Acute central nervous system toxicity during treatment of pediatric acute lymphoblastic leukemia: phenotypes, risk factors and genotypes.

Central nervous system (CNS) toxicity is common at diagnosis and during treatment of pediatric acute lymphoblastic leukemia (ALL). We studied CNS toxicity in 1,464 children aged 1.0-17.9 years, diagnosed with ALL and treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol. Genome-wide association studies, and a candidate single-nucleotide polymorphism (SNP; n=19) study were performed in 1,166 patients. Findings were validated in an independent Australian cohort of children with ALL (n=797) in whom two phenotypes were evaluated: diverse CNS toxicities (n=103) and methotrexate-related CNS toxicity (n=48). In total, 135/1,464 (9.2%) patients experienced CNS toxicity for a cumulative incidence of 8.7% (95% confidence interval: 7.31-10.20) at 12 months from diagnosis. Patients aged ≥10 years had a higher risk of CNS toxicity than had younger patients (16.3% vs. 7.4%; P<0.001). The most common CNS toxicities were posterior reversible encephalopathy syndrome (n=52, 43 with seizures), sinus venous thrombosis (n=28, 9 with seizures), and isolated seizures (n=16). The most significant SNP identified by the genome-wide association studies did not reach genomic significance (lowest P-value: 1.11x10-6), but several were annotated in genes regulating neuronal functions. In candidate SNP analysis, ATXN1 rs68082256, related to epilepsy, was associated with seizures in patients <10 years (P=0.01). ATXN1 rs68082256 was validated in the Australian cohort with diverse CNS toxicities (P=0.04). The role of ATXN1 as well as the novel SNP in neurotoxicity in pediatric ALL should be further explored.

Does minimal central nervous system involvement in childhood acute lymphoblastic leukemia increase the risk for central nervous system toxicity?

Central nervous system (CNS) involvement in childhood acute lymphoblastic leukemia (ALL) implicates enhanced intrathecal chemotherapy, which is related to CNS toxicity. Whether CNS involvement alone contributes to CNS toxicity remains unclear. We studied the occurrence of all CNS toxicities, seizures, and posterior reversible encephalopathy syndrome (PRES) in children with ALL without enhanced intrathecal chemotherapy with CNS involvement (n = 64) or without CNS involvement (n = 256) by flow cytometry. CNS involvement increased the risk for all CNS toxicities, seizures, and PRES in univariate analysis and, after adjusting for induction therapy, for seizures (hazard ratio [HR] = 3.33; 95% confidence interval [CI]: 1.26-8.82; p = 0.016) and PRES (HR = 4.85; 95% CI: 1.71-13.75; p = 0.003).

Posterior reversible encephalopathy syndrome in children with acute lymphoblastic leukemia: Clinical characteristics, risk factors, course, and outcome of disease.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a distinct entity with incompletely known predisposing factors. The aim of this study is to describe the incidence, risk factors, clinical course, and outcome of PRES in childhood acute lymphoblastic leukemia (ALL). PROCEDURE: Patients aged 1.0 to 17.9 years diagnosed with ALL from July 2008 to December 2015 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol were included. Patients with PRES were identified in the prospective NOPHO leukemia toxicity registry, and clinical data were collected from the medical records. RESULTS: The study group included 1378 patients, of whom 52 met the criteria for PRES. The cumulative incidence of PRES at one month was 1.7% (95% CI, 1.1-2.5) and at one year 3.7% (95% CI, 2.9-4.9). Older age (hazard ratios [HR] for each one-year increase in age 1.1; 95% CI, 1.0-1.2, P = 0.001) and T-cell immunophenotype (HR, 2.9; 95% CI, 1.6-5.3, P = 0.0005) were associated with PRES. Central nervous system (CNS) involvement (odds ratios [OR] = 2.8; 95% CI, 1.2-6.5, P = 0.015) was associated with early PRES and high-risk block treatment (HR = 2.63; 95% CI, 1.1-6.4, P = 0.033) with late PRES. At follow-up of the PRES patients, seven patients had epilepsy and seven had neurocognitive difficulties. CONCLUSION: PRES is a neurotoxicity in the treatment of childhood ALL with both acute and long-term morbidity. Older age, T-cell leukemia, CNS involvement and high-risk block treatment are risk factors for PRES.

Increased prescription rates of anxiolytics and hypnotics to survivors of cancer in childhood, adolescence, and young adulthood-A population-based study.

BACKGROUND: Survivors of cancer diagnosed in childhood, adolescence, or young adulthood (CAYACS) risk psychological morbidities later in life. The study compares prescription rates of anxiolytics and hypnotics among survivors to rates in age- and gender-matched controls. PROCEDURES: The population-based cohort included 5,341 cancer survivors, diagnosed ≤25 years of age during 1965-2000. For each survivor, three age- and gender-matched controls were randomly selected from the general population. Data were identified from the Norwegian Cancer and Population registries and linked to the Norwegian Prescription Database. A Cox proportional hazard model was applied to estimate hazard ratios (HRs) of prescriptions during 2004-2012 to the survivors with controls as referents. RESULTS: Survivors had an increased risk of being prescribed anxiolytics with crude rates of 16.9/1,000 person years compared to 11.8/1,000 person years in controls (HR 1.41; 95% confidence interval [CI] 1.29-1.54). The relative risk was highest for survivors of neuroblastomas (HR 2.62; 95% CI 1.11-6.16), bone tumors (HR 2.00; 95% CI 1.26-3.18), and central nervous system tumors (HR 1.90; 95% CI 1.40-2.51). The risk of being prescribed hypnotics was increased with crude rates of 20.8/1,000 person years compared to 14.3/1,000 person years in controls (HR 1.44; 95% CI 1.32-1.56). The relative risk was highest for survivors of gastrointestinal tumors (HR 1.80; 95% CI 1.04-3.10), leukemias (HR 1.78; 95% CI 1.32-2.38), and soft tissue cancers (HR 1.70; 95% CI 1.09-2.64). CONCLUSIONS: Certain groups of CAYACS have an increased risk for being prescribed anxiolytics or hypnotics compared to controls. Diagnostic reasons for prescriptions are unknown, but the results indicate an increased emotional burden among these groups of survivors.

Genetic Characterization of Pediatric Mixed Phenotype Acute Leukemia (MPAL).

BACKGROUND/AIM: Mixed phenotype acute leukemia (MPAL) is a rare hematologic malignancy in which the leukemic cells cannot be assigned to any specific lineage. The lack of well-defined, pathogenetically relevant diagnostic criteria makes the clinical handling of MPAL patients challenging. We herein report the genetic findings in bone marrow cells from two pediatric MPAL patients. PATIENTS AND METHODS: Bone marrow cells were examined using G-banding, array comparative genomic hybridization, RNA sequencing, reverse transcription polymerase chain reaction, Sanger sequencing, and fluorescence in situ hybridization. RESULTS: In the first patient, the genetic analyses revealed structural aberrations of chromosomal bands 8p11, 10p11, 11q21, and 17p11, the chimeras MLLT10::PICALM and PICALM::MLLT10, and imbalances (gains/losses) on chromosomes 2, 4, 8, 13, and 21. A submicroscopic deletion in 21q was also found including the RUNX1 locus. In the second patient, there were structural aberrations of chromosome bands 1p32, 8p11, 12p13, 20p13, and 20q11, the chimeras ETV6::LEXM and NCOA6::ETV6, and imbalances on chromosomes 2, 8, 11, 12, 16, 19, X, and Y. CONCLUSION: The leukemic cells from both MPAL patients carried chromosome aberrations resulting in fusion genes as well as genomic imbalances resulting in gain and losses of many gene loci. The detected fusion genes probably represent the main leukemogenic events, although the gains and losses are also likely to play a role in leukemogenesis.

Increase in peg-asparaginase clearance as a predictor for inactivation in patients with acute lymphoblastic leukemia.

Asparaginase is an essential component of acute lymphoblastic leukemia (ALL) therapy, yet its associated toxicities often lead to treatment discontinuation, increasing the risk of relapse. Hypersensitivity reactions include clinical allergies, silent inactivation, or allergy-like responses. We hypothesized that even moderate increases in asparaginase clearance are related to later inactivation. We therefore explored mandatory monitoring of asparaginase enzyme activity (AEA) in patients with ALL aged 1-45 years treated according to the ALLTogether pilot protocol in the Nordic and Baltic countries to relate mean AEA to inactivation, to build a pharmacokinetic model to better characterize the pharmacokinetics of peg-asparaginase and assess whether an increased clearance relates to subsequent inactivation. The study analyzed 1631 real-time AEA samples from 253 patients, identifying inactivation in 18.2% of the patients. This inactivation presented as mild allergy (28.3%), severe allergy (50.0%), or silent inactivation (21.7%). A pharmacokinetic transit compartment model was used to describe AEA-time profiles, revealing that 93% of patients with inactivation exhibited prior increased clearance, whereas 86% of patients without hypersensitivity maintained stable clearance throughout asparaginase treatment. These findings enable prediction of inactivation and options for either dose increments or a shift to alternative asparaginase formulations to optimize ALL treatment strategies.

Novel MYCBP::EHD2 and RUNX1::ZNF780A Fusion Genes in T-cell Acute Lymphoblastic Leukemia.

BACKGROUND/AIM: T-cell acute lymphoblastic leukemia (T-ALL) is a rare malignancy characterized by proliferation of early T-cell precursors that replace normal hematopoietic cells. T-ALL cells carry non-random chromosome aberrations, fusion genes, and gene mutations, often of prognostic significance. We herein report the genetic findings in cells from a T-ALL patient. MATERIALS AND METHODS: Bone marrow cells from a patient with T-ALL were examined using G-banding, array comparative genomic hybridization (aCGH), RNA sequencing, reverse transcription polymerase chain reaction (RT-PCR), Sanger sequencing, and fluorescence in situ hybridization. RESULTS: G-banding revealed del(1)(p34), add(5)(q14), trisomy 8, and monosomy 21 in the leukemic cells. aCGH detected the gross unbalances inferred from the karyotyping results, except that heterozygous loss of chromosome 21 did not include its distal part; 21q22.12-q22.3 was undeleted. In addition, aCGH detected a submicroscopic interstitial 7.56 Mbp deletion in the q arm of chromosome 19 from 19q13.2 to 19q13.33. RNA sequencing detected and RT-PCR/Sanger sequencing confirmed the presence of two novel chimeras, MYCBP::EHD2 and RUNX1::ZNF780A. They were generated from rearrangements involving subbands 1p34.3 (MYCBP), 19q13.2 (ZNF780A), 19q13.33 (EHD2), and 21q22.12 (RUNX1), i.e., at the breakpoints of chromosomal deletions. CONCLUSION: The leukemic cells showed the heterozygous loss of many genes as well as the generation of MYCBP::EHD2 and RUNX1::ZNF780A chimeras. Because the partner genes in the chimeras were found at the breakpoints of the chromosomal deletions, we believe that both the heterozygous losses and the generation of the two chimeras occurred simultaneously, and that they were pathogenetically important.

Chromosome Translocation t(14;21)(q11;q22) Activates Both OLIG1 and OLIG2 in Pediatric T-cell Lymphoblastic Malignancies and May Signify Adverse Prognosis.

BACKGROUND/AIM: The chromosome translocation t(14;21)(q11;q22) was reported in four pediatric T-cell lymphoblastic leukemias and was shown to activate the OLIG2 gene. MATERIALS AND METHODS: A pediatric T-cell lymphoblastic lymphoma was investigated using G-banding chromosome analysis, fluorescence in situ hybridization (FISH), and immunocytochemistry. RESULTS: The malignant cells carried a t(14;21)(q11;q22) aberration. The translocation moves the enhancer elements of TRA/TRD from band 14q11 to 21q22, a few thousands kbp downstream of OLIG1 and OLIG2, resulting in the production of both OLIG1 and OLIG2 proteins. CONCLUSION: The translocation t(14;21)(q11;q22) occurs in some pediatric T-cell lymphoblastic malignancies. Activation of both OLIG1 and OLIG2 by t(14;21)(q11;q22) in T-lymphoblasts and the ensuing deregulation of thousands of genes could explain the highly malignant disease and resistance to treatment that has characterized this small group of patients.

Seizures during treatment of childhood acute lymphoblastic leukemia: A population-based cohort study.

BACKGROUND: Seizures are common in children with acute lymphoblastic leukemia (ALL). As ALL survival rates are improving, the challenge to minimize treatment related side effects and late sequelae rises. Here, we studied the frequency, timing, etiology and risk factors of seizures in ALL patients. METHODS: The study included children aged 1-17.9 years at diagnosis of B-cell-precursor and T cell ALL who were treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol between 2008 and 2015. Detailed patient data were acquired from the NOPHO ALL2008 registry and by review of medical records. RESULTS: Seizures occurred in 81/1464 (5.5%) patients. The cumulative incidence of seizures at one months was 1.7% (95% CI: 1.2-2.5) and at one year 5.3% (95% CI 4.2-6.5%). Patients aged 10-17.9 years, those with T cell immunophenotype, CNS involvement, or high-risk induction with dexamethasone had higher risk for seizures in univariable analyses. Only age remained a risk factor in multivariable analyses (the cumulative incidence of seizures for patients 10-17.9 years old at one year was 9.0% (95% CI: 6.2-12.9)). Of the 81 patients with seizures, 43 had posterior reversible encephalopathy syndrome (PRES), 15 had isolated seizures, nine had sinus venous thrombosis (SVT), three had stroke-like syndrome, and 11 had other neurotoxicities. Epilepsy diagnosis was reported in totally 11 ALL survivors at last follow up. CONCLUSION: Seizures are relatively common in ALL patients and occur most often in patients with PRES, SVT, or as an isolated symptom. Older children have higher risk of seizures.

Prescriptions of Antidepressants to Survivors of Cancer in Childhood, Adolescence, and Young Adulthood: A Population-Based Study.

PURPOSE: Survivors of cancer may experience higher rates of psychological problems requiring pharmacological interventions than age-matched controls from the general population. This study compares prescription rates of antidepressants in survivors of cancer, diagnosed in childhood, adolescence, or early adulthood, to the rate in age- and gender-matched controls from the Norwegian population. METHODS: Antidepressants prescribed to 5341 cancer survivors, diagnosed ≤25 years during 1965-2000, were studied in a population-based cohort by linking data from the following nationwide registries: the Population Registry of Norway, the Cancer Registry of Norway, and the Norwegian Prescription Database. For each survivor, three age- and gender-matched controls were randomly selected from the population. A Cox proportional hazard model was applied to estimate hazard ratios (HRs) of antidepressant prescriptions during 2004-2012 to the survivors with controls as referents. RESULTS: Survivors had an increased risk of being prescribed antidepressants with crude rates of 26.9/1000 person-years compared with 22.5/1000 person-years in controls (HR 1.19; 95% confidence interval [CI] 1.12-1.28). The relative risk was highest for survivors of central nervous system tumors (HR 1.30; 95% CI 1.04-1.63), leukemias (HR 1.29; 95% CI 1.03-1.63), testicular tumors (HR 1.27; 95% CI 1.04-1.55), and "other tumors" (HR 1.42; 95% CI 1.10-1.84). No effect of age at cancer diagnosis was found. CONCLUSION: Certain groups of survivors of cancer in childhood, adolescence, or young adulthood have a slightly increased risk for being prescribed antidepressants than their peers. The results may indicate an increased prevalence of depression among these survivors, but diagnostic reasons for prescriptions need to be confirmed in clinical studies.

[Bacterial meningitis in one month-16 year old children at three Pediatric departments in Iceland during the period 1973-2000.].

OBJECTIVE: Bacterial meningitis is a serious disease most common in children. We report the epidemiology and outcome of bacterial meningitis in children between the age of one month to 16 years admitted to three Pediatric Departments in Iceland in 1973-2000 (28 years). MATERIAL AND METHODS: Information was collected retrospectively from the medical records of admitted children diagnosed with bacterial meningitis. RESULTS: 454 children were diagnosed; 255 boys and 199 girls; 77% were less than five years of age. Before 1989 the age specific incidence was 29/100.000/year and 12/100.000/year thereafter. The cerebral spinal fluid was culture positive in 74% but no organism was identified in 17%. The most common pathogens were N. meningitidis (44%), Hib (30%), and S. pneumoniae (7%). The incidence varied according to age. No child was diagnosed with Hib after launching of Hib vaccination in 1989. The mean age of the children increased significantly from less than two years prior to 1989 to less than three years thereafter and of children infected with N. meningitidis from around two year to three years. The mortality rate was 4,5%, none due to Hib. Fourteen percent suffered sensory-neural hearing impairment and no protective effects were seen of steroid therapy. CONCLUSIONS: The age specific incidence of bacterial meningitis of children in Iceland has decreased during the last decade, especially due to Hib vaccination. Further reduction can be expected by implementing general vaccination to N. meningitidis C and S. pneumoniae. Additionally, recognizing the symptoms of bacterial meningitis and starting proper therapy as soon as possible is crucial in order to minimize ominous outcome.