Intraventricular versus intralumbar methotrexate for central-nervous-system leukemia: Prolonged remission with the ommaya reservoir

Ten children had recurrence of central-nervous-system (CNS) leukemia despite monthly injections of methotrexate into their lumbar cerebrospinal fluid. Each child was then reinduced into remission and maintained with intraventricular methotrexate administered via an Ommaya reservoir and the length of this remission was compared with the duration of the child's previous intralumbar-treated remission. Of eight evaluable patients, seven had longer CNS remissions with intraventricular therapy than with intralumbar therapy (P < 0.02). The median CNS remission duration in all patients was 475 days with intraventricular and 286 days with intralumbar therapy (P < 0.05). The rate of CNS relapse was reduced from 2.94 relapses per thousand days at risk during intralumbar therapy to 0.93 relapse per thousand days of intraventricular therapy. We conclude that intraventricular chemotherapy is significantly more effective against CNS leukemia than the same therapy given by lumbar puncture.     

Immunophenotyping of the cerebrospinal fluid as a prognostic factor at diagnosis of acute lymphoblastic leukemia in children and adolescents

This study aimed at evaluating the use of immunophenotyping (IMP) in the identification of blast cells in the cerebrospinal fluid (CSF) of children and adolescents with acute lymphoblastic leukemia (ALL). Sixty-seven patients aged 18 years or younger were included. Fifty-five CSF samples were analyzed at initial diagnosis and 17 at the time of relapse. A cytological analysis (CA) was performed in all 72 samples, while IMP was done in 63. Blasts were identified in only three samples by CA, whereas all three samples were found negative by IMP, one of which had no isolation of nucleated cells after centrifugation. Among the samples analyzed by IMP, 11 showed a positive blast count, two of which had been inconclusive using CA. No equivalence was found between CA and IMP results (p = 0.55). CSF IMP positivity was not associated with other risk factors for ALL relapse. Among the 55 patients included at the time of diagnosis of ALL, eight relapsed during follow-up. Considering the cases of central nervous system (CNS) relapse, one of the patients belonged to the CSF IMP-positive group (11%) at diagnosis, and the other two cases, to the IMP-negative (5%) group. Detection of CSF blast cells using IMP was associated with a worse overall (p < 0.0001) and event-free survival (p < 0.0001). These results show that CSF IMP may be a useful additional method to conventional CA in the diagnosis of CNS involvement in ALL, and for the identification of high-risk subgroups that would benefit from an intensified therapy.     

急性淋巴细胞性白血病患儿脑脊液铁蛋白

研究目的发探讨白血病患儿脑脊液铁蛋白（CSF－Ft）含量的变化及其临床意义。研究方法经骨髓检查确诊的急性淋巴细胞性白血病患儿42例，分为3组，Ⅰ组（诱导治疗期不伴中枢神经系统白血病）14例，Ⅱ组（完全缓解期不伴中枢神经系统白血病）24例，Ⅲ组（合并中枢神经系统白血病）18例。病毒性脑炎（病脑）组17例，对照组15例均无中枢神经系统疾病。用放射免疫分析法检测CSF－Ft及血清铁蛋白。结果Ⅰ、Ⅱ、Ⅲ组、病脑组和对照组患者CSF－Ft含量分别为7．03±2．21μg／L，6．75±1．94μg／L，31．06±8．85μg／L，7．26±1．83μg／L和6．52±1．57μg／L。Ⅲ组患儿LCSF－Ft含量明显高于其它组（P均＜0．01）。10例中枢神经系统白血病患儿，随病情好转其CSF－Ft水平渐下降。结论CSF－Ft检测对中枢神经系统白血病诊断有重要价值，并可做为评价中枢神经系统白血病治疗效果的重要指标。     

Elevation of Cerebrospinal Fluid Sialic Acid Concentration in Children with Central Nervous System Leukemia

ABSTRACT. We studied sialic acid in the cerebrospinal fluid (CSF) of 52 children with leukemia and 51 children with non-leukemic diseases. The CSF sialic acid concentration in the children with central nervous system (CNS) leukemia was significantly higher than that in the children with acute lymphoblastic leukemia without CNS involvement, acute non-lymphocytic leukemia without CNS involvement, non-hemopoietic diseases, non-suppurative meningitis, epilepsy, and other neurologic diseases. Serial determinations revealed a rapid decline in the CSF sialic acid concentrations in the patients with CNS leukemia who responded well to the therapy and who were free from relapse of CNS leukemia. The simultaneously determined CSF β2 microglobulin concentration did not show any significant changes. These results suggest that the CSF sialic acid may be a good indicator of CNS leukemia.     

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??Childhood acute lymphoblastic leukemia is the first disseminated cancer shown to be curable. Central nervous system leukemia ??CNSL?? is one of reasons that cause leukemia replase and is associated with a poor prognosis. Pediatricians should master the diagnostic techniques??modalities of prophylaxis and therapy of CNSL in patients with childhood acute lymphoblastic leukemia.     

脑脊液细胞学检查在中枢神经系统白血病中的应用

目的探讨脑脊液(CSF)细胞学检查在中枢神经系统白血病(CNSL)中的诊断价值。方法采用细胞离心涂片机收集CSF细胞,经染色镜检进行CSF细胞学检查。结果在59例白血病患儿438次CSF细胞学检查中,发现病例和标本阳性率分别为15.3%(9/59)和8.7%(38/438)。结论CSF细胞学检查对CNSL的早期诊断和疗效观察及复发判断有重要价值。     

Ommaya储液囊植入治疗早产儿脑室内出血后脑积水的疗效及其影响因素分析

目的：观察Ommaya储液囊植入治疗早产儿脑室内出血后脑积水的临床疗效并探讨影响其疗效的相关因素。方法：采用双向性队列研究的方法分析20例因脑室内出血后脑积水而接受Ommaya储液囊植入术治疗的早产儿（胎龄＜32周,出生体重＜1500 g）的临床资料及随访资料,观察手术的治疗效果。根据治疗效果的不同分为治愈组和治疗失败组,采用单因素分析的方法探讨影响其疗效的相关因素。结果：(1)Ommaya储液囊植入术后 30 d,脑积水情况明显改善。(2)术后3个月,部分患儿临床疗效显著下降：术后3~6个月内7例转行脑室-腹腔分流术,4例因经济原因放弃治疗,1例因头皮下血肿伴皮肤坏死转行第三脑室底造瘘术;其余8例至12~18个月时脑室恢复正常大小。(3)并发症情况：术后继发性脑室内出血8例,颅内感染2例,头皮下血肿伴皮肤坏死1例。(4)单因素分析显示胎龄、出生体重、Ommaya储液囊植入时脑积水时间在治愈组和治疗失败组比较差异有统计学意义（P＜0.05）。结论：Ommaya储液囊植入术治疗早产儿颅内出血后脑积水短期内疗效显著,但随时间延长部分患儿治疗效果降低。小胎龄、低出生体重、脑积水时间长可能是影响疗效的主要因素。     

儿童中枢神经系统急性淋巴细胞白血病诊治进展

儿童急性淋巴细胞白血病是可治愈性疾病,多数患儿经过系统化治疗可持续完全缓解,但仍有部分复发,其中中枢神经系统受累是导致患儿复发以及影响生存质量的重要原因之一。临床儿科医生对中枢神经系统急性淋巴细胞白血病的诊断、防治等相关进展应有所了解。     

Central Nervous System Relapse Surveillance by Serial Beta2-Microglobulin Measurements in Childhood Acute Lymphoblastic Leukemia

ABSTRACT. Beta₂-microglobulin (β₂m) is synthesized particularly in lymphocytes. Its value for early detection of central nervous system (CNS) involvement in acute lymphoblastic leukemia in children was tested by serial determinations. Before 9 overt CNS relapses, the mean increase of the cerebrospinal fluid (CSF) β₂m concentration was 588 μg/l/month (range: -50 to +2020), which was significantly higher than the steady levels during maintenance treatment. Although the absolute value of CSF β₂m was increased to 1430 μg/l in the group with overt CNS relapse, individual variations in CSF β₂m before a relapse were so great that no difference was seen between samples from CSF with or without lymphoblasts. The ratio between β₂m in the CSF and in serum did not increase in serial samples prior to overt relapse, but the ratio was higher in patients with CNS relapse compared with a control group on maintenance therapy. In 9 children without CNS leukemia, the β₂m concentration in CSF and serum decreased to a nadir 4 weeks after the start of induction treatment. The subsequent increase of CSF β₂m was similar to the increase before a CNS relapse. Mean values of CSF β₂m changes differed between groups of children with and without CNS leukemia early in the induction phase and during the maintenance treatment, but the wide range in individual values made serial β₂m determinations unsuitable for detecting a CNS relapse.     

小儿急性淋巴细胞白血病中枢神经系统白血病诊治现状

中枢神经系统白血病(CNSL)的防治是小儿急性淋巴细胞白血病(ALL)治疗的一部分。诊断时高白细胞计数、T细胞型及分子遗传学为t(4;11)和Ph 是CNS复发的危险因素,脑脊液不同检查结果的预后价值有待明确。头颅放疗已不用于标危ALL患儿,头颅放疗的预防剂量已减为12Gy,鞘内及全身化疗对CNSL的治疗有重要作用。部分小儿CNS复发经挽救治疗可以长期存活,早期CNS复发的患儿应在第2次CR期进行异基因骨髓移植。     

儿童中枢神经系统白血病的诊治进展

鉴于急性白血病联合化疗时血脑屏障的作用,白血病细胞逃避化疗药物的杀伤最终导致中枢神经系统白血病(central nervous system leukemia,CNSL)发生.目前诊断CNSL的标准主要是依赖于脑脊液(carebrospinal fluid,CSF)检查、临床表现和影像学检查,早期诊断方法有CSF细胞形态学检查、CT和MRI等影像学检查、CSF微小残留病的检测、检测CSF硫化氢含量、分子生物学指标的检测.CNSL的预防主要包括直接鞘内注射药物、可透过血脑屏障的全身化疗药物和放射疗法.CNSL的治疗主要包括化疗放疗、异基因造血干细胞的移植和靶向治疗.     

Efficacy of prophylactic additional cranial irradiation and intrathecal chemotherapy for the prevention of CNS relapse after allogeneic hematopoietic SCT for childhood ALL

We evaluated the efficacy of CRT and IT chemotherapy, in addition to conditioning including TBI, for the prevention of CNS relapse, in allogeneic HSCT for childhood ALL. From January 1999 to December 2009, a total of 48 patients, without previous or presenting CNS involvement, underwent HSCT for ALL. All patients received myeloablative conditioning including TBI of 12 or 13.2 Gy and IT chemotherapy twice between days ?10 and ?2 prior to HSCT. Twenty‐five patients received CRT prior to TBI (CRT+), and 23 patients did not (CRT?). CRT+ and CRT? patients had a seven‐yr EFS rate of 40.0 ± 9.8% and 41.7 ± 10.6%, respectively (p = 0.8252). The seven‐yr relapse rates for CRT+ and CRT? patients were 45.0 ± 11.2% and 38.4 ± 11.6%, respectively (p = 0.7460). CNS relapses were evident in 1 (4.0%) CRT+ patient and 1 (4.4%) CRT? patient (p = 1.000). There were no significant differences in EFS and the probability of CNS relapse between CRT+ and CRT? patients. These results demonstrate that CRT and IT chemotherapy, in addition to conditioning chemotherapy, may not be necessary in childhood ALL patients without previous or presenting CNS involvement.     

儿童急性白血病合并中枢神经系统真菌感染5例并文献复习

目的通过5例儿童急性白血病合并中枢神经系统(CNS)真菌感染的临床总结及相关文献复习,提高对本病的认识。方法回顾性分析北京儿童医院收治的5例急性白血病合并CNS真菌感染患儿的临床特点及诊治经过并文献复习。结果(1)4例急性淋巴细胞白血病(ALL)患儿均接受强化疗,1例为急性非淋巴细胞白血病(AML-M2)半相合造血干细胞移植术后,发生CNS真菌感染前均有肺部真菌感染病史,其中2例合并肝、脾、肾真菌感染,1例合并下肢皮肤真菌感染(2)实验室检查3例有病原学依据,1例烟曲霉菌,2例念珠菌,2例无病原学依据。(3)影像学5例患儿均作头颅CTMRI,表现脓肿、梗塞、颅内出血。(4)治疗及预后1例患儿伊曲康唑+脂溶性两性霉素B治疗,2例患儿伏立康唑治疗,2例患儿伏立康唑和两性霉素B联合抗真菌治疗,抗真菌治疗均有效,4例存活,1例死于严重移植物抗宿主病(GVHD)。结论儿童急性白血病合并CNS真菌感染为侵袭性真菌感染的表现形式之一,多半有其他脏器感染,临床表现不典型,可有脑膜炎或脑脓肿症状和体征,诊断困难,CT、MRI影像学检查重要,伏立康唑、两性霉素B抗真菌治疗有效。     

The Prognosis and Survival of Childhood Acute Lymphoblastic Leukemia with Central Nervous System Relapse

Central nervous system (CNS) relapse in childhood acute lymphoblastic leukemia (ALL) has been overcome by sensitive therapatic approachs. This study was planned to present the development of CNS relapse and survival in newly diagnosed 190 ALL patients whose cases were followed in the authors' unit between March 1991 and May 2002. St. Jude Study XI protocol was given to the patients who applied between March 1991 and March 1997 (group A) (n = 122), and St. Jude Study XIII protocol was given to the patients who applied between March 1997 and May 2002 (group B) (n = 68). The patients having isolated CNS relapse in group A received craniospinal irradiation (CSI) median 3.5 months after CNS relapse (range 2–6 months), a short time after reinduction, and 2 cures of consolidation. In group B, patients having isolated CNS relapse received IT once a month and a high-dose methotrexate treatment once every 8 weeks and 3 or 4, cures later therapy CSI median 7 months after CNS relapse (range 6–8 months) was given. When the overall survival rates of the 2 groups are compared, a statistically significant higher survival rate at 5 years was determined in group B than in group A (respectively, 82.3%, 58.4%) (p < .05). When subgroups of the patients (that is, those with no relapse, isolated CNS or BM relapse, or CNS + BM relapse) were compared in both groups, it was found that survival was much higher for the ones with no relapse and with isolated CNS relapse (respectively, 87.9%, 72.7%) compared to isolated BM or CNS + BM relapse groups (respectively, 10%, 13.3%) (p < .05). In a conclusion, for children with acute lymphoblastic leukemia and an isolated CNS relapse, with delayed definitive craniospinal irradiation allowing more intensive systemic and intrathecal chemotherapy results in better overall survival than has been previously reported.     

以肥胖为首发症状的复发性中枢神经系统白血病

目的分析罕见的以肥胖为首发症状的中枢神经系统白血病(CNSL)的诊断。方法 1例6岁4个月男孩,近3个月来进行性肥胖伴性格改变,以往患急性淋巴细胞白血病(ALL,普通B细胞,BCR-ABL阴性,中危),经化疗后持续缓解超过2年。根据临床表现做一系列的实验室和影像学检查进行诊断和鉴别诊断,并进行相关中英文文献复习。结果脑脊液(CSF)白细胞中度升高,以单个核细胞为主,伴少量可疑的幼稚淋巴细胞,葡萄糖和氯化物低,蛋白稍高,MRI示脑膜、大脑皮质、下丘脑和垂体柄以及桥脑等中线结构、颅神经根等信号异常。临床检查分析排除单纯肥胖、Cushing综合征等继发性肥胖和结核性脑膜炎;CSF流式细胞术检查发现65%的有核细胞符合ALL细胞的特征而诊断为CNSL复发,经化疗和头颅放疗后缓解。目前中、英文文献只检索到3篇相似病例的个案报道。结论肥胖和性格改变可以是CNSL的首发症状,但由于罕见,需注意与其他疾病鉴别,传统的CSF细胞形态学结合流式细胞术检查将提高CNSL诊断的可靠性。     

CNS-3 status remains an independent adverse prognosis factor in children with acute lymphoblastic leukemia (ALL) treated without cranial irradiation: Results of EORTC Children Leukemia Group study 58951

AimTo evaluate the prognostic significance of initial central nervous system (CNS) involvement of children with acute lymphoblastic leukemia (ALL) enrolled in the EORTC 58951 trial.Patients and methodsFrom 1998 to 2008, 1930 ALL patients were included in the randomized EORTC 58951 trial. Overall treatment intensity was adjusted according to known prognostic factors including the level of minimal residual disease after induction treatment. CNS-directed therapy comprised four to 11 courses of i.v. methotrexate (5 g/m²), and 10 to 19 intrathecal chemotherapy injections, depending on risk group and CNS status. Cranial irradiation was omitted for all patients.ResultsThe overall 8-year event-free survival (EFS) and overall survival (OS) rates were 81.3% and 88.1%, respectively. In the CNS-1, TPL+, CNS-2, and CNS-3 groups, the 8-year EFS rates were 82.1%, 77.1%, 78.3%, and 57.4%, respectively. Multivariable analysis indicated that initial CNS-3 status, but not CNS-2 or TLP+, was an independent adverse predictor of outcome. The 8-year incidence of isolated CNS relapse was 1.7% and of isolated or combined CNS relapse it was 3.7%. NCI high-risk group, male sex, CNS-2 and CNS-3 status were independent predictors for a higher incidence of any CNS relapse.ConclusionsCNS-3 status remains associated with poor prognosis and requires intensification of both systemic and CNS-directed therapy.This trial was registered at https://clinicaltrials.gov/under/NCT00003728.     

Extramedullary leukemia in children with acute myeloid leukemia: A population‐based cohort study from the Nordic Society of Pediatric Hematology and Oncology (NOPHO)

1 Background

The prognostic significance of extramedullary leukemia (EML) in childhood acute myeloid leukemia is not clarified.

2 Procedure

This population‐based study included 315 children from the NOPHO‐AML 2004 trial.

3 Results

At diagnosis, 73 (23%) patients had EML: 39 (12%) had myeloid sarcoma, 22 (7%) had central nervous system disease, and 12 (4%) had both. EML was associated with young age (median age: 2.6 years), a high white blood cell count (median: 40 × 10⁹/l), M5 morphology (40%), and 11q23/MLL (KMT2A) rearrangements (34%). No patient received involved field radiotherapy. Five‐year event‐free survival did not differ significantly between the EML and the non‐EML patients (54% vs. 45%, P = 0.57), whereas 5‐year overall survival (OS) was significantly lower in the EML group (64% vs. 73%, P = 0.04). The risk of induction death was significantly higher for EML patients (8% vs. 1%, P = 0.002). There was a trend toward a lower risk of relapse for EML patients (5‐year cumulative incidence of relapse 33% vs. 49%, P = 0.16). Traumatic lumbar puncture did not adversely affect survival in this cohort.

4 Conclusions

EML was associated with increased risk of induction death impacting the OS. No patients relapsed at the primary site of the myeloid sarcoma despite management without radiotherapy.