儿童急性淋巴细胞性白血病治疗中微量残留病与泼尼松窗口治疗反应比较的探讨

目的 探讨儿童急性淋巴细胞性白血病(ALL)微量残留病(MRD)和糖皮质激素窗口疗效的相关性.方法 2005年1月-2007年7月37例ALL初发患儿接受糖皮质激素窗口治疗7 d,根据外周血幼稚细胞计数,分为泼尼松反应良好(PGR)和泼尼松反应不良(PPR)两组,监测MRD并与窗口结果对临床预后预测进行比较.结果 ①33/37例有MRD合适标记,其中治疗1年内MRD<0.01%者为30/33例(90.91%),MRD≥0.01%者为3/33例(9.09%),两组临床缓解与复发差异有统计学意义.②)32/37例为PGR(占86.49%);5/37例为PPR(占13.51%).MRD结果和泼尼松窗口治疗反应差异无统计学意义.③4/37例未检出MRD标记,2/4例缓解(50.00%).结论 MRD结果和泼尼松窗口治疗反应,均能够作为评判ALL预后的参考指标.     

101例儿童急性髓细胞性白血病免疫表型与预后相关分析

目的探讨免疫表型对儿童急性髓细胞性白血病的预后价值。方法采用流式细胞术检测101例儿童急性髓细胞性白血病(AML)患儿相关免疫表型,分析免疫表型对完全缓解(CR)及无疾病生存期(DFS)的影响。结果CD34阴性组及CD34、HLA-DR同时阴性组一疗程CR率均明显高于非阴性组,差异有统计学意义(P=0.008,0.000);DFS的CD34阴性组,HLA-DR阴性组以及CD34和HLA-DR同时阴性组均明显高于非阴性组,差异有统计学意义(P=0.004,0.006,0.040),而CD14,CD15,CD7,CD19差异对CR和DFS均无统计学意义。结论免疫表型对评估AML患儿的预后有一定意义。     

儿童急性髓系白血病微小残留病检测技术的应用进展

近年来,虽然儿童急性髓系白血病(acute myeloid leukemia,AML)的治疗效果有了很大改善,但其复发仍然是影响预后的主要因素.大量研究表明微小残留病(minimal residual disease,MRD)的水平不仅与AML复发密切相关,而且对于判断其预后、指导个体化治疗同样具有重要意义.寻找特异性高、灵敏度高、简便、适用的检测方法一直是MRD研究的热点之一,该文将对AML的MRD检测技术最新的应用进展进行综述.     

Treatment of recurrence of acute myeloid leukemia in childhood. A retrospective analysis of recurrence in the AML-BFM-83 study]

Complete remission (CR) rates of 80% are achieved with the AML-BFM protocols but one third of patients relapse within the first three years. There are few reports of treatment of relapsed childhood AML, and these deal with the evaluation of new drugs for frontline therapy. We performed a retrospective analysis to investigate how patients previously treated with the AML-BFM-83 protocol were treated after relapse and how many long term remissions were achieved. 48 of 139 patients relapsed after having achieved complete remission with the AML-BFM-83 protocol which consists of continous infusion of ARA-C 100 mg/m2 day 1-2, ARA-C 200 mg/m2 day 3-8, Daunorubicin 60 mg/m2 day 3, 4, and 5, and VP-16 150 mg/m2 day 6, 7, and 8, and an 8 week consolidation therapy consisting of Prednisolone, Thioguanine, Vincristine, ADR, ARA-C, Cyclophosphamide, intrathecal ARA-C and cranial irradiation followed by maintenance therapy. Duration of first remission ranged from 1.5 months to 66.3 months. Excluding 5 children with either isolated or combined extramedullary relapses and another 4 patients for missing data, 39 children were evaluable. 20 children received no therapy or palliative therapy while 16 patients received chemotherapy and another 3 children were transplanted in relapse. Although 9 different intensive chemotherapy regimens were used for reinduction, a high number (12 of 16 = 75%) of second complete remissions was achieved. Several therapeutic options were used to maintain a second remission: regular maintenance therapy (7 patients), allogeneous bone marrow transplantation (BMT) (2 patients), autologous BMT (3 patients).(ABSTRACT TRUNCATED AT 250 WORDS)     

Prognostic significance of eosinophilia in children with acute myeloid leukemia in the studies AML-BFM-78 and -83

Initial eosinophilia (greater than or equal to 3%) in the bone marrow was found in 73 out of 269 (27%) patients studied in AML studies BFM-78 and -83. It was predominantly seen in children with FAB types M2 (44%) and M4 (41%). Atypical eosinophils were mostly found in FAB type M4 (20/28 = 71%). Cytogenetic studies in eight children with FAB M4 and eosinophilia showed normal karyotypes in four patients, inversion 16 in one and other aberrations in three children. Study AML-BFM-78 did not demonstrate any differences in prognosis between patients with and without eosinophilia (event-free survival = EFS after 5 years 37%, SD 8%, vs. 38%, SD 6%). In study AML-BFM-83, however, a clear increase in EFS was seen in children with eosinophilia (EFS 72%, SD 8%, vs. 43%, SD 5%, p = 0.001). This improvement of prognosis mainly concerns patients with FAB M4 and eosinophilia (EFS 81%, SD 10%, vs. 23%, SD 11%, p = 0.006). None of the 12 children in study AML-BFM-83 with FAB M4 and atypical eosinophils has suffered a relapse, two patients belong to the early death group. Multivariate analysis shows only eosinophilia as a favorable prognostic factor in FAB type M4. According to these results FAB type M 4 with eosinophilia is a favorable prognostic parameter in children treated according to the therapy protocol of study AML-BFM-83.     

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。     

Incidence and prognostic significance of Auer rods in children with acute myeloid leukemia in the studies AML-BFM-78 and -83

The prognostic significance of Auer rods in children with AML was investigated in 129 patients of the study AML-BFM-78 and 154 patients of the study AML-BFM-83. Auer rods were found in 68 patients (53%) in the study AML-BFM-78 and 69 patients (45%) in the study AML-BFM-83. The incidence was higher in the subtypes FAB M1 (61%) and M2 (75%) compared to the subtypes FAB M4 (44%) and M5 (5%). In both studies the remission rate was higher in Auer rod-positive patients. Moreover, in the study AML-BFM-83 patients with Auer rods had a significant longer remission duration: the probability of an event-free interval (EFI) of 5 years was 77% (SD 6%) in Auer rod-positive patients compared with 44% (SD 7%) in Auer rod-negative patients (p less than 0.01). In the study AML-BFM-78 no differences regarding remission duration between both groups were detected. Analysis of the individual FAB subtypes revealed a significant higher event-free survival rate (EFS) after 5 years in Auer rod-positive compared with 18% (SD 12%) in Auer rod-negative patients (p less than 0.0001). No prognostic significance of Auer rods in other subtypes could be detected. In the overall group of all patients absence of Auer rods was associated with the unfavourable parameters hyperleucocytosis (greater than or equal to 100 x 10(3)/microliters) and acute monocytic leukemia (FAB M5) (p less than 0.01, p less than 0.001, respectively). The multivariate analysis in the study AML-BFM-83 showed that Auer rods were of prognostic significance independent from the initial leukocyte count and the FAB type M5.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of chemotherapy alone with allogeneic bone marrow transplantation in first full remission in children with acute myeloid leukemia in the AML-BFM-83 and AML-BFM-87 studies--matched pair analysis]

16 patients of studies AML-BFM-83 and -87 with allogeneic bone marrow transplantation (BMT) in first complete remission (CR) were compared with matched controls with postremission chemotherapy (CT-MC). CT-MC were selected from 250 non-grafted patients with a minimum of remission duration corresponding to the median interval between remission and allogeneic BMT (7.3 and 3.6 months in studies BFM-83 and BFM-87). Matched pair criteria according to prognostic significance were: blast cell reduction day 15 in bone marrow, FAB subtypes, white blood cell count, age, and time to CR. Therapy results in BMT and CT-MC groups were comparable: 2 relapses and 2 treatment-related deaths after BMT vs. 5 relapses. The probability for event-free interval of 9 years was: .73 (SD .12) in the BMT group vs. .67 (SD .12) in the CT-MC group. Early and late toxicity was higher in the BMT group. 3 children of the BMT group had tolerable or severe sequelae (convulsive seizures, hemiparesis). Currently, there is no advantage for allogeneic BMT in first CR according to our results. Only high risk patients should be grafted as soon as possible after achieving CR.     

基于流式细胞术的可测量残留病对儿童急性髓系白血病预后意义的前瞻性研究

目的 通过分析以可测量残留病（measurable residual disease,MRD）为导向的风险分层治疗,评估MRD在儿童急性髓系白血病（acute myeloid leukemia,AML）治疗过程中的预后价值。 方法 前瞻性纳入93例AML患儿,按照初诊时遗传学异常、诱导治疗Ⅰ后MRD及骨髓细胞学决定的风险分层完成2015-AML-03方案化疗。以多参数流式细胞术动态监测MRD,分析MRD对3年累积复发（cumulative recurrence,CIR）率、无事件生存（event-free survival,EFS）率、总生存（overall survival,OS）率的影响。 结果 93例AML患儿中,3年CIR率为48%±6%,中位复发时间是11（范围：2~32）个月,3年OS率为65%±6%,3年EFS率为50%±5%。诱导治疗Ⅰ和强化治疗Ⅰ后MRD阳性患儿的3年CIR率均高于MRD阴性患儿,3年EFS率、OS率均低于MRD阴性患儿（P<0.05）。初诊时低危的MRD阳性患儿调整化疗强度后的3年CIR率、EFS率、OS率与MRD阴性患儿相比,差异无统计学意义（P>0.05）。多因素分析表明,强化治疗Ⅰ后MRD阳性是AML患儿3年OS率的危险因素（P<0.05）。 结论 MRD对儿童AML预后有预测价值;利用基于MRD的风险导向治疗,合理应用化疗可能改善儿童AML患儿的整体预后。 引用格式:     

儿童急性白血病微小残留病检测方法与评价

白血病的微小残留病常成为白血病复发的根源,定量检测微小残留病对指导临床治疗具有重要意义.目前常用的定量检测方法有三种,包括检测异常抗原表型的流式细胞技术、抗原受体基因重排的PCR扩增技术、融合基因的PCR扩增技术.每种方法原理及特点不同导致I临床应用范围不同.根据患者自身特点,选择合适的检测方法,能使微小残留病定量更准确.     

儿童急性白血病微小残留病检测方法与评价

白血病的微小残留病常成为白血病复发的根源,定量检测微小残留病对指导临床治疗具有重要意义.目前常用的定量检测方法有三种,包括检测异常抗原表型的流式细胞技术、抗原受体基因重排的PCR扩增技术、融合基因的PCR扩增技术.每种方法原理及特点不同导致I临床应用范围不同.根据患者自身特点,选择合适的检测方法,能使微小残留病定量更准...     

Improved results in the treatment of acute myeloid leukemia - Results of study AML-BFM-93 in East Germany with comparisons to the preceding studies AML-I-82 and AML-II-87

BACKGROUND: Three multicenter studies were conducted in East Germany on the treatment of acute myeloid leukaemia in children. The latest of the three studies (AML-BFM-93-OST) was part of the common German study AML-BFM-93. PATIENTS AND METHODS: The total number of registered patients was 262. The number and dosage of administered chemotherapeutic agents was elevated with each new study. RESULTS: Both the remission rate (85 %) and the likelihood of an event free survival (52 % after 5 years) could be improved significantly in study AML-BFM-93-OST. The results of the common German study AML-BFM-93 were identical to those of the East German part AML-BFM-93-OST. Compared with international studies it was one of the most successful treatment strategies in children with AML. Patients who showed toxic side effects to heart, liver, kidneys, skin or nervous system during the chemotherapy had a significantly lower risk of relapse, once they overcame the intensive therapy. During the five years of study AML-BFM-93-OST, treatment results could be improved despite an unchanged therapy strategy. This may partly be due to the modernisations and restorations that were carried out in many East German hospitals in this time. CONCLUSIONS: The therapy regimen of study AML-BFM-93 allowed a substantial improvement in the treatment of children with AML. Further intensification of chemotherapy should only be undertaken in accordance to the individual sensitivity of each patient.     

Epidemiological evaluation and survival of children with acute myeloid leukemia

ObjectiveThis study aims to describe the epidemiological characteristics and survival rates of children with acute myeloid leukemia treated in hospitals in southern Brazil and compare them with international data.MethodsA multicenter cohort study was conducted with retrospective data collection of all new patients with acute myeloid leukemia under 18 treated at five referral centers in pediatric hematology-oncology in southern Brazil between January 2005 and December 2015.ResultsOf the 149 patients with acute myeloid leukemia, 63.0% (n = 94) were male. The median age at diagnosis was 10.5 years (range 0–18 years) and 40.3% (n = 60) had a white blood cell count below 50,000/mm². The most common Franco-American-British (FAB) subtype was M3 (n = 43, 28.9%). Nine (6.0%) patients had central nervous system disease. In M3 patients, overall survival (OS) was 69.2% and 3-year event-free survival was 67.7%; in non-M3 patients, these rates were 45.3% and 36.7%, respectively. In non-M3 patients, OS was significantly different between transplanted (61.8%) and non-transplanted (38.2%) patients (p = 0.031).ConclusionsThese results show a higher prevalence of the Franco-American-British M3 subtype than that reported in the international literature, as well as a decreased OS compared with that of developed countries. Further multicenter Brazilian studies with a larger sample size are encouraged to better understand the characteristics of acute myeloid leukemia, and to improve the treatment and prognosis in this population.     

实时定量聚合酶链反应检测微小残留白血病的临床研究

目的 探讨并研究实时定量聚合酶链反应(RQ—PCR)技术定量检测小儿急性淋巴细胞白血病(ALL)微小残留病(MRD)的临床适用性和临床价值。方法 以免疫球蛋白重链(IgH)基因重排作为ALL的肿瘤标志,应用RQ—PCR、胚系探针策略,定量检测了34例B细胞ALL(B—ALL)患儿的MRD,并对其中的16例患儿进行了缓解期MRD的定量动态追踪观察。结果在34例B—ALL患儿的初治标本中IgH基因单克隆重排16例,对16例单克隆IgH重排靶基因进行序列分析发现,V片段使用最频繁的是V3家族,J片段使用最频繁的是J4和J6。在16个靶基因中,RQ—PCR的检测敏感度有9例为10-4,6例为10-5,1例为10-3,非特异性扩增见于6例患儿。16例初治患儿的标准曲线相关系数均为0.99以上,斜率均值为-3.34±0.37,截距均值为24.30±2.95。对16例患儿随访期样本的MRD动态追踪研究发现,复发患儿的MRD水平较高且复发前有动态增加。诱导化疗结束时的MRD水平与ALL高危因素无明显相关性(P>0.05)。结论 研究表明,RQ—PCR技术胚系探针策略检测ALL患儿的MRD具有临床适用性,随访期标本MRD的定量检测及动态追踪监测具有临床价值。     

Effect of cranial irradiation on rate of recurrence in children with acute myeloid leukemia. Initial results of the AML-BFM-87 study. The AML-BFM Study Group]

Study AML-BFM-87 compared prospectively if cranial irradiation could be abandoned by adding two blocks of intensification with high dose ARA-C and VP-16 after consolidation and furthermore, improve prognosis compared to study -83. 210 children were enrolled in study AML-BFM-87 until March 31, 1991. 164 (78%) achieved complete remission. Probabilities for event-free survival (EFS) and event-free interval (EFI) of 5 years were: .45 (SD .04) and .57 (SD .05). In the first 2.5 years of the study irradiation was randomized (n = 31), selected or refused (n = 24). However, during this period irradiation was mandatory in patients with leukocyte count greater than 70,000/mm3, and also in children with initial CNS involvement. Since July 1989 prophylactic cranial irradiation was abandoned. Patients of the group with mandatory irradiation (n = 39) presented with more unfavourable risk parameters than the group of non-irradiated children, who were enrolled in the study after randomisation had been stopped. Nevertheless, results showed in randomized and selected patient groups as well as in the total cohort a longer relapse-free interval (RFI) in irradiated (n = 66) compared to non-irradiated (n = 94) patients (RFI of 5 years: .70, SD .04 vs. .51, SD .07, p less than .05). Relapses in non-irradiated children occurred mainly in the bone marrow and less often in the CNS. The increase in relapse rate was seen especially in non-irradiated patients of the low risk group as defined in study AML-BFM-83 (RFI: .40, SD .14 vs. .79, SD .09 with irradiation, p less than .01). In the high risk group, however, the differences were not significant. Our results suggest that cranial irradiation is an important part of therapy in childhood AML, and that the good prognosis of the low risk group in study AML-BFM-83 was probably based on the combination of intensive chemotherapy and cranial irradiation.     

急性淋巴细胞性白血病微小残留病与中枢神经系统白血病的相关分析

目的 探讨急性淋巴细胞性白血病（简称急淋）缓解时和缓解期微小残留病（MRD）的水平和变化以及与发生中枢神经系统白血病（CNSL）的关系。方法 用改良一步煮沸法提取脑脊液DNA，酚／氯方法提取骨髓DNA，巢式聚合酶链反应（PCR）法和极限稀释定量PCR法追踪检测微小残留病，数据处理用Kaplan-Meier方法及COX回归模型等。结果 46例急淋患儿缓解时骨髓MRD定量值与中枢神经系统白血病的发生呈正相关（COX回归模型，γ＝0．3496，P＜0．05），脑脊液MRD阳性可预示发生CNSL的相对危险度（P＜0．05）；缓解期脑脊液MRD持续阳性或由阴性转为阳性，发生中枢神经系统白血病的相对危险度明显增高（P＜0．05）。结论 缓解时骨髓MRD定量值和脑脊液MRD定性结果以及缓解期间脑脊液MRD的变化可以预示CNSL的危险度，MRD检测对判断急性淋巴细胞性白血病的预后和指导治疗有重要意义。     

儿童急性白血病微小残留病的检测及意义

通常急性白血病(AL)在诊断时,体内白血病细胞总数将达到1012(重量约为1kg),经诱导化疗取得临床完全缓解后,残留的白血病细胞总数应低于109(重量约为1g),这种体内仍残存少量白血病细胞的状态称为白血病微小残留病(minimal residual disease,MRD),目前已经明确MRD是造成AL复发的重要原因之一,因此,正确认识MRD检测的重要性并提高MRD检测的灵敏度是AL诊治过程中急待解决的问题.