumulative dose during maintenance therapy may be the critical factor for effective maintenance therapy in childhood ALL.     

6-巯嘌呤细胞药理学研究对急性淋巴细胞白血病治疗的指导作用

目的建立一种高效、快速、灵敏的方法，探讨6-巯嘌呤（6-MP）细胞药理学。方法应用反相高效液相色谱分析技术，定量测定急性淋巴细胞白血病(ALL)患儿红细胞内6-MP三种代谢产物浓度6-巯嘌呤核苷酸（6-TGN）,6-次黄巯嘌呤单核苷酸(6-TIMP)和6-甲基巯嘌呤（6-MeMP）。选择31例ALL缓解期随访的患儿，口服6-MP50～75mg/（m     

Folic acid supplements in vitamin tablets: a determinant of hematological drug tolerance in maintenance therapy of childhood acute lymphoblastic leukemia

Methotrexate (MTX) is an antifolate that inhibits cell division by reducing intracellular amounts of reduced tetrahydrofolates. Of 53 children with acute lymphoblastic leukemia (ALL) in maintenance treatment with MTX and 6-mercaptopurine (6-MP), 25 had received daily folic acid supplements in vitamin tablets containing 75-200 micrograms folic acid for at least the preceding 3-month period. Experimental data have shown that increased folate concentrations intracellularly inhibit MTX metabolism and toxicity. Therefore we found it relevant to investigate the extent to which folic acid supplements affect hematological tolerance to MTX and 6-MP in children during maintenance therapy for ALL. The erythrocyte folate (ery-folate) concentration was significantly higher in children who received extra folic acid than in those who did not (p less than 0.001). The ery-folate in MTX-treated children was only marginally reduced compared with the controls. The erythrocyte methotrexate (ery-MTX) concentration correlated with the weekly dose of MTX but not with any of the investigated hematological parameters. Children who received vitamin tablets containing folic acid had higher thrombocyte counts (p = 0.0056), higher leukocyte counts (p = 0.06), higher neutrophil counts (p = 0.05), and lower erythrocyte mean cell volumes (p = 0.05) than children who received no folic acid. We conclude that folic acid supplements of 75-200 micrograms/day affect the proliferative capacity of the bone marrow. Since none of the children was folate deficient as judged by the ery-folate, we recommend that vitamins given to children in maintenance treatment with MTX and 6-MP for ALL should not contain folic acid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Symptomatic hypoglycemia: an unusual side effect of oral purine analogues for treatment of ALL

Symptomatic hypoglycemia is an unusual complication in children receiving oral purine analogues for treatment of childhood acute lymphoblastic leukemia (ALL). The exact mechanism of the hypoglycemic effect of the antimetabolic therapy remains unclear. Reduced hepatic glycogen stores or impaired hepatic glyconeogenesis may partly explain the hypoglycemia. To prevent hypoglycemia, food containing complex carbohydrates is recommended before sleep. In severe cases of hypoglycemia due to 6-mercaptopurine (6-MP), the dose can be given in the morning and if this fails 6-MP can be discontinued for a short period of time. We report a 3-year-old child who developed severe early morning hypoglycemia episodes that resolved after decreasing 6-MP while receiving non-high risk ALL therapy.     

儿童急性淋巴细胞白血病南方ALL99方案临床疗效分析

目的对82例儿童急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)治疗结果进行分析,探讨如何提高儿童ALL无病生存率。方法应用南方ALL99方案治疗82例ALL患儿。该方案引进德国BFM95和香港-新加坡ALL97方案,作了少许改动,形成南方ALL99方案。改动方面包括将三联鞘注中的氢化可的松换成地塞米松,将外院不规则化疗过的标危患者按中危治疗,将每一疗程开始时的中性粒细胞和血小板的标准提高到中性粒细胞≥1×109/L,血小板≥100×109/L。采用SPSS软件进行寿命表法分析。结果对1999年4月至2003年9月收治的82例ALL患儿按南方ALL99方案进行治疗,78例获完全缓解(completeremission,CR),CR率为95%;13例患者因经济困难或其他原因失访。其中按南方ALL99方案坚持治疗的69例,预期2年无病生存率91%,预期5年以上无病生存率75%;因感染死亡3例(死亡率为4%),复发死亡6例。结论引进德国BFM95和香港-新加坡ALL97方案而成的南方ALL99方案治疗儿童ALL疗效好,化疗相关死亡率低,该方案对中国人耐受性好,值得推广应用。     

Liver function studies in children with acute lymphocytic leukemia after cessation of therapy

We investigated liver function in 27 children with acute lymphocytic leukemia (ALL) after cessation of therapy. Induction therapy consisted of prednisolone + vincristine (VP regimen) alone (16 patients) or with addition of daunorubicin (4 patients) or L-asparaginase (7 patients). Patients treated with VP regimen short courses of VP regimen every 12 weeks for the first year of maintenance. Twenty-five patients remained in first complete remission and had completed 3-year maintenance therapy with methotrexate (MTX) and 6-mercaptopurine (6-MP) 1–7 years prior to this study. Twenty-three patients had transfusions of packed red blood cells or fresh whole blood (1–11 units; median: 2 units) but none had evidence of either hepatitis B or hepatitis C. Alanine aminotransferase (ALT), which was measured every 3 months during maintenance therapy, had values more than three times the upper limit of the normal range in 25% of the measurements in more than half of the patients. However, by 3 months after the completion of maintenance therapy, ALT had normalized in all patients and remained normal in all but two patients until the time of this study. Serum bilirubin, serum albumin, and prothrombin time were all within normal limits. Fasting and 2-hour postprandial total serum bile acids were high in 5 of 13 patients and in 6 of 13 patients, respectively. The ratio of cholic acids + deoxycholic acids to chenodeoxycholic acids + lithocholic acids was below 1 in all but two patients, whereas this ratio was above 1 in all controls. Our bile acid profile results indicate the necessity of careful long-term follow-up of survivors of ALL treated with hepatotoxic chemotherapy during childhood. © 1994 Wiley-Liss, Inc.     

Prognosis after Relapse in Acute Lymphoblastic Leukemia in Childhood

This is a survey of all the 265 relapses occurring in 515 children with ALL diagnosed in Sweden in the years 1973-1980. Two hundred and nineteen relapses occurred on therapy, and 46 after discontinuation of therapy. Bone marrow was involved in the relapse in 71% and 67% of the two groups, respectively. Only 38/265 (14%) children with relapse were still alive at follow-up in January 1985. Of these, 16/219 (7%) had relapsed during therapy (median survival time after relapse 9 months) compared to 22/46 children (48%) with a relapse after cessation of therapy (median 43 months). The prognosis was better if relapse occurred after cessation of therapy and in children with isolated testicular relapse. Thirteen children were bone marrow transplanted, and 6 of these were alive at follow-up. It is concluded that children with ALL relapse have very bad prognosis with cytostatic regimens used today, especially if the bone marrow is involved.