Electrophysiological Signs of Neurocognitive Deficits in Long-Term Leukemia Survivors

The long-term effects of disease and treatment on electrophysiologicalmeasures of neurocognitive function were studied in childrenwho had survived acute lymphoblastic leukemia (ALL) for at least4 years and were currently in remission. We report here changesin cognitive processing time as shown by the latency of theP3 wave of the auditory event-related EEG potential (ERP). P3latency was significantly prolonged in long-term ALL surivors,as well as in patients successfully trreated for solid tumors(ST)outside the CNS who received similar chemotherapy but did notreceive prophylactic treatment to the CNS. P3 latencies werestrongly correlated with measures of school performance andIQ in these individuals. The similarity in P3 latency betweenthe ALL and ST groups suggests that the treatments used on thesepateints produce changes in electrophysiological responses thatare associated with mild, but significant, cognitive deficits.     

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.     

Sex differences in cognitive processing in children treated with CNS prophylaxis for acute lymphoblastic leukemia

Evaluated cognitive processing in 51 children (27 female, 24 male) who had been treated for acute lymphoblastic leukemia (ALL) with CNS prophylaxis (cranial radiation in combination with intrathecal chemotherapy) and were continuously disease-free for 5 to 12 years. The control group comprised 15 children treated for Wilm's tumor. Functions assessed included visuoperceptual skills, generation of organizational strategies, sensitivity to organizational structure, and attention. The ALL group showed performance deficits relative to the solid tumor controls in appreciating the organization inherent in complex visuospatial material and alertness, with females more severely affected than males. Sex differences favoring males on IQ and academic achievement were related to these cognitive processes.     

Veränderungen der Blut-Liquorschranke für Serumproteine bei Kindern mit akuter lymphatischer Leukämie

Summary The blood-CSF barrier inhibits permeation of most chemotherapeutic agents into the central nervous system (CNS). The influence of systemic chemotherapy and prohylactic CNS irradiation on the permeability of the blood-CSF barrier was studied in 49 children treated for acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma.To study the permeability of the blood-CSF barrier under treatment according to BFM-ALL protocols, nephelometric determinations of albumin, immunoglobulin G (IgG), and alpha-2-macroglobulin in serum and CSF and total protein in CSF were performed at several time intervals during chemotherapy and prophylactic cranial irradiation.During systemic induction chemotherapy, no significant changes of blood-CSF barrier could be observed. In contrast, in the course of prophylactic CNS irradiation and intrathecal methotrexate application, a significant elevation of albumin, alpha-2-macroglobulin and total protein in CSF, and a significant decrease of blood: CSF ratios for albumin and alpha-2-macroglobulin were observed. IgG did not change significantly.After prophylactic CNS treatment and during maintenance chemotherapy protein concentrations and blood:CSF ratios gradually returned to normal range. This normalization was accelerated by cortisone treatment during the reinduction period.

     

Allogeneic Hematopoietic Cell Transplantation in Children with Relapsed Acute Lymphoblastic Leukemia Isolated to the Central Nervous System

Allogeneic hematopoietic cell transplantation (HCT) is the standard of care for pediatric patients with early medullary relapse of acute lymphoblastic leukemia (ALL). Most patients with isolated central nervous system (CNS) relapse have good outcomes when treated with intrathecal and systemic chemotherapy followed by irradiation to the neuroaxis. However, the role of HCT remains unclear for those patients with early isolated CNS relapse (<18 months) or who had high risk disease at diagnosis. We therefore compared the HCT outcomes of 116 children treated at the University of Minnesota from 1991 to 2006 with relapsed ALL involving the CNS alone (CNS, n = 14), the bone marrow alone (BM, n = 85), or both bone marrow and CNS (BM + CNS, n = 17). There were no significant differences among groups in age at diagnosis or transplant, length of first complete remission (CR1), remission status (CR2 versus ≥CR3), graft source, or preparative regimen. The incidence of acute GVHD was similar between groups. Patients with isolated CNS relapse had the lowest cumulative incidence of mortality following transplant (CNS: 0%, BM: 19%, BM + CNS: 29%, P = .03) and relapse (CNS: 0% BM: 30%, BM + CNS: 12%, at 2 years, P = .01) and highest leukemia-free survival (CNS: 91%, BM: 35%, BM + CNS: 46%, P < .01) at 5 years. Risk factors for poor survival were: T cell leukemia or BCR-ABL gene rearrangement, history of marrow relapse, and receipt of HLA-mismatched marrow. These data support the use of allogeneic HCT in the treatment of children with poor prognosis isolated CNS relapse.     

Leukemia in the central nervous system

The frequency of central nervous system (CNS) leukemia was studied in patients aged 15-59 with acute leukemia, who had received induction treatment in the years 1971-1986. Twelve out of 103 patients with acute lymphoblastic leukemia (ALL) developed CNS leukemia in spite of prophylaxis consisting of intrathecal methotrexate. Ten out of 217 patients with acute myelogenous leukemia (AML) developed CNS leukemia. None had been given preventive treatment. Leukemic blasts with either M4 or M5 morphology appeared to increase the risk of CNS relapse. Treatment was adjusted to the clinical problem of each patient, but always included intrathecal methotrexate. Median survival after a diagnosis of CNS leukemia was 8 and 6 months in ALL and AML respectively, with bone marrow failure due to hematologic relapse as the leading cause of death. CNS leukemia, if properly treated, does probably not shorten survival. An active approach to diagnosis and treatment is therefore mandatory.     

Neuropsychological, neuroanatomical, and neurophysiological consequences of CNS chemotherapy for acute lymphoblastic leukemia.

Medical treatment for acute lymphoblastic leukemia (ALL) has improved survival rates to 70% for children currently diagnosed with this disease. Intrathecal (IT) chemotherapy replaced CNS radiation therapy (CRT) for those with a favorable diagnosis as research revealed cognitive deficits associated with CRT. The literature pertaining to the potential adverse intellectual and neurophysiological consequences of IT chemotherapy is reviewed. It is concluded that IT chemotherapy may not be a benign form of treatment, although its effects may be more subtle than those produced by CRT. Future studies implementing more comprehensive test batteries are needed to illuminate these deficits so that remediation may be possible for ALL survivors.     

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.     

Central Nervous System Relapse of Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Little information is available regarding central nervous system (CNS) relapse of adult leukemia after allogeneic hematopoietic stem cell transplantation (HSCT). Therefore, we reviewed the data of 1226 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML) who received first allogeneic HSCT between 1994 and 2004, using the database of the Kanto Study Group for Cell Therapy (KSGCT), and analyzed the incidence, risk factors, and outcome of patients with CNS relapse. Twenty-nine patients developed CNS relapse at a median of 296 (9-1677) days after HSCT with a cumulative incidence of 2.3%. Independent significant factors associated with CNS relapse included ALL as the underlying diagnosis (relative risk [RR] = 9.55, 95% confidence interval [CI] = 1.26-72.2, P = .029), nonremission at HSCT (RR = 2.30, 95% CI = 1.03-5.15, P = .042), the history of CNS invasion before HSCT (RR = 5.62, 95% CI = 2.62-12.0, P = 9.2 × 10⁻⁶), and the prophylactic intrathecal chemotherapy after HSCT (RR = 2.57, 95% CI = 1.21-5.46, P = .014). The 3-year overall survival (OS) after CNS relapse was 18%. In 7 of 29 patients with CNS relapse, leukemia was observed only in CNS. Three of 7 patients were alive without systemic relapse, resulting in 3-year survival after CNS relapse of 46%. Although the outcome of patients with CNS relapse was generally poor, long-term disease-free survival could be achieved in some patients.     

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.     

Intellectual functioning of childhood leukemia survivors - relation to Tau protein - a marker of white matter injury

PurposeChemo- and radiotherapy used in acute lymphoblastic leukemia (ALL) can influence on brain functioning in the future. In a prospective study we analysed the cognitive functions of ALL survivors in relation to Tau protein as a marker of white matter injury.Material and methodsThirty-one survivors of childhood ALL (6.3 years after diagnosis); without the signs of CNS involvement, treated with chemotherapy alone, rested in first remission; underwent Intelligence tests- Wechsler Intelligence Scales (WISC-R, WAIS-R). Their results were analyzed in relation to the levels of Tau in cerebrospinal fluid (CSF) obtained during the treatment.ResultsThe analysis showed that all survivors attained the average scores in intelligence tests. A negative correlation was found between methotrexate (MTX) doses and Freedom from Distractibility (FFD). Females had higher values of Performance Intelligence Quotient (PIQ) than males. A negative correlation was noted of Tau protein levels obtained from the last CSF with: Total and Verbal Intelligence Quotient, PIQ, Perceptual Organisation Index and FFD but not with Verbal Comprehension Index.ConclusionOur results suggest the possibility of white matter injury during the treatment for ALL with chemotherapy alone. Elevated Tau protein level in CSF at the end of treatment might indicate future difficulties in neurocognitive functioning.     

Chemotherapeutic CNS prophylaxis and neuropsychologic change in children with acute lymphoblastic leukemia: a prospective study

OBJECTIVE: To determine whether prophylactic CNS chemotherapy for childhood acute lymphoblastic leukemia is associated with declines in neuropsychological abilities. METHODS: Growth curve analysis was used to examine neuropsychological outcome and treatment-related change in children (N = 30) who were treated at two childhood cancer centers. A comprehensive test battery was administered at baseline (8 months), 2, 3, and 4 years postdiagnosis (age at diagnosis M = 5.90 years, SD = 4.2C). RESULTS: Results indicated modest declines in arithmetic, visual motor integration, and verbal fluency. Intrathecal and systemic treatment was related to poorer visual motor integration at 4 years postdiagnosis and a faster rate of decline in visual motor integration skills across the observation period than intrathecal treatment alone. Arithmetic proficiency at 4 years after diagnosis was related to maternal education, but the rate of decline was not. Verbal fluency was unrelated to demographic or treatment variables. CONCLUSIONS: These findings suggest that neuropsychological outcome and declines are related to both demographic and treatment characteristics depending on the cognitive domain examined.     

The subacute effects of CNS prophylaxis for acute lymphoblastic leukemia on neuropsychological performance: a comparison of four protocols.

We report an assessment of the intellectual functioning after one year of therapy of 117 children treated for acute lymphoblastic leukemia (ALL) who were assigned to one of four protocols for central nervous systems (CNS) prophylaxis. These protocols were (a) 2400 rad cranial irradiation plus concurrent intrathecal methotrexate (i.t. MTX), (b)i.t. MTX alone, (c) 1800 rad cranial irradiation plus concurrent i.t. MTX, and (d) a protocol for high-risk patients that included intensive systemic chemotherapy plus 2400 rad delayed irradiation. Neuropsychological evaluation consisted of the Wechsler intelligence scales, the Wide Range Achievement Test, and selected tests from the Halstead-Reitan Neuropsychological Battery administered one year after diagnosis. All patients performed in the average range on measures, although the high-risk patients performed marginally worse than did the others. In general, our results do not support previous reports that cranial irradiation results in early adverse neuropsychological sequelae.     

Neurocognitive Outcome in Survivors of Childhood Acute Lymphoblastic Leukemia: Experience at a Tertiary Care Hospital in Korea

This study was conducted to investigate long-term neurocognitive outcomes and to determine associated risk factors in a cohort of Korean survivors of childhood acute lymphoblastic leukemia (ALL). Forty-two survivors of ALL were compared with 42 healthy controls on measures of a neurocognitive test battery. We analysed potential risk factors (cranial irradiation, sex, age at diagnosis, elapsed time from diagnosis, and ALL risk group) on neurocognitive outcomes. ALL patients had lower, but non-significant full-scale intelligence quotient (FSIQ, 107.2±12.2 vs. 111.7±10.2), verbal intelligence quotient (VIQ, 107.7±13.6 vs. 112.2±11.4), and performance intelligence quotient (PIQ, 106.3±14.2 vs. 110.1±10.7) scores than healthy controls. However, patients treated with cranial irradiation performed significantly lower on FSIQ (102.2±8.1), VIQ (103.3±11.7), and PIQ (101.4±13.2) compared to non-irradiated patients and healthy controls. ALL patients also had poor attention, concentration, and executive functions. Among ALL survivors, cranial irradiation was a risk factor for poor FSIQ, being male was a risk factor for poor PIQ, and younger age was a risk factor for poor attention. Therefore, the delayed cognitive effects of ALL treatment and its impact on quality of life require continuing monitoring and management.

Graphical Abstract

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Hyperfractionated, twice-a-day, radiotherapy may decrease IQ deterioration due to prophylactic cranial irradiation in childhood acute lymphoblastic leukemia: a radiobiological analysis.

High cure rates in childhood acute lymphoblastic leukemia (ALL) are being achieved with aggressive systemic chemotherapy and treatment to sanctuary sites including prophylactic cranial irradiation. However, IQ deterioration is a dreaded complication of prophylactic cranial irradiation. IQ deterioration is a late sequela. Since there is evidence--both radiobiological and clinical--to suggest that acute tissue (including tumor) response and late tissue response can be separated by hyper-fractionation, we propose a twice-a-day radiotherapy in prophylactic cranial irradiation of childhood ALL to decrease delayed toxicity. Analysis based on current radiobiological models favors such a treatment scheme. However, only a prospective clinical trial can confirm whether IQ deterioration can be prevented or decreased with hyper-fractionated radiotherapy.     

Malnutrition is an adverse prognostic factor in the response to treatment and survival of patients with acute lymphoblastic leukemia at the usual risk

A group of 43 pediatric patients with standard risk acute lymphoblastic leukemia (ALL) was studied prospectively and treated with a protocol that included adriamycin, vincristine and prednisone (HOP) to induce remission; cranial irradiation and intrathecal methotrexate (MTX) as CNS prophylaxis and mercaptopurine and MTX together with pulses of HOP every three months to maintain remission. Complete remission (CR) was achieved in 95.3% of the group; 5-year survival was 67%. The following variables were analyzed in the outcome to treatment: Age, sex, WBC at diagnosis, FAB morphology, CALLA/CD10 reactivity of the blast cells, lymph node, liver or spleen enlargement, site of treatment (private practice versus city hospital) and malnutrition. None of these variables had a significant impact in survival, but malnutrition. Under-nourished children (UNC) n = 16, had a significant worse outcome than well-nourished children (WNC) n = 27. Although CR was achieved in 98% of WNC versus 94% of UNC, five-year survival was 83% for WNC and 26% for UNC (p less than .001); relapses were observed in 18% of WNC and 75% of UNC (p less than .0005). Relapses presented more frequently in the bone marrow in UNC than in WNC (56% versus 7% p less than .0001). The doses of maintenance chemotherapy had to be reduced in 68% of UNC and 10% of WNC (p less than .005). The poor outcome to treatment observed in UNC was due to systemic relapses, apparently related to a poor tolerance to maintenance chemotherapy. Malnutrition might be included as an adverse prognostic factor in the outcome to treatment of children with ALL, in developing countries.     

Neuropsychological sequelae of central nervous system prophylaxis in survivors of childhood acute lymphoblastic leukemia

We assessed neuropsychologically 106 children with acute lymphoblastic leukemia (ALL) who had all received cranial irradiation for the prevention of central nervous system (CNS) leukemia 1-13 years previously. Children were assessed for adverse late effects of their therapy, using age-appropriate Wechsler measures of overall intellectual ability and supplementary tests. Forty-five siblings near in age to the patients were tested as controls. The patients who had had the most intensive central nervous system (CNS) prophylaxis were found to have a WISC-R Full Scale IQ 17 points lower than the sibling control group. Performance IQ was more affected than verbal IQ. The patients were more easily distracted and less able to concentrate. The severity of the aftereffects was related to younger age at the time of CNS prophylaxis and to a higher dose of cranial irradiation but not to time since CNS prophylaxis. CNS prophylaxis using a combination of cranial irradiation and intrathecal methotrexate has lowered the incidence of CNS relapse in childhood ALL but is associated with considerable long-term morbidity in survivors.     

White Matter Microstructure and Information Processing at the Completion of Chemotherapy-Only Treatment for Pediatric Acute Lymphoblastic Leukemia

Little is known about white matter microstructure and its role in information processing abilities of children treated for acute lymphoblastic leukemia (ALL) early posttreatment. Twenty-one survivors of ALL and 18 controls (7–16 years) underwent neurocognitive assessment. A subsample underwent diffusion-weighted magnetic resonance imaging. The ALL group performed poorer on measures of processing capacity, and had widespread areas of decreased fractional anisotropy and increased radial diffusivity. Significant group by white matter microstructure interactions was found when predicting processing speed. Findings provide evidence for an atypical brain–behavior relationship early posttreatment for childhood ALL. Replication in a larger sample is required.     

Premature chromosome condensation as a predictive indicator of relapse in children and adolescents with acute leukemia: initial observations

Premature chromosome condensation has been used to determine a proliferative potential index (PPI) in a study of children in leukemia remission at varying times during the disease. Values 35% and greater were considered predictive of relapse. Such values preceded relapse with a mean of 5 months in acute lymphoblastic leukemia (ALL) patients who had previously relapsed and in myeloid leukemia patients. ALL patients followed from diagnosis and children off therapy had fluctuating and false predictive PPI values preceding long courses of continued remission. This study suggests that the PPI as a predictive indicator for relapse may be useful for patients with ALL who have previously relapsed and for patients with myeloid leukemias. Future exploration to further evaluate this mechanism of prediction is to be attempted by investigating the ability to obtain similar and more detailed information through the use of peripheral blood rather than bone marrow samples.     

Acute neurocognitive response to methylphenidate among survivors of childhood cancer: a randomized, double-blind, cross-over trial

OBJECTIVE: To investigate the acute efficacy and adverse side effects of methylphenidate (MPH) among survivors of childhood cancer [acute lymphoblastic leukemia (ALL) or brain tumor (BT)] with learning impairments. METHODS: Participants (N = 122) completed a two-day, in-clinic, double-blind, cross-over trial during which they received MPH (0.60 mg/kg of body weight) and placebo that were randomized in administration order across participants. Performance was evaluated using measures of attention, memory, and academic achievement. RESULTS: A significant MPH versus placebo effect was revealed on a measure of attention, cognitive flexibility, and processing speed (Stroop Word-Color Association Test). Male gender, older age at treatment, and higher intelligence were predictive of better medication response. No significant differences were found for number or severity of adverse side effects as a function of active medication. CONCLUSIONS: MPH shows some neurocognitive benefit and is well tolerated by the majority of children surviving ALL and BT.