Cognitive effects of childhood leukemia therapy: a case for four specific deficits

Prophylactic treatment of the central nervous system (CNS) with cranial irradiation and antineoplastic drugs has made childhood acute lymphoblastic leukemia (ALL) a survivable disease, but at the same time there have been many reports of iatrogenic effects, including deficits in cognitive functioning. Previous research suggests a particular effect on the Freedom from Distractibility factor of the WISC-R, memory, and attention. These particular abilities are tested in a group of 43 ALL survivors, with comparisons against solid tumor as well as sibling controls. The results indicate that four cognitive processes are affected by CNS prophylaxis for ALL: short-term memory, speed of processing, visuomotor coordination, and sequencing ability. Younger children have a more severe speed of processing deficit and children treated with a less rigorous protocol appear to be slightly less affected generally. The specific cognitive deficits found are related to neurological evidence on both theoretical and empirical grounds. Results suggest that children who have received CNS prophylaxis are able to learn, but may be slower to acquire new material and may benefit from bimodal presentation.     

Cognitive and Academic Late Effects Among Children Previously Treated for Acute Lymphocytic Leukemia Receiving Chemotherapy as CNS Prophylaxis

Objective: Examine cognitive and academic late effects amongchildren and adolescents who had received central nervous system(CNS) prophylactic chemotherapy alone for acute lymphocyticleukemia (ALL); none had received whole brain radiation therapy(RT). Method: Subjects included 47 children and adolescents from 5to 22 years of age who were treated on the same protocol andhad been off treatment from 2 to 7 years at the time of assessment. Results: As a group the survivors displayed generally averageperformance on measures of cognitive and academic abilities,although they differed from normative means on tests of nonverbalskills. Girls performed more poorly than the normative sampleon nonverbal tasks, while no differences were found for boys.Age at diagnosis and time off treatment were not significantlyassociated with cognitive and academic functioning for survivorsof this particular chemotherapy-only protocol. Conclusions: Data were interpreted to support generally modestpotential late effects in specific areas for children and adolescentssurviving ALL. These findings suggest a need for monitoringnonverbal cognitive skills for childhood survivors of ALL, particularlyfor girls.     

Cognitive status of children treated with central nervous system prophylactic chemotherapy for acute lymphocytic leukemia.

Treatment-related cognitive impairments have been reported for survivors of childhood leukemia following prophylactic central nervous system (CNS) treatment with craniospinal radiation. We examined the neurocognitive status of 46 children with acute lymphocytic leukemia (ALL) to assess the impact of a regimen consisting of systemic chemotherapy and prophylactic CNS chemotherapy. By comparing three groups of ALL children (i.e., patients whose diagnosis was recent, patients 1 year postdiagnosis currently receiving CNS prophylactic chemotherapy, and off-therapy patients who had been treated with chemotherapy for 3 years) and their healthy siblings on measures of sequential and simultaneous processing, we were able to examine the effects of CNS prophylactic and systemic chemotherapy at various points during treatment. Results indicate that the children who had received a 3-year course of chemotherapy (off-therapy patients) were more impaired on tasks involving right-hemisphere simultaneous processing than were sibling controls or ALL children whose diagnosis was recent and whose treatment had just begun. Age at diagnosis did not interact with the effects of chemotherapy. These findings support the need for continued evaluation of cognitive functioning in ALL, children receiving CNS prophylactic chemotherapy to identify potential harmful neurocognitive sequelae of treatment.     

急性淋巴细胞白血病患儿骨髓基质细胞的粘附行为

目的和方法:用MTT方法检测了急性淋巴细胞白血病(ALL)患儿骨髓基质细胞(BMSC)对正常骨髓造血细胞和淋巴瘤Raji细胞的粘附行为,用流式细胞仪检测了BMSC表面的粘附分子ICAM-1和VCAM-1的表达。结果:急性期组ALLBMSC对骨髓造血细胞的粘附能力明显下降。长期缓解组ALLBMSC对肿瘤细胞的粘附能力明显增高。急性期组ALLBMSC表面ICAM-1表达明显降低。结论:ALL患儿BMSC对骨髓造血细胞和肿瘤细胞的粘附行为的异常,BMSC粘附行为的变化与细胞表面粘附分子的表达异常有关。     

Acute lymphoblastic leukemia in children below two years of age

From among 1464 children with ALL 167 (11.4%) at diagnosis had two or less than two years, 53 of them were infants. Most of them had a great tumor bulk, 15 had initial CNS infiltration and 31 WBCc greater than or equal to 100000/ML. 66 were treated according to St. Jude or LSA2L2 programs (the I group), 101 according to BFM programs (the II group). Complete remission was obtained in 85% of patients. In 63 children relapses occurred in the course of treatment whereas in 5 after the therapy cessation. In majority of cases, there were isolated relapses, mostly, they involved bone marrow. CNS involvement was found, in both mixed and isolated relapses, in 28 children (20%). 64 children are alive, in 43 of them the therapy was stopped. Kapla-Meier estimates for event free survival (EFS) after 8 years were 19 +/- 4.7% in the first group vs 37.38 +/- 6.3% in the second group. Due to therapy intensification the treatment results have been improved (p = 0.05) but still they are not satisfactory, particularly in case of infants and children with WBC greater than or equal to 100000/ML. Analysis of the lot of children showed that apart from age at ALL diagnosis and the initial WBC the methods of treatment are also the prognostic factors.     

Intellectual, neuropsychological, and academic functioning in long-term survivors of leukemia

OBJECTIVE: To assess the effects of treatment for acute lymphoblastic leukemia (ALL) on children's cognitive functioning. METHOD: Participants were long-term survivors of ALL treated with cranial irradiation and central nervous system (CNS) chemotherapy (n = 20), or CNS chemotherapy only (n = 21), healthy children (n = 21), and children with chronic asthma (n = 21). The groups were compared on measures of intellectual, neuropsychological, and academic functioning. RESULTS: CNS chemotherapy, with and without cranial irradiation, was associated with significantly lower levels of intellectual and academic functioning. Children with chronic asthma obtained lower scores than healthy controls, but these differences were not significant. Tests of neuropsychological functioning did not consistently separate the groups. CONCLUSIONS: CNS chemotherapy and, to a lesser extent, chronic illness both contribute to the poorer performance of long-term survivors of ALL on measures of intellectual and academic functioning.     

Laboratory correlates and prognostic significance of granular acute lymphoblastic leukemia in children. A Pediatric Oncology Group study.

As part of a comprehensive prospective clinicopathologic study by the Pediatric Oncology Group (POG), 2,092 children with acute lymphoblastic leukemia (ALL) were evaluated by uniform morphologic, cytochemical, and immunologic methods to assess the frequency and implications of granular lymphoblasts. All cases were Sudan black or myeloperoxidase negative and met French-American-British (FAB) morphologic criteria for ALL. Granular ALL, characterized by the presence of more than 5% marrow blasts with at least three clearly defined azurophilic cytoplasmic granules, was identified in 56 of the 1,252 fully studied cases (4.5%). The frequency of granular features did not differ among early pre-B (4.3%), pre-B (3.6%), and T (5.8%) ALL; no cases were identified among the 12 patients with B ALL. Within the early pre-B/pre-B group, granular ALL was equally distributed between good- and poor-risk clinical groups but was more frequent among FAB L2 than FAB L1 cases (12% vs. 2%; P less than or equal to 0.001). Patients were treated with standard POG protocols for early pre-B/pre-B and T ALL. Complete remission (CR) rates were significantly lower for those with granular lymphoblasts, regardless of risk group, immunophenotype, or FAB type. Analysis of event-free survival (EFS) showed a significantly poorer outcome for granular early pre-B/pre-B cases with FAB L2 morphologic characteristics (P less than 0.001) and for those classified as poor risk (P = 0.015). These findings suggest a relationship between granules and L2 morphologic characteristics in childhood ALL and indicate that the presence of granular lymphoblasts conveys a worse prognosis for certain subgroups of children with ALL.     

Exchange transfusion in children with blastic hyperleukocytosis in acute lymphoblastic leukemia

In 10 children with acute lymphoblastic leukaemia (mean leucocyte count 452 x 10(9)/l) 17 exchange transfusions were done for rapid reduction of this count. The control group comprised 11 children with similar values of white blood cell counts (mean 324 x 10(9)/l) treated initially with small, increasing doses of corticosteroids. In contrast to acute myeloid leukaemia the results do not support the usefulness of exchange transfusions in children with hyperleukocytosis during ALL.     

Analysis of microsatellite instability in children treated for acute lymphocytic leukemia with elevated HPRT mutant frequencies

Survival rates of children treated for cancer have increased dramatically over the last 25 years following the development of risk-directed multi-modality treatment protocols. As a result, there is a rapidly growing population of children and young adult cancer survivors in which the long-term genotoxic effects of chemotherapeutic intervention is unknown. We have previously observed that children treated for acute lymphocytic leukemia (ALL) have significantly increased somatic mutant frequencies (Mfs) (30- to 1300-fold higher) at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) reporter gene in their non-malignant peripheral T cells compared with children at diagnosis or controls. In order to gain insight into the etiology of the observed dramatic increase in Mfs following antineoplastic therapy, we investigated the prevalence of microsatellite instability (MSI), reflective of a defect in DNA mismatch repair (MMR), in children with ALL at diagnosis, during and after chemotherapy and compared them with healthy age-matched controls. MSI analysis using five microsatellite markers was performed on 167 T cell isolates from 40 healthy children and on 842 T cell isolates from 50 patients treated for ALL. High-frequency MSI (MSI-high) was identified in 2 healthy children (5%) and in 2 of 20 ALL subjects at the time of disease recurrence (relapse) (10%). There was no statistically significant difference between the prevalence of MSI-high in patients at the time of ALL relapse and healthy children, nor between the children with ALL at other time points and healthy children. These data indicate that MMR defects, represented by MSI, are not a significant contributor to the elevated HPRT Mfs seen in children treated for ALL. However, in a small number of patients chemotherapy may play a role in the selection of cells with defects in MMR that may have long-term clinical implications.     

Brief report: effect of intravenous methotrexate dose and infusion rate on neuropsychological function one year after diagnosis of acute lymphoblastic leukemia

OBJECTIVE: To compare the effects of two intravenous (IV) methotrexate (MTX) infusion protocols on cognitive function in children newly diagnosed with acute lymphoblastic leukemia (ALL). METHODS: We compared 19 children treated with 1 g/m(2) of IV MTX over 24 hr (Group 1) to 13 children treated with 2 g/m(2) of IV MTX over 4 hr (Group 2) on measures of working memory, nonverbal, and verbal skills shortly after diagnosis (Time 1) and 1 year later (Time 2). RESULTS: A significant GroupxTime interaction was found for a composite measure of working memory with Group 2 declining from Time 1 to Time 2. Group 2 performed significantly worse than Group 1 on a composite measure of nonverbal skills at both time points. CONCLUSIONS: Findings suggest that difficulties in working memory and nonverbal skills may be evident during the first year of treatment for ALL and that severity may be dependent on IV MTX dose and/or infusion rate.     

Scholarly literature review: management of neurocognitive late effects with stimulant medication

OBJECTIVE: To examine the extant literature on stimulant drug therapy for survivors of childhood cancer during the late-effects period. METHODS: A review of literature is provided on the mechanism of and cognitive toxicities for children and adolescents treated for acute lymphoblastic leukemia (ALL) and malignant brain tumors (BT) as well as the pharmacotherapy of stimulant medications, with a specific review of literature on the efficacy and safety of the stimulants for children with ALL and BT. RESULTS: Only four studies were found that have examined the effects of stimulant medication on the cognitive toxicities of childhood survivors of cancer during the late-effects period and only two of these investigations were controlled clinical trials. Findings suggest efficacy of the stimulants on parent and teacher ratings of attention and putative tasks of attention and executive functioning. CONCLUSIONS: Although there is some preliminary support for the efficacy and safety of the stimulants for survivors of ALL and BT, more research is needed concerning the long-term effects of the stimulants among cancer survivors.     

Cognitive Predictors of Adaptive Functioning Vary According to Pediatric Brain Tumor Location

This archival study sought to determine if the relationship between cognitive and adaptive abilities varied according to brain tumor location. Participants were 36 children treated for brain tumors. The best cognitive predictors of adaptive functioning were hypothesized to be attention span within the cerebellar group and verbal memory within the third ventricle group. Auditory attention span significantly predicted communication skills for the cerebellar group, whereas verbal memory significantly predicted socialization skills for the third ventricle group. These findings suggest that cognitive predictors vary according to tumor location, and highlight the need for more research examining adaptive functioning and its correlates.     

Cognitive predictors of adaptive functioning vary according to pediatric brain tumor location

This archival study sought to determine if the relationship between cognitive and adaptive abilities varied according to brain tumor location. Participants were 36 children treated for brain tumors. The best cognitive predictors of adaptive functioning were hypothesized to be attention span within the cerebellar group and verbal memory within the third ventricle group. Auditory attention span significantly predicted communication skills for the cerebellar group, whereas verbal memory significantly predicted socialization skills for the third ventricle group. These findings suggest that cognitive predictors vary according to tumor location, and highlight the need for more research examining adaptive functioning and its correlates.     

Clinico-immunological characteristics of lymphoid tumors in children

The clinical and immunological characteristics of lymphoid tumors were compared in 591 children with acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). Comprehensive investigation of a tumor cell by using cytological, morphological, and immunological studies revealed the most significant criteria for differential diagnosis of ALL and NHL in children and showed the specific features of the site of a tumor and the extent of its growth in ALL and NHL in relation to the immunological affiliation of a tumor cell. The predominance of immature forms, such as stem-cell CD34+, pre-pre-B, pre-B and less commonly T-cell forms with almost none peripheral B- and T-cell markers could be immunophenotypically detected in ALL. NHL was, on the contrary, characterized by the prevalence of mature immunological subtypes with peripheral B- and T-cell markers and much less frequently pre-B and pre-T cells and at the same time there was no CD34 antigen in the tumor cells. Anaplastic giant lymphoma was a peculiar type of NHL characterized by the presence of large cells having marked anaplasia and expression on the surface of CD30 antigen. A comprehensive study of lymphoid tumors in children showed that immunophenotyping was of great value, whose results were associated with the specific feature of tumor growth and prognosis, which should be borne in mind while planning antitumor therapy programmes.     

儿童急淋大剂量甲氨蝶呤延迟解救的安全性研究

目的 探讨大剂量使用甲氨蝶呤（HD-MTX）治疗儿童急性淋巴细胞白血病（ALL）后延迟6 h解救的安全性。方法 选择2006年1月~2018年12月在我院接受治疗的中高危ALL患儿108例作为研究对象,所有患儿均接受HD-MTX治疗,根据开始使用亚叶酸钙（CF）解救时间分为36H组及42H组,各54例。比较两组患儿的临床表现、常见不良反应情况及第2、3次解救后血药浓度。结果 36H组患儿骨髓抑制、口腔黏膜损害、胃肠道反应、肝功能异常、皮疹、继发感染发生率分别为81.48%（44/54）、20.37%（11/54）、24.07%（13/54）、44.44%（24/54）、11.11%（6/54）、11.11%（6/54）,42H组分别为88.89%（48/54）、12.96%（7/54）、16.67%（9/54）、51.85%（28/54）、7.41%（4/54）、9.26%（5/54）,组间比较,差异无统计学意义（P＞0.05）;两组第2、3次解救后血药浓度比较,差异无统计学意义（P＞0.05）。结论 ALL患儿接受HD-MTX治疗后42 h解救与36 h解救的安全性基本一致,但延迟6 h解救可以更好的发挥MTX的抗肿瘤作用。     

Brief report: sluggish cognitive tempo among pediatric survivors of acute lymphoblastic leukemia

OBJECTIVE: The purpose of the present study was to assess sluggish cognitive tempo (SCT) behavioral symptoms among pediatric survivors of acute lymphoblastic leukemia (ALL) and to determine the relationship of these behaviors with cognitive late effects. METHODS: ALL survivors (n = 80) and a sibling control group (n = 19) were administered intelligence (IQ) testing, achievement testing and SCT behavioral items. Group differences (patients vs. siblings) were examined on the SCT behaviors and partial correlations were conducted to explore the relationship of the SCT behaviors with IQ and achievement, while controlling for age at treatment and time since treatment. RESULTS: ALL survivors exhibited significantly more SCT symptoms than the sibling control group and increased SCT symptoms were associated with lower IQ and achievement scores. CONCLUSIONS: ALL survivors are vulnerable to SCT symptoms and these behaviors are associated with cognitive late effects. SCT symptoms may represent a behavioral component of cognitive late effects.     

Visuomotor Function in Children Treated for Acute Lymphoblastic Leukaemia With Chemotherapy Only

This study aimed to evaluate visuomotor function in children treated for acute lymphoblastic leukaemia (ALL). The performance of 64 children, 1–7 years post-chemotherapy for ALL, was compared to that of their healthy peers (n?=?56) on visuomotor integration (VMI) and motor coordination (MC) tasks. Children posttreatment for ALL displayed significantly reduced VMI, but not MC, performances as compared to controls. Children treated on chemotherapy-only ALL regimes are at heightened risk for visuomotor integration deficits. Monitoring of visuomotor skills and implementation of appropriate interventions targeting higher level visuomotor integration skills should form an important component of any ALL long-term effects program.     

Dendritic cell regeneration in the bone marrow of children treated for acute lymphoblastic leukaemia

Dendritic cells (DC) play a pivotal role in coordinating functions of the immune system. Little is known about DC levels in the bone marrow (BM) of patients receiving cytostatic treatment. We investigated DC levels by flow cytometry in BM at diagnosis, during and post-treatment in 76 children with acute lymphoblastic leukaemia (ALL). The levels of both plasmacytoid DC (pDC) and myeloid DC (mDC) were profoundly reduced at diagnosis. However, the levels of pDC and mDC were significantly higher in T-precursor ALL patients when compared with B-precursor ALL patient group (P = 0.044 and 0.041 respectively). Both subsets normalized in both standard-risk (SR) and high-risk patients after the end of induction at day 50. Patients with minimal residual disease (MRD) at day 50 had significantly higher pDC levels than MRD-negative patients (P = 0.021). In B-precursor SR ALL patients, mDC levels but not pDC levels decreased during prolonged maintenance treatment, remaining reduced at the end of treatment (P = 0.032) and at 6 months post-treatment (P = 0.028). In conclusion, levels of DC in BM normalize quickly in children treated for ALL. Long-term treatment may more profoundly affect mDC subset, which shows reduced levels several months after treatment.     

淋巴母细胞淋巴瘤/白血病临床病理、免疫表型及预后相关性研究

目的 探讨淋巴母细胞淋巴瘤/急性淋巴母细胞白血病(LBL/ALL)临床病理、免疫组织化学特征并行预后相关性分析.方法 回顾性研究153例LBL/ALL患者的临床病理资料,根据临床和随访结果,对其预后与免疫表型、Ann Arbor分期、纵隔肿块、骨髓受累、肝脾肿大、Ki-67指数以及患者年龄、性别多因素进行相关性研究.结果 TdT和CIY99阳性率分别为79.1%(121/153例)和96.3%(131/136例).按免疫表型分为T-、B-LBI/ALL及未定类.(1)T-LBL/ALL占69.3%(106/153例),男75例,女31例,中位年龄17.5(2～68)岁,92例(86.8%)表现为外周淋巴结肿大,其中59例(55.7%)伴有纵隔肿块,91例(85.8%)为Ⅲ～进展期.1年与5年生存率分别为36.1%和8.1%,年龄大于25岁(P=0.049)、Ⅲ～Ⅳ期(P=0.001)是T-LBL/ALL预后不良的指征.(2)B-LBL/ALL占19.O%(29/153例),男18例,女11例,中位年龄14岁(9个月～75岁),17例(58.6%)表现为外周淋巴结肿大,其中13例(44.8%)有骨髓或外周血受累,5例(17.2%)伴有纵隔病变,21例病变处于Ⅲ～Ⅳ期.1年与5年生存率分别为53.3%和36.7%.(3)未定类组为11.7%(18/153例),所检抗体如CD3ε/CD3、CD45RO、CD79a、CD20、髓过氧化物酶(MPO)、CD5、CD56、cyclin D1、CK、神经元特异性烯醇化酶(NSE)、嗜铬粒素A(CgA)和突触素(Syn)均阴性.男13例,女5例,中位年龄15.5(4～53)岁,原发淋巴结病变15例(83.3%),7例(38.9%)有纵隔病变.(4)与B-LBL/ALL比较,T-LBI/ALL患者伴有纵隔肿块较为常见(P=0.0003),中位生存期短[分别为(15.0±7.0)个月和(6.0±1.1)个月],但差异无统计学意义(P=0.07).结论 TdT与CD99是前驱淋巴细胞重要的特异性标志物;T-LBL/ALL多见于青少年男性,常伴有纵隔占位及浅表或多处淋巴结肿大;B-LBL/ALL易累及骨髓或外周血;T-LBL/ALL预后较差,年龄和临床分期是影响T-LBL/ALL患者生存的重要预后参数.