Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia.

PURPOSE: Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in those with newly diagnosed disease. PATIENTS AND METHODS: From 2007 to 2014, Children's Oncology Group trial AALL0434 (ClinicalTrials.gov identifier: NCT00408005) enrolled 1,562 evaluable patients with T-ALL age 1-31 years who received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2 × 2 pseudo-factorial randomization to receive escalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned after induction to receive or not receive six 5-day courses of nelarabine that was incorporated into ABFM. Patients who experienced induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease (CNS3; ≥ 5 WBCs/µL with blasts) received HDMTX and were randomly assigned to receive or not receive nelarabine. All patients, except those with low-risk disease, received cranial irradiation. RESULTS: The 5-year event-free and overall survival rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. The 5-year disease-free survival (DFS) rates for patients with T-ALL randomly assigned to nelarabine (n = 323) and no nelarabine (n = 336) were 88.2% ± 2.4% and 82.1% ± 2.7%, respectively (P = .029). Differences between DFS in a four-arm comparison were significant (P = .01), with no interactions between the MTX and nelarabine randomizations (P = .41). Patients treated with the best-performing arm, C-MTX plus nelarabine, had a 5-year DFS of 91% (n = 147). Patients who received nelarabine had significantly fewer isolated and combined CNS relapses compared with patients who did not receive nelarabine (1.3% ± 0.63% v 6.9% ± 1.4%, respectively; P = .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms. CONCLUSION: The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.

Optimizing pegylated asparaginase use: An institutional guideline for dosing, monitoring, and management.

The incorporation of L-asparaginase and pegylated asparaginase into pediatric-inspired regimens has conferred a survival advantage in treatment of adults with acute lymphoblastic leukemia. Use of asparaginase products requires careful prevention, monitoring, and management of adverse effects including hypersensitivity, hepatotoxicity, pancreatitis, coagulopathy, and thrombosis. Currently, there is limited published literature to offer guidance on management of these toxicities. At the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, a standard of practice guideline was created to prevent and manage asparaginase-related adverse events. By sharing our long-term experience with asparaginase products and clinical management of asparaginase-induced toxicities, this article aims to improve patient safety and optimize treatment outcomes.

Asparaginase combined with discontinuous dexamethasone improves antileukemic efficacy without increasing osteonecrosis in preclinical models.

INTRODUCTION: Combination therapy for acute lymphoblastic leukemia (ALL) is highly effective but results in significant toxicity including osteonecrosis. Asparaginase is known to potentiate both the antileukemic and osteonecrosis-inducing effects of dexamethasone. The schedule of dexamethasone alters osteonecrosis risk. However, the effects of the interaction with asparaginase are unknown when dexamethasone is given on a discontinuous schedule. METHODS: Using the murine model of osteonecrosis, we compared the frequency of osteonecrosis in mice receiving discontinuous dexamethasone (3.5 days/ week) with mice receiving asparaginase and discontinuous dexamethasone. We then tested the effect on antileukemic efficacy using six pediatric ALL xenografts. RESULTS: The addition of asparaginase to discontinuous dexamethasone did not alter the rate of osteonecrosis compared to dexamethasone alone (7/35 in dexamethasone with asparaginase combination vs. 10/36 in dexamethasone alone, p = 0.62) despite increasing steady-state plasma dexamethasone levels (103.9 nM vs. 33.4 nM, p = 9.2x10-7). Combination therapy with asparaginase and dexamethasone demonstrated synergistic antileukemic effects across all six xenografts studied. CONCLUSIONS: When discontinuous dexamethasone was given, its anti-leukemic activity synergized with asparaginase but the osteonecrosis-worsening effects of asparaginase (above dexamethasone alone) were not observed. Thus, there is a favorable drug interaction (unchanged toxicity, synergistic efficacy) between discontinuous dexamethasone and asparaginase.

Improved Survival for Children and Young Adults With T-Lineage Acute Lymphoblastic Leukemia: Results From the Children's Oncology Group AALL0434 Methotrexate Randomization.

PURPOSE: Early intensification with methotrexate (MTX) is a key component of acute lymphoblastic leukemia (ALL) therapy. Two different approaches to MTX intensification exist but had not been compared in T-cell ALL (T-ALL): the Children's Oncology Group (COG) escalating dose intravenous MTX without leucovorin rescue plus pegaspargase escalating dose, Capizzi-style, intravenous MTX (C-MTX) regimen and the Berlin-Frankfurt-Muenster (BFM) high-dose intravenous MTX (HDMTX) plus leucovorin rescue regimen. PATIENTS AND METHODS: COG AALL0434 included a 2 × 2 randomization that compared the COG-augmented BFM (ABFM) regimen with either C-MTX or HDMTX during the 8-week interim maintenance phase. All patients with T-ALL, except for those with low-risk features, received prophylactic (12 Gy) or therapeutic (18 Gy for CNS3) cranial irradiation during either the consolidation (C-MTX; second month of therapy) or delayed intensification (HDMTX; seventh month of therapy) phase. RESULTS: AALL0434 accrued 1,895 patients from 2007 to 2014. The 5-year event-free survival and overall survival rates for all eligible, evaluable patients with T-ALL were 83.8% (95% CI, 81.2% to 86.4%) and 89.5% (95% CI, 87.4% to 91.7%), respectively. The 1,031 patients with T-ALL but without CNS3 disease or testicular leukemia were randomly assigned to receive ABFM with C-MTX (n = 519) or HDMTX (n = 512). The estimated 5-year disease-free survival ( P = .005) and overall survival ( P = .04) rates were 91.5% (95% CI, 88.1% to 94.8%) and 93.7% (95% CI, 90.8% to 96.6%) for C-MTX and 85.3% (95% CI, 81.0%-89.5%) and 89.4% (95% CI, 85.7%-93.2%) for HDMTX. Patients assigned to C-MTX had 32 relapses, six with CNS involvement, whereas those assigned to HDMTX had 59 relapses, 23 with CNS involvement. CONCLUSION: AALL0434 established that ABFM with C-MTX was superior to ABFM plus HDMTX for T-ALL in approximately 90% of patients who received CRT, with later timing for those receiving HDMTX.

Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice.

Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule.

Cost comparison by treatment arm and center-level variations in cost and inpatient days on the phase III high-risk B acute lymphoblastic leukemia trial AALL0232.

The Children's Oncology Group (COG) develops and implements multi-institutional clinical trials with the primary goal of assessing the efficacy and safety profile of treatment regimens for various pediatric cancers. However, the monetary costs of treatment regimens are not measured. AALL0232 was a COG randomized phase III trial for children with acute lymphoblastic leukemia that found that dexamethasone (DEX) was a more effective glucocorticoid than prednisone (PRED) in patients younger than 10 years, but PRED was equally effective and less toxic in older patients. In addition, high-dose methotrexate (HD-MTX) led to better survival than escalating doses of methotrexate (C-MTX). Cost data from the Pediatric Health Information System database were merged with clinical data from the COG AALL0232 trial. Total and component costs were compared between treatment arms and across hospitals. Inpatient costs were higher in the HD-MTX and DEX arms when compared to the C-MTX and PRED arms at the end of therapy. There was no difference in cost between these arms at last follow-up. Considerable variation in total costs existed across centers to deliver the same therapy that was driven by differences in inpatient days and pharmacy costs. The more effective regimens were found to be more expensive during therapy but were ultimately cost-neutral in longer term follow-up. The variations in cost across centers suggest an opportunity to standardize resource utilization for patients receiving similar therapies, which could translate into reduced healthcare expenditures.

Neurocognitive Functioning of Children Treated for High-Risk B-Acute Lymphoblastic Leukemia Randomly Assigned to Different Methotrexate and Corticosteroid Treatment Strategies: A Report From the Children's Oncology Group.

Purpose Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for neurocognitive deficits that are associated with treatment, individual, and environmental factors. This study examined the impact of different methotrexate (MTX) and corticosteroid treatment strategies on neurocognitive functioning in children with high-risk B-lineage ALL. Methods Participants were randomly assigned to receive high-dose MTX with leucovorin rescue or escalating dose MTX with PEG asparaginase without leucovorin rescue. Patients were also randomly assigned to corticosteroid therapy that included either dexamethasone or prednisone. A neurocognitive evaluation of intellectual functioning (IQ), working memory, and processing speed (PS) was conducted 8 to 24 months after treatment completion (n = 192). Results The method of MTX delivery and corticosteroid assignment were unrelated to differences in neurocognitive outcomes after controlling for ethnicity, race, age, gender, insurance status, and time off treatment; however, survivors who were age < 10 years at diagnosis (n = 89) had significantly lower estimated IQ ( P < .001) and PS scores ( P = .02) compared with participants age ≥ 10 years. In addition, participants who were covered by US public health insurance had estimated IQs that were significantly lower ( P < .001) than those with US private or military insurance. Conclusion Children with high-risk B-lineage ALL who were age < 10 years at diagnosis are at risk for deficits in IQ and PS in the absence of cranial radiation, regardless of MTX delivery or corticosteroid type. These data may serve as a basis for developing screening protocols to identify children who are at high risk for deficits so that early intervention can be initiated to mitigate the impact of therapy on neurocognitive outcomes.

Role of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase.

The anti-leukemic agent asparaginase activates the integrated stress response (ISR) kinase GCN2 and inhibits signaling via mechanistic target of rapamycin complex 1 (mTORC1). The study objective was to investigate the protective role of activating transcription factor 4 (ATF4) in controlling the hepatic transcriptome and mediating GCN2-mTORC1 signaling during asparaginase. We compared global gene expression patterns in livers from wildtype, Gcn2 -/-, and Atf4 -/- mice treated with asparaginase or excipient and further explored selected responses in livers from Atf4 +/- mice. Here, we show that ATF4 controls a hepatic gene expression profile that overlaps with GCN2 but is not required for downregulation of mTORC1 during asparaginase. Ingenuity pathway analysis indicates GCN2 independently influences inflammation-mediated hepatic processes whereas ATF4 uniquely associates with cholesterol metabolism and endoplasmic reticulum (ER) stress. Livers from Atf4 -/- or Atf4 +/- mice displayed an amplification of the amino acid response and ER stress response transcriptional signatures. In contrast, reduction in hepatic mTORC1 signaling was retained in Atf4 -/- mice treated with asparaginase. CONCLUSIONS: GCN2 and ATF4 serve complementary roles in the hepatic response to asparaginase. GCN2 functions to limit inflammation and mTORC1 signaling whereas ATF4 serves to limit the amino acid response and prevent ER stress during amino acid depletion by asparaginase.

Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children's Oncology Group study AALL0232.

Minimal residual disease (MRD) is highly prognostic in pediatric B-precursor acute lymphoblastic leukemia (B-ALL). In Children's Oncology Group high-risk B-ALL study AALL0232, we investigated MRD in subjects randomized in a 2 × 2 factorial design to receive either high-dose methotrexate (HD-MTX) or Capizzi methotrexate (C-MTX) during interim maintenance (IM) or prednisone or dexamethasone during induction. Subjects with end-induction MRD ≥0.1% or those with morphologic slow early response were nonrandomly assigned to receive a second IM and delayed intensification phase. MRD was measured by 6-color flow cytometry in 1 of 2 reference labs, with excellent agreement between the two. Subjects with end-induction MRD <0.01% had a 5-year event-free survival (EFS) of 87% ± 1% vs 74% ± 4% for those with MRD 0.01% to 0.1%; increasing MRD amounts was associated with progressively worse outcome. Subjects converting from MRD positive to negative by end consolidation had a relatively favorable 79% ± 5% 5-year disease-free survival vs 39% ± 7% for those with MRD ≥0.01%. Although HD-MTX was superior to C-MTX, MRD retained prognostic significance in both groups (86% ± 2% vs 58% ± 4% for MRD-negative vs positive C-MTX subjects; 88% ± 2% vs 68% ± 4% for HD-MTX subjects). Intensified therapy given to subjects with MRD >0.1% did not improve either 5-year EFS or overall survival (OS). However, these subjects showed an early relapse rate similar to that seen in MRD-negative ones, with EFS/OS curves for patients with 0.1% to 1% MRD crossing those with 0.01% to 0.1% MRD at 3 and 4 years, thus suggesting that the intensified therapy altered the disease course of MRD-positive subjects. Additional interventions targeted at the MRD-positive group may further improve outcome. This trial was registered at www.clinicaltrials.gov as #NCT00075725.

Midtreatment ¹8F-FDG PET/CT Scan for Early Response Assessment of SMILE Therapy in Natural Killer/T-Cell Lymphoma: A Prospective Study from a Single Center.

UNLABELLED: In a prospective study of newly diagnosed or relapsed histologically proven extranodal natural killer/T-cell lymphoma (ENKTL) patients, we aimed to determine the accuracy of midtreatment (18)F-FDG PET for response assessment using both visual and quantitative analyses. METHODS: Twenty-four patients (12 men, 12 women; median age, 50 y; age range, 16-83 y) were referred for pre-, mid- (after 2-3 cycles of SMILE [prednisolone, methotrexate, ifosfamide, L-asparaginase, etoposide] chemotherapy), and end-treatment PET/CT scans (n = 24, 24, and 17, respectively) using a standardized protocol. Sixty-five PET/CT scans were analyzed visually using the Deauville 5-point score (DS), and the lesion with the highest maximum standardized uptake value (SUV(max)) was recorded. Survival curves were obtained using Kaplan-Meier analysis and compared using the log rank test, followed by multivariate analysis using the Cox proportional hazards model to assess the independent effects of International Prognostic Index (IPI) score (0-1 vs. 2-5), stage (stage I/II vs. stage III/IV), sex, DS (1-3 vs. 4-5), SUV(max), and change in SUV(max) on overall survival (OS) and progression-free survival (PFS). The mean (±SD) follow-up period was 32 mo (±21 mo). RESULTS: For 2-y OS, the following parameters were predictive: IPI score (P = 0.047), DS at mid- and end-treatment (P < 0.001), and SUV(max) at mid- and end-treatment (P < 0.001 and 0.045, respectively). For 2-y PFS, the following parameters were predictive: sex (P = 0.006), stage (P = 0.034), IPI score (P = 0.038), DS at mid- and end-treatment (P < 0.001 and 0.001, respectively), and SUV(max) at midtreatment (P = 0.001). Multivariate analysis showed DS on mid- and end-treatment scans to be the only significant independent predictor of both OS (P = 0.004 and 0.018, respectively) and PFS (P = 0.004 and 0.014, respectively). The 2-y estimate for OS and PFS was 81% and 62%, respectively, in patients with a DS of 1-3, compared with 17% in patients with a DS of 4-5 (P < 0.001 and 0.001, respectively). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the midtreatment DS for prediction of OS and PFS were 63%, 94%, 83%, 83%, and 83%, respectively. CONCLUSION: Midtreatment PET/CT is a valuable tool for early treatment response assessment in extranodal natural killer/T-cell lymphoma patients.

Asparagine depletion potentiates the cytotoxic effect of chemotherapy against brain tumors.

UNLABELLED: Targeting amino acid metabolism has therapeutic implications for aggressive brain tumors. Asparagine is an amino acid that is synthesized by normal cells. However, some cancer cells lack asparagine synthetase (ASNS), the key enzyme for asparagine synthesis. Asparaginase (ASNase) contributes to eradication of acute leukemia by decreasing asparagine levels in serum and cerebrospinal fluid. However, leukemic cells may become ASNase-resistant by upregulating ASNS. High expression of ASNS has also been associated with biologic aggressiveness of other cancers, including gliomas. Here, the impact of enzymatic depletion of asparagine on proliferation of brain tumor cells was determined. ASNase was used as monotherapy or in combination with conventional chemotherapeutic agents. Viability assays for ASNase-treated cells demonstrated significant growth reduction in multiple cell lines. This effect was reversed by glutamine in a dose-dependent manner--as expected, because glutamine is the main amino group donor for asparagine synthesis. ASNase treatment also reduced sphere formation by medulloblastoma and primary glioblastoma cells. ASNase-resistant glioblastoma cells exhibited elevated levels of ASNS mRNA. ASNase cotreatment significantly enhanced gemcitabine or etoposide cytotoxicity against glioblastoma cells. Xenograft tumors in vivo showed no significant response to ASNase monotherapy and little response to temozolomide alone. However, combinatorial therapy with ASNase and temozolomide resulted in significant growth suppression for an extended duration of time. Taken together, these findings indicate that amino acid depletion warrants further investigation as adjunctive therapy for brain tumors. IMPLICATIONS: Findings have potential impact for providing adjuvant means to enhance brain tumor chemotherapy.

Current issues in dietary acrylamide: formation, mitigation and risk assessment.

Acrylamide (AA) is known as a neurotoxin in humans and it is classified as a probable human carcinogen by the International Agency of Research on Cancer. AA is produced as by-product of the Maillard reaction in starchy foods processed at high temperatures (>120 °C). This review includes the investigation of AA precursors, mechanisms of AA formation and AA mitigation technologies in potato, cereal and coffee products. Additionally, most relevant issues of AA risk assessment are discussed. New technologies tested from laboratory to industrial scale face, as a major challenge, the reduction of AA content of browned food, while still maintaining its attractive organoleptic properties. Reducing sugars such as glucose and fructose are the major contributors to AA in potato-based products. On the other hand, the limiting substrate of AA formation in cereals and coffee is the free amino acid asparagine. For some products the addition of glycine or asparaginase reduces AA formation during baking. Since, for potatoes, the limiting substrate is reducing sugars, increases in sugar content in potatoes during storage then introduce some difficulties and potentially quite large variations in the AA content of the final product. Sugars in potatoes may be reduced by blanching. Levels of AA in different foods show large variations and no general upper limit is easily applicable, since some formation will always occur. Current policy is that practical measures should be taken voluntarily to reduce AA formation in vulnerable foods since AA is considered a health risk at the concentrations found in foods.

Cell-penetrating peptides meditated encapsulation of protein therapeutics into intact red blood cells and its application.

Red blood cells (RBCs) based drug carrier appears to be the most appealing for protein drugs due to their unmatched biocompatability, biodegradability, and long lifespan in the circulation. Numerous methods for encapsulating protein drugs into RBCs were developed, however, most of them induce partial disruption of the cell membrane, resulting in irreversible alterations in both physical and chemical properties of RBCs. Herein, we introduce a novel method for encapsulating proteins into intact RBCs, which was meditated by a cell penetrating peptide (CPP) developed in our lab-low molecular weight protamine (LMWP). l-asparaginase, one of the primary drugs used in treatment of acute lymphoblastic leukemia (ALL), was chosen as a model protein to illustrate the encapsulation into erythrocytes mediated by CPPs. In addition current treatment of ALL using different l-asparaginase delivery and encapsulation methods as well as their associated problems were also reviewed.

Implementation of acrylamide mitigation strategies on industrial production of French fries: challenges and pitfalls.

This study evaluated various additives or process aids on the industrial production of French fries, based on their acrylamide mitigation potential and other quality parameters. The application of acetic and citric acid, calcium lactate and asparaginase was investigated on the production of frozen par-fried French fries at the beginning and end of the 2008 and 2009 potato storage season. Despite the fact that some of these treatments significantly reduced acrylamide content of the final product in preliminary laboratory experiments, their application on the industrial production of French fries did not result in additional acrylamide reductions compared to the standard product. Asparaginase was additionally tested in a production line of chilled French fries (not par-fried). Since for this product a longer enzyme-substrate contact time is allowed, a total asparagine depletion was observed for the enzyme treated fries after four days of cold storage. French fries upon final frying presented acrylamide contents below the limit of detection (12.5 µg kg⁻¹) with no effects on the sensorial properties of the final product.

Evaluating the potential for enzymatic acrylamide mitigation in a range of food products using an asparaginase from Aspergillus oryzae.

Asparaginase, an enzyme that hydrolyzes asparagine to aspartic acid, presents a potentially very effective means for reducing acrylamide formation in foods via removal of the precursor, asparagine, from the primary ingredients. An extracellular asparaginase amenable to industrial production was cloned and expressed in Aspergillus oryzae . This asparaginase was tested in a range of food products, including semisweet biscuits, ginger biscuits, crisp bread, French fries, and sliced potato chips. In dough-based applications, addition of asparaginase resulted in reduction of acrylamide content in the final products of 34-92%. Enzyme dose, dough resting time, and water content were identified as critical parameters. Treating French fries and sliced potato chips was more challenging as the solid nature of these whole-cut products limits enzyme-substrate contact. However, by treating potato pieces with asparaginase after blanching, the acrylamide levels in French fries could be lowered by 60-85% and that in potato chips by up to 60%.

[Auditory evoked potentials in patients after acute children's lymphoblastic leukemia treatment]. / Egzogenne potencjaly wywolane bodzcem sluchowym u pacjentów po zakonczonym leczeniu z powodu ostrej dzieciecej bialaczki limfoblastycznej.

BACKGROUND: Acute lymphoblastic leukaemia (ALL), and especially its treatment often leads to irreversible consequences in the central and peripheral nervous system. ALL and its treatment as well, may cause disturbances of central transmission of acoustic stimuli. THE AIM: To establish, if testing of egzogenic provoked brain stem potentials can be useful for evaluation of complications of ALL treatment. The issue of analysis was the influence of past ALL and type of therapy on parameters of egzogenic potentials triggered by acoustic stimulus (BAEP) in patients after termination of treatment. RESULTS: In the group of patients treated with NY program results of middle latencies of the wave I and III were normal, however latencies of wave V and interlatencies of waves I-III, I-IV and III-V were mildly elongated. Latencies and interlatencies elongated above the upper normal range were detected in 4 patients of this group: in one patient elongation of the wave V and interlatencies of waves I-IV and III-V was detected, while in the other one interlatencies of waves I-III and I-V and in the last two patients only interlatencies of waves I-III. In the group of patients treated with BFM 86/87 programs results were similar. Latencies of waves I and III were normal, while mean latencies of wave V and interlatencies of waves I-III, I-V and III-V were mildly elongated. In this group mild pathological elongation of BAEP interlatencies were detected in 5 patients. Non of them had elongation of latencies of waves I, III or V. In one patient elongated interlatencies of waves I-V and III-V were detected, in another one interlatencies of waves I-III, while in other 3 patients elongation of latencies of waves I-V. In the group of patients treated with BFM 95 program latencies of waves I, III and V were normal, while interlatencies of waves I-III, I-V and III-V were mildly elongated. In 2 patients of this group mild elongation of interlatencies of waves I-III or III-V were detected. In each patient of this group, similar as in the group BFM 86/87, latencies of waves I, III and V were normal. CONCLUSIONS: (1) BAEP abnormalities in 22.4% of patients after the treatment of childhood ALL suggest that hearing monitoring in these patients is recommended. (2) Elongation of BAEP interlatencies and latency of wave V in patients after radiation OUN therapy warrant to develop new and less toxic therapies.

Central nervous system prophylaxis with high-dose methotrexate does not give rise to significant electroencephalographic changes in children with acute lymphoblastic leukemia.

Acute, subacute, and chronic neurologic complications have been reported in children treated with high-dose methotrexate for various malignant diseases. It was the aim of this study to monitor central nervous system treatment with high-dose methotrexate in children with acute lymphoblastic leukemia by serial electroencephalographic (EEG) examinations. Electroencephalographic examinations with quantitative computed analysis were performed in 21 children before and on the third day after each of four high-dose methotrexate infusions with leucovorin rescue according to protocol M of trial ALL-BFM 90 of the German Society for Pediatric Haematology and Oncology. Six patients with a medium risk of relapse also received L-asparaginase. In the cohort treated with methotrexate solely, no statistically significant changes of the quantitative EEG parameters could be demonstrated. Only two children with delayed serum methotrexate clearance showed reversible diffuse EEG slowing of a slight to moderate degree. In the group with additional L-asparaginase treatment, slight transient EEG slowing also occurred. Our findings indicate that in patients with a normal methotrexate clearance during central nervous system treatment with high-dose methotrexate according to trial BFM-ALL 90, usually no subacute or cumulative EEG changes have to be expected. If neurologic or psychiatric symptoms or EEG slowing occur, delayed methotrexate clearance must be suspected.

Neurodevelopmental outcome of infants with acute lymphoblastic leukemia: a Children's Cancer Group report.

BACKGROUND: Infants diagnosed with acute lymphoblastic leukemia (ALL) are considered the patient subgroup at the highest risk for central nervous system (CNS) disease, both at presentation and as an isolated extramedullary relapse. In addition, they are highly vulnerable to adverse developmental sequelae from CNS-directed therapy. METHODS: Thirty patients younger than 12 months at diagnosis (12 males, 18 females) in first hematologic remission were evaluated after completion of ALL therapy (mean age = 62.1 months; standard deviation = 17.2 months; range = 38-102 months). CNS-directed treatment included very high dose infusions of methotrexate (MTX) and intrathecal cytarabine and MTX. Three patients had meningeal leukemia that required additional therapy. Children were administered the McCarthy Scales of Children's Abilities, and parents completed a sociodemographic questionnaire to obtain information about occupation and education. RESULTS: Mean scores on all 6 cognitive and motor indices of the McCarthy Scales were in the average range (Verbal = 52.0; Perceptual = 53.6; Quantitative = 49.6; General Cognitive Index [GCI] = 102.1; Memory = 49.2; Motor = 51.0). Score distributions for each neurodevelopmental index were comparable to age-based population standards. One patient obtained a GCI that exceeded 2 standard deviations above the mean; none scored more than 2 standard deviations below. There was no report of developmental disabilities or neurologic disorders for any of the patients. Risk factors, including age at diagnosis, gender, additional CNS-directed treatment, and family socioeconomic status, were not associated with developmental outcome. CONCLUSIONS: Test findings indicated a generally positive neurodevelopmental outcome for ALL patients diagnosed in infancy who were treated with very high dose MTX as CNS-directed therapy. Combined with the reduction in the isolated CNS relapse rate achieved by the Children's Cancer Group (CCG) clinical trial CCG-107, the results of this study represent a substantial improvement in neurodevelopmental outcome for very young patients compared with infants treated for ALL in the past.

Changes of hemostatic factors in children with acute lymphoblastic leukemia receiving combined chemotherapy including high dose methylprednisolone and L-asparaginase.

In this study, protein C (PC), protein S (PS), heparin cofactor II (HCFII), prothrombin fragment 1+2 (PF 1,2), thrombin-antithrombin III complex (TAT), von Willebrand factor (vWF) and thrombomodulin (TM) were investigated in 19 patients with acute lymphoblastic leukemia, (ALL) receiving combined chemotherapy including L-asparaginase (L-ASP) and high dose methylprednisolone (HDMP). HDMP was administered in doses of 30 mg/kg/day for 7 days, and 20 mg/kg/day for another 7 days. In order to evaluate the effect of HDMP on the hemostatic system, the 8 patients studied here received HDMP (30 mg/kg/day) therapy for 4 days before the combined chemotherapy. These parameters were also studied in 12 healthy children as a control group. PC levels were normal in the patients while PS levels were decreased both before and after combined chemotherapies. Patients with ALL have laboratory signs of coagulation activation such as PF 1,2, TAT prior to initiation of chemotherapy. With combined chemotherapy, TAT levels were found to be normal while PF1,2 were not. TM levels were found to be increased both before and after therapies whereas HCFII and vWF levels were not different from those of the control group. The short course of HDMP therapy did not prominently influence these hemostatic parameters. These results indicate that both the malignant process and the drugs used in combined chemotherapy cause a decrease in natural inhibitors and an increase in procoagulant activity and endothelial injury. These hemostatic changes may contribute to a thrombotic tendency in the patients with ALL.