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Marcoux S, Robaey P, Gahier A, et al.
Role of NOS3 DNA variants in externalizing behavioral problems observed in childhood leukemia survivors.
J Pediatr Hematol Oncol. 2013; 35(4):e157-62 [PubMed]

OBJECTIVE: Neuropsychological problems occurrence varies among childhood cancer survivors, and associated risk factors have not been fully deciphered. We wanted to study the role of genetic variants in behavioral problems in this population.
STUDY DESIGN: Behavioral problems in pediatric acute lymphoblastic leukemia patients (n=138) were investigated longitudinally, using the Child Behavior Checklist questionnaire and multilevel statistical modeling. Thirty-four candidate polymorphisms, related to anticancer drug effects, were investigated.
RESULTS: NOS3 gene functional polymorphisms showed significant association: patients homozygous for the minor allele at investigated loci showed decreased externalizing behavioral problems scores over time (t tests: T-786C n=69, P=0.003; G894T n=71, P=0.065). The effect was even more pronounced for individuals that are homozygous for the -786C844T haplotype (t test, n=69, P<0.001) and results were supported by multilevel modeling analyses (P<0.001). No such association was observed for internalizing behavioral problems.
CONCLUSION: NOS3 variants modulate externalizing problems individual trajectories, likely in relationship with glucocorticoid exposure.

Lo Nigro L
Biology of childhood acute lymphoblastic leukemia.
J Pediatr Hematol Oncol. 2013; 35(4):245-52 [PubMed]

Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood, accounting for almost 30% of pediatric cancers. Despite the high rate of cure, ALL is one of the leading causes of death in children with tumor. For this reason, there is a keen interest in identifying genetic and biological features that influence the pathogenesis of ALL and the risk of treatment failure. The application of standard diagnostic technologies such as a conventional karyotype and polymerase chain reaction methodologies, together with gene expression profiling and genome-wide analyses, allows us to genetically characterize almost 100% of children with ALL. This review provides basic information about well-established genetic alterations associated with specific clinical subtypes and new molecular lesions with potential prognostic impact. New insights are reported on the natural history of ALL. Genetic aberrations in childhood ALL are considered both markers of disease and potential targets of treatment. Here, each biological subtype under the genetic point of view has been dissected, including genes involved in the development of lymphocytes and considerations on ALL in infancy. It is also crucial to discuss the issue of relapse. Finally, as future treatment will be individualized on the basis of biological features, the pediatric hemato-oncologists need to be ready and prepared to tailor the "right treatment" to the "right children" with ALL.

Gholami A, Salarilak S, Hejazi S, Khalkhali HR
Birth weight and risk of childhood acute leukaemia.
East Mediterr Health J. 2013; 19(2):156-61 [PubMed]

Studies of risk factors for acute leukaemia are inconclusive. This case-control study was done in West Azerbaijan province, Islamic Republic of Iran, to determine the relationship between birth weight and acute leukaemia in children aged under 15 years. For every patient 2 age- and sex-matched controls were selected from hospital and community populations. Of 130 cases diagnosed over the period 2003-2009,108 (83.1%) had lymphoblastic and 22 (16.9%) myloblastic type. Significantly more of them were male than female (55.4% versus 44.6%). In a multivariate logistic regression model variables significantly associated with acute leukaemia were: birth weight (OR = 2.25), birth order (OR = 2.25), birth place (OR = 7.93), history of chickenpox (OR = 0.46) and mothers' education (OR = 3.23). The risk of acute leukaemia increased significantly with increasing birth weight in the total group and among girls, but not among boys.

Yatsenko Y, Kalennik O, Maschan M, et al.
NPM1, FLT3, and c-KIT mutations in pediatric acute myeloid leukemia in Russian population.
J Pediatr Hematol Oncol. 2013; 35(3):e100-8 [PubMed]

We evaluated frequencies of NPM1, FLT3, c-KIT mutations in childhood acute myeloid leukemia (AML) in Russia and assessed prognostic relevance of the mutations. RNA and DNA were extracted from bone marrow samples of 186 (106 male and 80 female) pediatric patients younger than 17 year with de novo AML. Mutations and chromosomal rearrangements were detected by sequencing of a corresponding gene. NPM1 mutations were found in 5.2%, FLT3 mutations in 12.1%, c-KIT mutations in 3.7% of the patients. NPM1 mutations were associated with the absence of chromosomal aberrations (P=0.007) and FLT3/ITD (P=0.018). New data on incidence of c-KIT mutations in various AML subtypes as well as new variations of c-KIT mutations in the exon 8 are presented. The results are compared to previously published studies on NPM1, FLT3, c-KIT mutations in various populations. No statistically significant differences in survival rates between groups with or without of FLT3, NPM1, c-KIT mutations were found (P>0.05). Meanwhile, 4-year overall survival rates were higher in patients having NPM1 mutations comparing with NPM1/WT patients (100% vs. 50%) and in patients having FLT3 mutations comparing with FLT3/WT patients (70% vs. 50%). The data presented contribute to knowledge on incidence and prognostic significance of the mutations in pediatric AML.

Chaber R, Fiszer-Maliszewska L, Noworolska-Sauren D, et al.
The BCL-2 protein in precursor B acute lymphoblastic leukemia in children.
J Pediatr Hematol Oncol. 2013; 35(3):180-7 [PubMed]

The BCL-2 protein plays an important role in controlling apoptosis. Disorders of this process can lead to the emergence and development of acute lymphoblastic leukemia (ALL) and can determine the resistance of leukemic cells to chemotherapy. The levels of BCL-2 mRNA were determined in 20 children with pre-B ALL using RT-polymerase chain reaction and the percentage of BCL-2+ cells in 51 patients using flow cytofluorometry. Similar levels of BCL-2 mRNA (P=0.18) with a higher percentage of cells BCL-2+ (P=0.04) were shown in the bone marrow of patients with pre-B ALL compared to normal peripheral blood mononuclear cells. We could not find any connection between the level of BCL-2 mRNA or the percentage of BCL-2+ cells and selected clinical features. A high percentage of BCL-2+ cells and high levels of BCL-2 mRNA did not affect the 5-year overall survival probability nor the 5-year relapse-free survival probability. These results may indicate a high activity of mechanisms promoting the development of the final form of the BCL-2 protein from mRNA in leukemic cells. A high BCL-2 level does not affect the clinical course or worsen the prognosis in children with ALL.

Martinez-Mancilla M, Rodriguez-Aguirre I, Tejocote-Romero I, et al.
Clinical relevance of the fusion transcripts distribution pattern in mexican children with acute lymphoblastic leukemia.
J Pediatr Hematol Oncol. 2013; 35(3):170-3 [PubMed]

Chromosomal translocation-generated fusion genes in childhood acute lymphoblastic leukemia (ALL) are well-known indicators of prognostic outcome. This study was conducted to establish the clinical relevance of the fusion genes distribution pattern in Mexican children with newly diagnosed ALL. Multiplex RT-PCR assays were used to detect 4 commonest fusion transcripts in 261 Mexican children with B-cell precursor ALL aged 1 to 14 years old, comparing differences in the distribution of the patients between molecular subgroups to a common collection of clinical parameters. We documented a 13% significant proportion of all patients who are more than 10 years of age, harboring fusion transcripts associated with leukocytosis and poor response to remission-induction chemotherapy, than those negative children for chimeric transcripts (P<0.001). Most notable observation was identified a significant number of e2a-pbx1-positive patients who showed a more aggressive disease at diagnosis. As presented here, this report gives an overview of the clinical implications of the fusion gene positivity in Mexican children with ALL in the context of traditional risk stratification variables. Our data support the existence of important ethnic and geographic differences in Mexican population.

Balatzenko G, Guenova M, Kalinova I, et al.
Simultaneous occurrence of ETV6-RUNX1 and BCR-ABL1 (e1a2) transcripts in a child with B-cell acute lymphoblastic leukemia.
Cancer Genet. 2013; 206(3):97-101 [PubMed]

We report on a rare case of a 3-year-old boy with B-cell acute lymphoblastic leukemia (B-ALL), which was characterized simultaneously with two different fusion transcripts: ETV6-RUNX1 and BCR-ABL1 (e1a2). The patient presented with fever, diarrhea, normal white blood cell counts of 5.9×10(9)/L without circulating abnormal cells, anemia, and thrombocytopenia, as well as an enlarged liver without splenomegaly. The bone marrow was markedly hypercellular with a total infiltration of agranular lymphoid blast cells with a B-II (pre-B) lymphoblastic phenotype: cyCD79α(+), CD19(+), sCD22(+), CD10(+), CD20(-), CD34(+), and sIgM(-), with dim aberrant co-expression of the myeloid-associated markers CD13(+) and CD33(+). Conventional cytogenetic analysis was unsuccessful; however, molecular analysis revealed the BCR-ABL1 (p190) and ETV6-RUNX1 transcripts. A diagnosis of BCR-ABL1 (p190)-positive and ETV6-RUNX1-positive B-ALL was made, and treatment was initiated according to the AIEOP-BFM-ALL2000 protocol. A complete remission was achieved after the first induction course of chemotherapy. Twelve months after the diagnosis, the child is alive with levels of residual disease of <0.05% estimated both by 8-color flow cytometry and real-time quantitative reverse transcription polymerase chain reaction.

Styczynski J, Piatkowska M, Czyzewski K, et al.
Individual tumor response testing in multiple relapsed acute myeloid leukemia in children.
Anticancer Res. 2013; 33(3):1189-93 [PubMed]

AIM: The analysis of the individualized tumor response testing (ITRT) at first and subsequent relapse in children with acute myeloid leukemia (AML).
PATIENTS AND METHODS: A total of 76 pediatric AML samples underwent ITRT for up to 21 drugs.
RESULTS: No significant differences between ITRT at first and subsequent relapse were found, and no drug was found, for which significantly higher resistance of myeloblasts was observed at subsequent relapse, when compared to first relapse of AML. For most tested drugs, patients with relapse had higher IRTR than those with de novo AML. The median relative resistance value between patients with relapse and those with de novo diagnosis for all 21 drugs tested was 1.6. Samples of relapsed AML samples were significantly more resistant to: Idarubicin (1.8-fold), etoposide (5.9-fold), cytarabine (1.7-fold), fludarabine (3.7-fold) and busulfan (4.3-fold).
CONCLUSION: ITRT in relapsed AML is higher in comparison to that at initial diagnosis, while no differences in ITRT between first and subsequent relapse of AML were found.

Taskinen MH, Kurimo M, Kanerva J, Hovi L
Physical performance of nontransplanted childhood ALL survivors is comparable to healthy controls.
J Pediatr Hematol Oncol. 2013; 35(4):276-80 [PubMed]

Physical fitness is an essential feature of overall health. Our objective was to compare the physical performance between nontransplanted acute lymphoblastic leukemia (ALL) patients (study patients), healthy controls, and ALL patients after stem cell transplantation (SCT). Forty-five ALL patients (median age, 13.3 y) treated without cranial irradiation were compared with 34 ALL patients (12.0 y) treated with SCT and total body irradiation and 522 age-matched and sex-matched controls. Their physical performance was assessed by 6 muscle tests measuring speed and dynamic endurance, flexibility, acceleration, maximal speed, and speed differentiation. The patients were tested at a minimum of 3 years after treatment. The muscle test results of the study patients did not differ from that of the healthy controls. The study patients had normal body mass indexes (BMI). Only 42% of them exercised at least once a week. Those who exercised >3 times a week and those with a BMI below median had better results. SCT patients had inferior results in 4 out of 6 tests. The physical performance of nontransplanted ALL patients did not differ from that of healthy controls. A higher physical exercise activity and a BMI below median positively correlated with better muscle performance, supporting the importance of encouraging ALL survivors to exercise and avoid obesity.

Nousome D, Lupo PJ, Okcu MF, Scheurer ME
Maternal and offspring xenobiotic metabolism haplotypes and the risk of childhood acute lymphoblastic leukemia.
Leuk Res. 2013; 37(5):531-5 [PubMed] Article available free on PMC after 01/05/2014

Discovering genetic predictors of childhood acute lymphoblastic leukemia (ALL) necessitates the evaluation of novel factors including maternal genetic effects, which are a proxy for the intrauterine environment, and robust epidemiologic study designs. Therefore, we evaluated five maternal and offspring xenobiotic metabolism haplotypes and the risk of childhood ALL among 120 case-parent triads. Two of the five haplotypes were significantly associated with risk: GSTM3/GSTM4 (P=0.01) and GSTP1 (P=0.02). The EPHX1 haplotype was marginally associated with risk (P=0.05), whereas haplotypes in CYP1B1 and GSTA4 were not. Our results suggest genetic variation in xenobiotic metabolism is important in childhood ALL etiology.

Hao L, Zhao J, Wang X, et al.
Hepatotoxicity from arsenic trioxide for pediatric acute promyelocytic leukemia.
J Pediatr Hematol Oncol. 2013; 35(2):e67-70 [PubMed]

The aim of this study was to investigate the hepatotoxicity induced by arsenic trioxide (As2O3) at a therapeutic dose for pediatric acute promyelocytic leukemia (APL). A total of APL patients received As2O3 treatment by IV drip. Hepatotoxicity was monitored based on the observations of the dynamic changes in liver function and treatment responses. The influencing factors of hepatotoxicity were further analyzed. Liver impairment occurred in 24.4% of the patients, most of which was mild and moderate in severity. Liver impairment was primarily manifested by increases in alanine aminotransferase, aspertate aminotransferase, and γ-glutamyl transferase, and these increases mostly occurred within 1 to 3 weeks and then returned to normal levels after 4 weeks. Patients' ages, sex, disease time, hepatomegaly and liver dysfunction, and disseminated intravascular coagulation did not show correlations with hepatotoxicity. Their hemogram and lactate dehydrogenase numerical values obtained from preliminary diagnosis did not show significant correlations with hepatotoxicity. Aggravated hepatotoxicity was not observed in patients receiving marcellomycin for the sake of complete remission. Changes in short-term cumulative dose of As2O3 did not exhibit a correlation with hepatotoxicity. However, patients suffering from differentiation syndrome were more likely at the risk of hepatotoxicity. Liver impairment improved after the suspension of As2O3 and liver protection treatment. No patient died of liver failure. Hepatotoxicity induced by As2O3 at a therapeutic dose for pediatric APL is mild and temporary. The first to the third week of the remission induction is the important period for monitoring. Great attention should be given to differentiation syndrome as it may worsen hepatotoxicity.

Manola KN, Panitsas F, Polychronopoulou S, et al.
Cytogenetic abnormalities and monosomal karyotypes in children and adolescents with acute myeloid leukemia: correlations with clinical characteristics and outcome.
Cancer Genet. 2013; 206(3):63-72 [PubMed]

The whole spectrum of chromosomal abnormalities and their prognostic significance in children and adolescents with acute myeloid leukemia (AML) has not been fully elucidated yet, although a considerable amount of knowledge has been gained recently. Moreover, the incidence and prognostic impact of monosomal karyotypes (MKs), which are new cytogenetic categories reported recently in adults with AML, are currently unknown for childhood and adolescent AML. In this study, we investigated the cytogenetic and clinical characteristics of 140 children and adolescents (≤21 y) with AML, and correlated their cytogenetic features with both the clinical characteristics and outcomes of our patient cohort. The most frequent cytogenetic abnormality found in our study was the t(15;17), followed by the t(8;21). Striking differences in the genetic abnormalities and French-American-British subtypes were found among infants, children, and adolescents. Of 124 cases, 15 (12.1%) met the criteria of the MK definition, and 12 of the 15 MKs (80%) were complex karyotypes. Of 124 cases, 27 (21.8%) had cytogenetic abnormalities sufficient to be diagnosed as AML with myelodyspastic sydrome-related features. As expected, patients with the t(15;17) had the most favorable outcomes, whereas patients with 11q23 rearrangements and monosomy 7 had the worst outcomes. These data expand our knowledge by providing novel insights into the cytogenetic features and their correlations with clinical characteristics and outcomes in childhood and adolescent AML.

Vora A, Goulden N, Wade R, et al.
Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial.
Lancet Oncol. 2013; 14(3):199-209 [PubMed]

BACKGROUND: Minimal residual disease (MRD) is the most sensitive and specific predictor of relapse risk in children with acute lymphoblastic leukaemia (ALL) during remission. We assessed whether treatment intensity could be adjusted for children and young adults according to MRD risk stratification.
METHODS: Between Oct 1, 2003 and June 30, 2011, consecutive children and young adults (aged 1-25 years) with ALL from the UK and Ireland were recruited. Eligible patients were categorised into clinical standard, intermediate, and high risk groups on the basis of a combination of National Cancer Institute (NCI) criteria, cytogenetics, and early response to induction therapy, which was assessed by bone marrow blast counts taken at days 8 (NCI high-risk patients) and 15 (NCI standard-risk patients) after induction began. Clinical standard-risk and intermediate-risk patients were assessed for MRD. Those classified as MRD low risk (undetectable MRD at the end of induction [day 29] or detectable MRD at day 29 that became undetectable by week 11) were randomly assigned to receive one or two delayed intensification courses. Patients had received induction, consolidation, and interim maintenance therapy before they began delayed intensification. Delayed intensification consisted of pegylated asparaginase on day 4; vincristine, dexamethasone (alternate weeks), and doxorubicin for 3 weeks; and 4 weeks of cyclophosphamide and cytarabine. Computer randomisation was done with stratification by MRD result and balancing for sex, age, and white blood cell count at diagnosis by method of minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcome was event-free survival (EFS), which was defined as time to relapse, secondary tumour, or death. Our aim was to rule out a 7% reduction in EFS in the group given one delayed intensification course relative to that given two delayed intensification courses. Analyses were by intention to treat. This trial is registered, number ISRCTN07355119.
FINDINGS: Of 3207 patients registered in the trial overall, 521 MRD low-risk patients were randomly assigned to receive one (n=260) or two (n=261) delayed intensification courses. Median follow-up of these patients was 57 months (IQR 42-72). We recorded no significant difference in EFS between the group given one delayed intensification (94·4% at 5 years, 95% CI 91·1-97·7) and that given two delayed intensifications (95·5%, 92·8-98·2; unadjusted odds ratio 1·00, 95% CI 0·43-2·31; two-sided p=0·99). The difference in 5-year EFS between the two groups was 1·1% (95% CI -5·6 to 2·5). 11 patients (actuarial relapse at 5 years 5·6%, 95% CI 2·3-8·9) given one delayed intensification and six (2·4%, 0·2-4·6) given two delayed intensifications relapsed (p=0·23). Three patients (1·2%, 0-2·6) given two delayed intensifications died of treatment-related causes compared with none in the group given one delayed intensification (p=0·08). We recorded no significant difference between groups for serious adverse events and grade 3 or 4 toxic effects; however, the second delayed intensification course was associated with one (<1%) treatment-related death, and 74 episodes of grade 3 or 4 toxic effects in 45 patients (17%).
INTERPRETATION: Treatment reduction is feasible for children and young adults with ALL who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD by the end of induction therapy.
FUNDING: Medical Research Council and Leukaemia and Lymphoma Research.

Ross CS, Brown TM, Kotagal S, Rodriguez V
Cerebral venous sinus thrombosis in pediatric cancer patients: long-term neurological outcomes.
J Pediatr Hematol Oncol. 2013; 35(4):299-302 [PubMed]

Cerebral venous sinus thrombosis (CVST) is an uncommon but recognized complication of treatment for leukemia. Our goal was to determine the long-term neurocognitive outcomes in childhood cancer survivors who had CVST during therapy. Nine patients were identified from an institutional database. All had experienced CVST in the setting of L-asparaginase therapy in combination with other chemotherapeutic agents. Four patients completed neuropsychological evaluation. Their neurological examinations were normal. Neuropsychological testing showed that the participants performed well, with average to above-average scores on cognitive and behavioral testing. Three exhibited difficulties on a visual-motor integration task and 1 had difficulty with fine-motor dexterity, nonverbal memory, emotional control, shifting attention, and anxiety. Overall, by patient and parent report, the survivors had few problems. CVST is a known complication associated with treatment for leukemia and non-Hodgkin lymphoma, most commonly observed if asparaginase is used in combination with other chemotherapeutic agents. Although subtle difficulties were noted in survivors on neuropsychological testing, survivors themselves were not aware of the deficits. Further evaluation of leukemia survivors with a history of CVST is needed to assess for deficits and to understand whether further intervention is necessary.

Hochberg J, Khaled S, Forman SJ, Cairo MS
Criteria for and outcomes of allogeneic haematopoietic stem cell transplant in children, adolescents and young adults with acute lymphoblastic leukaemia in first complete remission.
Br J Haematol. 2013; 161(1):27-42 [PubMed]

Most children, adolescents and young adults with acute lymphoblastic leukaemia (ALL) in first complete remission (CR1) have an excellent prognosis with multi-agent chemotherapy in induction, consolidation, re-induction and maintenance therapy. However, there is a subset of patients with a more guarded prognosis using this approach, who may benefit from haematopoietic allogeneic stem cell transplantation (alloHSCT). Commonly used criteria for alloHSCT in children, adolescents and young adults with ALL in CR1 include: induction failure, poor cytogenetics, persistent minimal residual disease (MRD), age, immunophenotype, white blood cell count at diagnosis and rapidity of induction response. Two-year event-free survival following alloHSCT in patients with ALL in CR1 ranges from 50 to 80% depending on disease status, donor source, conditioning therapy, age and other risk factors. Future studies should focus on more precisely identifying poor-risk features, such as disease genomics and host pharmacogenomics, refining MRD measurements, improving unrelated donor matching, reducing MRD prior to alloHSCT, and developing post-alloHSCT humoral and cellular therapy approaches.

Meyer JA, Wang J, Hogan LE, et al.
Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia.
Nat Genet. 2013; 45(3):290-4 [PubMed]

Relapsed childhood acute lymphoblastic leukemia (ALL) carries a poor prognosis, despite intensive retreatment, owing to intrinsic drug resistance. The biological pathways that mediate resistance are unknown. Here, we report the transcriptome profiles of matched diagnosis and relapse bone marrow specimens from ten individuals with pediatric B-lymphoblastic leukemia using RNA sequencing. Transcriptome sequencing identified 20 newly acquired, novel nonsynonymous mutations not present at initial diagnosis, with 2 individuals harboring relapse-specific mutations in the same gene, NT5C2, encoding a 5'-nucleotidase. Full-exon sequencing of NT5C2 was completed in 61 further relapse specimens, identifying additional mutations in 5 cases. Enzymatic analysis of mutant proteins showed that base substitutions conferred increased enzymatic activity and resistance to treatment with nucleoside analog therapies. Clinically, all individuals who harbored NT5C2 mutations relapsed early, within 36 months of initial diagnosis (P = 0.03). These results suggest that mutations in NT5C2 are associated with the outgrowth of drug-resistant clones in ALL.

Tanir MK, Kuguoglu S
Impact of exercise on lower activity levels in children with acute lymphoblastic leukemia: a randomized controlled trial from Turkey.
Rehabil Nurs. 2013 Jan-Feb; 38(1):48-59 [PubMed]

This randomized, controlled experimental study was carried out to determine the effects of an exercise program on both physical parameters and the quality of life of children with acute lymphoblastic leukemia (ALL). A total of 41 children with ALL (20 trial and 21 control cases) at two university hospitals were accepted into the study. Due to the demise of one of the children in the trial group, the study was completed with 19 trial and 21 control patients, a total of 40 children and their parents. Regular and systematic exercise regimens implemented by children with ALL have resulted in improved testing results, enhanced physical performance, and better laboratory results compared with a control group and to children's scores before the initiation of such a program.

Vrooman LM, Stevenson KE, Supko JG, et al.
Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber Cancer Institute ALL Consortium Protocol 00-01.
J Clin Oncol. 2013; 31(9):1202-10 [PubMed] Article available free on PMC after 20/03/2014

PURPOSE: We assessed the toxicity and efficacy of dexamethasone and a novel dosing method of Escherichia coli L-asparaginase (EC-Asnase) in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL).
PATIENTS AND METHODS: Patients achieving complete remission (CR) on Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 were eligible for random assignment to 1) dexamethasone or prednisone, administered as 5-day pulses, every 3 weeks, and 2) weekly EC-Asnase, administered as a 25,000 IU/m(2) fixed dose (FD) or individualized dose (ID) starting at 12,500-IU/m(2), adjusted every 3 weeks based on nadir serum asparaginase activity (NSAA) determinations.
RESULTS: Between 2000 and 2004, 492 evaluable patients (ages 1 to 18 years) enrolled; 473 patients (96%) achieved CR. Four hundred eight patients (86%) participated in the corticosteroid randomization and 384 patients (81%) in the EC-Asnase randomization. With 4.9 years of median follow-up, dexamethasone was associated with superior 5-year event-free survival (EFS; 90% v 81% for prednisone; P = .01) but higher rates of infection (P = .03) and, in older children, higher cumulative incidence of osteonecrosis (P = .02) and fracture (P = .06). ID EC-Asnase had superior 5-year EFS (90% v 82% for FD; P = .04), but did not reduce the frequency of asparaginase-related toxicity. Multivariable analysis identified both dexamethasone and ID EC-Asnase as independent predictors of favorable EFS.
CONCLUSION: There was no overall difference in skeletal toxicity by corticosteroid type; dexamethasone was associated with more infections and, in older children, increased incidence of osteonecrosis and fracture. There was no difference in asparaginase-related toxicity by EC-Asnase dosing method. Dexamethasone and ID EC-Asnase were each associated with superior EFS. Monitoring NSAA during treatment with EC-Asnase may be an effective strategy to improve outcome in pediatric ALL.

Kanellopoulos A, Hamre HM, Dahl AA, et al.
Factors associated with poor quality of life in survivors of childhood acute lymphoblastic leukemia and lymphoma.
Pediatr Blood Cancer. 2013; 60(5):849-55 [PubMed]

BACKGROUND: Previous studies of health-related quality of life (QoL) in childhood cancer survivors have hardly focused on factors associated with poor QoL. The aims of our study were: (1) to assess QoL in long-term survivors (LTSs) of childhood acute lymphoblastic leukemia (ALL) and lymphomas compared to age-matched controls from the general population (NORMs). (2) To investigate factors associated with poor QoL in LTSs.
PROCEDURE: This population-based cross-sectional study enrolled 285 LTSs of ALL and lymphomas diagnosed between 1970 and 2002 at age <18 years. The LTSs completed an extensive mailed questionnaire including the Short Form 36 (SF-36) as QoL-measure. NORMs consisted of five age-matched controls for each LTS (N = 1,425). Poor QoL was defined as SF-36 physical or mental component summary score <40.
RESULTS: The median age of LTSs' at survey was 30 years (range: 18-54), median follow-up time 21 years (range: 7-39). Compared to NORMs, LTSs scored significantly lower on 7 of 8 SF-36 subscales. Among LTSs 32% reported poor QoL versus 19% among NORMs (P < 0.001). Among LTSs, psychosocial, lifestyle- and health-related variables, but not type of malignancy, treatment factors or socio-demographic factors were clinically significantly associated with poor QoL in bivariate regression analyses. In multivariate analysis, levels of fatigue, anxiety and depression, as well as obesity and insomnia remained significantly associated with poor QoL.
CONCLUSION: Significantly more LTSs than age-matched NORMs experienced poor QoL. Clinically significant associations with fatigue, anxiety, depression, obesity and insomnia were observed, which may be amenable for interventions, and thereby improvement of QoL in LTSs.

Dastugue N, Suciu S, Plat G, et al.
Hyperdiploidy with 58-66 chromosomes in childhood B-acute lymphoblastic leukemia is highly curable: 58951 CLG-EORTC results.
Blood. 2013; 121(13):2415-23 [PubMed]

The aim of our study was to analyze the factors contributing to heterogeneity of prognosis in patients with hyperdiploidy>50 chromosomes (HD>50), a group of B-cell precursor acute lymphoblastic leukemia with favorable outcome. The 541 HD>50 patients registered prospectively in the 58951 European Organisation for Research and Treatment of Cancer (EORTC) Children's Leukemia Group (CLG) trial, identified by karyotype (446 patients) and by DNA index (DI) (490 patients), had a 6-year event-free survival (EFS) of 89.0% (standard error [SE] = 1.5%) and a 6-year overall survival (OS) of 95.9% (SE = 0.9%). The strongest prognostic factor was the modal number of chromosomes (MNC): the 6-year EFS of 51-53, 54-57, and 58-66 MNC groups were 80%, 89%, and 99%, respectively (P < .0001). Ploidy assessed by DI was also a favorable factor: the higher the DI, the better the outcome. The 6-year EFS of the 3 subgroups of DI < 1.16/≥1.16-<1.24/≥1.24 were 83%, 90%, and 95%, respectively (P = .009). All usual combinations of trisomies (chromosomes 4, 10, 17, 18) were significant favorable factors but had lower EFS when MNC was lower than 58. In multivariate analysis, MNC remained the strongest factor. Consequently, the best indicator for excellent outcome was ploidy assessed by karyotype because patients with 58-66 chromosomes stood every chance of being cured (OS of 100% at 6-year follow-up) with less-intensive therapy. This trial was registered at www.clinicaltrials.gov as #NCT00003728. Registered: http://www.eortc.org/, http://clinicaltrials.gov/show/NCT00003728.

Kaspers GJ, Zimmermann M, Reinhardt D, et al.
Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group.
J Clin Oncol. 2013; 31(5):599-607 [PubMed]

PURPOSE: In pediatric relapsed acute myeloid leukemia (AML), optimal reinduction therapy is unknown. Studies suggest that liposomal daunorubicin (DNX; DaunoXome; Galen, Craigavon, United Kingdom) is effective and less cardiotoxic, which is important in this setting. These considerations led to a randomized phase III study by the International Berlin-Frankfurt-Münster Study Group.
PATIENTS AND METHODS: Patients with relapsed or primary refractory non-French-American-British type M3 AML who were younger than 21 years of age were eligible. Patients were randomly assigned to fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) or to FLAG plus DNX in the first reinduction course. The primary end point was status of the bone marrow (BM) sampled shortly before the second course of chemotherapy (the day 28 BM). Data are presented according to intention-to-treat for all 394 randomly assigned patients (median follow-up, 4.0 years).
RESULTS: The complete remission (CR) rate was 64%, and the 4-year probability of survival (pOS) was 38% (SE, 3%). The day 28 BM status (available in 359 patients) was good (≤ 20% leukemic blasts) in 80% of patients randomly assigned to FLAG/DNX and 70% for patients randomly assigned to FLAG (P = .04). Concerning secondary end points, the CR rate was 69% with FLAG/DNX and 59% with FLAG (P = .07), but overall survival was similar. However, core-binding factor (CBF) AML treated with FLAG/DNX resulted in pOS of 82% versus 58% with FLAG (P = .04). Grade 3 to 4 toxicity was essentially similar in both groups.
CONCLUSION: DNX added to FLAG improves early treatment response in pediatric relapsed AML. Overall long-term survival was similar, but CBF-AML showed an improved survival with FLAG/DNX. International collaboration proved feasible and resulted in the best outcome for pediatric relapsed AML reported thus far.

Blijdorp K, van Waas M, van der Lely AJ, et al.
Endocrine sequelae and metabolic syndrome in adult long-term survivors of childhood acute myeloid leukemia.
Leuk Res. 2013; 37(4):367-71 [PubMed]

This study focuses on the effect of chemotherapy on endocrinopathies and the metabolic syndrome in adult survivors of childhood acute myeloid leukemia (AML). Endocrine function and metabolic syndrome were evaluated in 12 AML survivors, treated with chemotherapy, and in 9 survivors of myeloid leukemias treated with stem cell transplantation (SCT), after a median follow-up time of 20 years (range 9-31). In survivors treated with chemotherapy, no endocrinopathies or metabolic syndrome were present, although AMH and Inhibin B levels tended to be lower than in controls. In SCT survivors, pituitary deficiencies and metabolic syndrome were more frequent.

Puumala SE, Ross JA, Aplenc R, Spector LG
Epidemiology of childhood acute myeloid leukemia.
Pediatr Blood Cancer. 2013; 60(5):728-33 [PubMed] Article available free on PMC after 01/05/2014

Although leukemia is the most common childhood cancer diagnosis, the subtype, acute myeloid leukemia (AML), is less common and fewer etiologic studies exist. This review summarizes the major risk factors for AML. We searched the literature using PubMed for articles on childhood AML and reviewed 180 articles. While few risk factors are definitive, we identified several with consistent evidence of a possible effect. Thorough analysis of genetic and epigenetic factors is missing from this literature and methodological issues are unresolved. Future studies should more closely examine causal mechanisms, improve exposure measurement, and include analysis using genetic and epigenetic factors.

Gowda C, Dovat S
Genetic targets in pediatric acute lymphoblastic leukemia.
Adv Exp Med Biol. 2013; 779:327-40 [PubMed]

Acute leukemia represents 31% of all cancers diagnosed in children and 80% of it is of Lymphoblastic type. Multiple genetic lesions in the hematopoietic progenitor cells prior to or during differentiation to B and T cell lead to development of leukemia. There are several subtypes of Acute Leukemia based on chromosome number changes, the presence of certain translocations and gene mutations, each of which has different clinical, biological and prognostic features. High throughput genomic technologies like array-based comparative genomic hybridization (array-CGH) and single nucleotide polymorphism microarrays (SNP arrays), have given us insight through a very detailed look at the genetic changes of leukemia, specifically, ALL. Here, we discuss various genetic mutations identified in Acute Lymphoblastic Leukemia. We also explore various genetic targets and currently available as well as upcoming targeted therapies for ALL.

Roman E, Lightfoot T, Smith AG, et al.
Childhood acute lymphoblastic leukaemia and birthweight: insights from a pooled analysis of case-control data from Germany, the United Kingdom and the United States.
Eur J Cancer. 2013; 49(6):1437-47 [PubMed]

BACKGROUND: Heavy birthweight is one of the few established risk factors for childhood acute lymphoblastic leukaemia (ALL). To provide new insight into this relationship, particularly at the extremes (<1500 and > 4500 g), we pooled data from three of the largest childhood cancer case-control studies ever conducted.
METHODS: Birthweight and gestational age on 4075 children with ALL and 12,065 controls were collected during the course of three studies conducted in the USA, the UK and Germany in the 1990s. Information was obtained from mothers at interview, and the impact of bias was evaluated using the UK study which accessed birth registrations of participants and non-participants. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models.
RESULTS: Children with ALL were, on average, heavier than controls at all gestations, the disparity being driven by a deficit of low-birthweight at all gestations and an excess of high-birthweight at ≥ 40 weeks. Overall, a 1.2 (95% CI 1.1-1.3) increase in ALL risk per kg increase in birthweight was observed; the ORs rising from 0.2 (0.1-0.7) at ≤ 1500 g through to 1.2 (0.9-1.6) at ≥ 4500 g; and 0.8 (0.7-0.9) <10th centile through to 1.3 (1.1-1.4) ≥ 90th centile.
CONCLUSION: Our findings demonstrate the importance of looking across the full birthweight spectrum when examining associations with disease risk. The new observation of a deficit of very-low-birthweight cases at all gestations has aetiological and study design implications for future work examining not only the in utero origins of ALL, but also other childhood and adult cancers.

Diamanti P, Cox CV, Moppett JP, Blair A
Parthenolide eliminates leukemia-initiating cell populations and improves survival in xenografts of childhood acute lymphoblastic leukemia.
Blood. 2013; 121(8):1384-93 [PubMed]

Approximately 20% of children with acute lymphoblastic leukemia (ALL) relapse because of failure to eradicate the disease. Current drug efficacy studies focus on reducing leukemia cell burden. However, if drugs have limited effects on leukemia-initiating cells (LICs), then these cells may expand and eventually cause relapse. Parthenolide (PTL) has been shown to cause apoptosis of LIC in acute myeloid leukemia. In the present study, we assessed the effects of PTL on LIC populations in childhood ALL. Apoptosis assays demonstrated that PTL was effective against bulk B- and T-ALL cells, whereas the CD34(+)/CD19(-), CD34(+)/CD7(-), and CD34(-) subpopulations were more resistant. However, functional analyses revealed that PTL treatment prevented engraftment of multiple LIC populations in NOD/LtSz-scid IL-2Rγ(c)-null mice. PTL treatment of mice with established leukemias from low- and high-risk patients resulted in survival and restoration of normal murine hemopoiesis. In only 3 cases, disease progression was significantly slowed in mice engrafted with CD34(+)/CD19(-) or CD34(+)/CD7(-) and CD34(-) cells, but was not prevented, demonstrating that individual LIC populations within patients have different responses to therapy. These observations indicate that PTL may have therapeutic potential in childhood ALL and provide a basis for developing effective therapies that eradicate all LIC populations to prevent disease progression and reduce relapse.

Bektaş-Kayhan K, Küçükhüseyin Ö, Karagöz G, et al.
Is the MDR1 C3435T polymorphism responsible for oral mucositis in children with acute lymphoblastic leukemia?
Asian Pac J Cancer Prev. 2012; 13(10):5251-5 [PubMed]

BACKGROUND AND AIM: Although the functional consequences of MDR-1 polymorphisms have been the subject of numerous studies, to the best to our knowledge, associations with clinical side effects of anticancer drugs have yet to be assessed. Our aim was to clarify any role of the C3435T polymorphism of the MDR1 gene in oral mucositis and its relation with elevated reactive oxygen species (ROS) levels, in children with acute lymphoblastic leukemia (ALL).
MATERIALS AND METHODS: The distribution of the MDR-1 C3435T polymorphism in 47 patients with ALL was determined by RFLP and compared with that of 68 healthy controls.
RESULTS: There were no association in distribution of genotypes of MDR-1 C3435T polymorphism and the risk of ALL. Oral mucositis were detected in 78.7% (n=37) of the patients and significantly related to the MDR-1 CT genotype (p=0.042), as confirmed by logistic regression analysis.
CONCLUSION: Our preliminary data suggest that children carrying the CT genotype are more prone to develop oral mucositis, which might mean that the heterozygous genotype leads to accumulation of more reactive oxygen species. Since a limited number of patients was investigated, further studies are needed to confirm these findings.

Redell MS, Ruiz MJ, Gerbing RB, et al.
FACS analysis of Stat3/5 signaling reveals sensitivity to G-CSF and IL-6 as a significant prognostic factor in pediatric AML: a Children's Oncology Group report.
Blood. 2013; 121(7):1083-93 [PubMed] Article available free on PMC after 14/02/2014

Signal transducer and activator of transcription 3 (Stat3) and Stat5 are critical signaling intermediates that promote survival in myeloid leukemias. We examined Stat3 and Stat5 activation patterns in resting and ligand-stimulated primary samples from pediatric patients with acute myeloid leukemia. Phosphorylated Stats were measured by FACS before and after stimulation with increasing doses of granulocyte-colony stimulating factor or IL-6. We also measured positive and negative regulators of Stat signaling, and we compared the variation in multiple parameters to identify biologic relationships. Levels of constitutively phosphorylated Stats were variable and did not correlate with survival. In terms of induced phospho-Stats, 15 of 139 specimens (11%) phosphorylated Stat3 in response to moderate doses of both granulocyte-colony stimulating factor and IL-6. Compared with groups that were resistant to 1 or both ligands, this pattern of dual sensitivity was associated with a superior outcome, with a 5-year event-free survival of 79% (P = .049) and 5-year overall survival of 100% (P = .006). This study provides important and novel insights into the biology of Stat3 and Stat5 signaling in acute myeloid leukemia. Patterns of ligand sensitivity may be valuable for improving risk identification, and for developing new agents for individualized therapy.

Rayar M, Webber CE, Nayiager T, et al.
Sarcopenia in children with acute lymphoblastic leukemia.
J Pediatr Hematol Oncol. 2013; 35(2):98-102 [PubMed]

Children with acute lymphoblastic leukemia experience musculoskeletal morbidity during therapy. We examined the patterns of change in skeletal muscle mass (SMM) and the relationship between change in SMM and the burden of illness as reflected in days of hospitalization. Ninety-one children had dual energy x-ray absorptiometry (DXA scans) during treatment, yielding the sum of lean tissue mass in all 4 limbs; the appendicular lean mass. SMM was derived from appendicular lean mass. The number of inpatient days was recorded. DXA scans at 5 time points showed a profile of change in SMM characterized by a drop in the mean Z score from -0.18 at diagnosis to -1.08 after 6 months of therapy, with a partial recovery 12 to 24 months after diagnosis. Levels of serum creatinine, a surrogate measure of SMM, were mainly unchanged. The extent of the drop in SMM during early therapy was associated with the duration of hospitalization (r=0.31, P<0.05). Children with acute lymphoblastic leukemia experience a notable reduction in SMM early in treatment, with incomplete recovery. The degree of loss is associated with the burden of illness. These findings provide a target for a therapeutic intervention and a measure to determine its efficacy.

Styczynski J, Piatkowska M, Jaworska-Posadzy A, et al.
Comparison of prognostic value of in vitro drug resistance and bone marrow residual disease on day 15 of therapy in childhood acute lymphoblastic leukemia.
Anticancer Res. 2012; 32(12):5495-9 [PubMed]

AIM: The analysis of the prognostic impact of residual disease at day 15 of induction therapy, individual tumor response testing (ITRT) at diagnosis, initial factors and initial therapy response to the risk of relapse in children with precursor B-cell acute lymphoblastic leukemia (ALL).
PATIENTS AND METHODS: A total of 87 children were tested at diagnosis for ITRT and for persistence of blasts in bone marrow at day 15 (BML15>0.5%) and were followed-up in long-term analysis.
RESULTS: The probability of disease-free survival (pDFS) was significantly better for patients with an ITRT profile showing sensitivity to prednisolone, vincristine, daunorubicin, and L-asparaginase. Patients with BML15>0.5% had higher ITRT for prednisolone, daunorubicin, L-asparaginase, and etoposide. Three factors had predictive impact for relapse: BML15>0.5%, ITRT for prednisolone and high combined ITRT profile for prednisolone, vincristine and L-asparaginase (PVA score).
CONCLUSION: Persistence of blasts in bone marrow at day 15, ITRT showing resistance to prednisolone and high PVA score were the strongest and comparable prognostic factors predicting relapse in childhood ALL.

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