Leukaemia is the most common cancer of childhood. The body produces lymphocytes to protect the body from infection, in leukaemia these cells do not mature properly and become too numerous in the blood and bone marrow. Leukaemias may be acute or chronic. The most common type is acute lymphoblastic leukaemia (ALL). There are a number of other less common acute types which may be grouped together as acute non-lymphoblastic leukaemia (ANLL), this includes acute myeloid leukaemia (AML).
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Targeting cancer genes to treat childhood leukaemia
Leukaemia & Lymphoma Research Dr Owen Williams talks about developing new drugs to treat childhood leukaemia. Dr Williams is from the UCL Institute of Child Health and Great Ormond Street Hospital for children NHS Trust.
The NCLF is a non-profit organization providing services, support, and referrals for leukemia patients and their families.The site provides details of their telephone help line, and information on various topics related to childhood leukemia.
PubMed Central search for free-access publications about Childhood Leukaemia MeSH term: Leukemia US National Library of Medicine PubMed has over 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Constantly updated.
SEER, National Cancer Institute Part of a SEER report on statistical trends and risk factors associated with childhood cancers. From: Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995. (PDF)
This list of publications is regularly updated (Source: PubMed).
Li ZG, Jiao Y, Li WJ, et al. Hypermethylation of two CpG sites upstream of CASP8AP2 promoter influences gene expression and treatment outcome in childhood acute lymphoblastic leukemia. Leuk Res. 2013; 37(10):1287-93 [PubMed] Related Publications
DNA hypermethylation of Caspase 8 associated protein 2 (CASP8AP2) and its role in childhood acute lymphoblastic leukemia (ALL) is unclear. We analyzed methylation status of CpG sites upstream of CASP8AP2 gene in 86 children with ALL by bisulfite sequencing and quantitative PCR. Methylation percentage of two CpG sites at positions of -1189 and -1176 was inversely correlated with mRNA expression (Spearman correlation: -0.333, P=0.002). High methylation was associated with the existence of minimal residual disease (MRD) at day 78 (P=0.035), The patients in high methylation group had a poor treatment outcome. The combination of methylation level and MRD at day 33 might improve current risk stratification.
Gruhn B, Naumann T, Gruner D, et al. The expression of histone deacetylase 4 is associated with prednisone poor-response in childhood acute lymphoblastic leukemia. Leuk Res. 2013; 37(10):1200-7 [PubMed] Related Publications
This study aimed at the identification of histone deacetylase (HDAC) isoforms relevant for childhood acute lymphoblastic leukemia (ALL). Expression of HDAC1-11 was determined in 93 primary ALL and eight healthy donor samples. HDAC1, HDAC2 and HDAC8 showed significantly higher expressions in ALL samples. Correlation analysis of HDAC expression with clinicopathological parameters revealed that high HDAC1, HDAC2, HDAC4 and HDAC11 levels were significantly associated with unfavorable prognostic factors. Particularly, high HDAC4 expression was associated with high initial leukocyte count, T cell ALL and prednisone poor-response. siRNA-mediated inhibition of HDAC4 sensitized a T-ALL cell line to etoposide-induced cell death. In conclusion, our data point to HDAC4 as drug target in childhood ALL, especially in prednisone poor-responders.
Locatelli F, Crotta A, Ruggeri A, et al. Analysis of risk factors influencing outcomes after cord blood transplantation in children with juvenile myelomonocytic leukemia: a EUROCORD, EBMT, EWOG-MDS, CIBMTR study. Blood. 2013; 122(12):2135-41 [PubMed] Related Publications
We retrospectively analyzed 110 patients with juvenile myelomonocytic leukemia, given single-unit, unrelated donor umbilical cord blood transplantation. Median age at diagnosis and at transplantation was 1.4 years (age range, 0.1-6.4 years) and 2.2 years (age range, 0.5-7.4 years), respectively. Before transplantation, 88 patients received chemotherapy; splenectomy was performed in 24 patients. Monosomy of chromosome 7 was the most frequent cytogenetic abnormality, found in 24% of patients. All but 8 patients received myeloablative conditioning; cyclosporine plus steroids was the most common graft-versus-host disease prophylaxis. Sixteen percent of units were HLA-matched with the recipient, whereas 43% and 35% had either 1 or 2 to 3 HLA disparities, respectively. The median number of nucleated cells infused was 7.1 × 10(7)/kg (range, 1.7-27.6 × 10(7)/kg). With a median follow-up of 64 months (range, 14-174 months), the 5-year cumulative incidences of transplantation-related mortality and relapse were 22% and 33%, respectively. The 5-year disease-free survival rate was 44%. In multivariate analysis, factors predicting better disease-free survival were age younger than 1.4 years at diagnosis (hazard ratio [HR], 0.42; P = .005), 0 to 1 HLA disparities in the donor/recipient pair (HR, 0.4; P = .009), and karyotype other than monosomy 7 (HR, 0.5; P = .02). Umbilical cord blood transplantation may cure a relevant proportion of children with juvenile myelomonocytic leukemia. Because disease recurrence remains the major cause of treatment failure, strategies to reduce incidence of relapse are warranted.
Zappolo K, DeFeo D, Dang D, Covino J How to recognize and treat childhood leukemia. JAAPA. 2013; 26(7):37-41 [PubMed] Related Publications
Acute leukemia may be difficult to diagnose in children because of the lack of specific findings. The key is to recognize unexplained symptoms and consider leukemia as a differential. Prompt treatment improves outcomes.
Acute lymphoblastic leukemia (ALL) is the commonest childhood malignancy and is characterized by recurring structural genetic alterations. Previous studies of DNA methylation suggest epigenetic alterations may also be important, but an integrated genome-wide analysis of genetic and epigenetic alterations in ALL has not been performed. We analyzed 137 B-lineage and 30 T-lineage childhood ALL cases using microarray analysis of DNA copy number alterations and gene expression, and genome-wide cytosine methylation profiling using the HpaII tiny fragment enrichment by ligation-mediated PCR (HELP) assay. We found that the different genetic subtypes of ALL are characterized by distinct DNA methylation signatures that exhibit significant correlation with gene expression profiles. We also identified an epigenetic signature common to all cases, with correlation to gene expression in 65% of these genes, suggesting that a core set of epigenetically deregulated genes is central to the initiation or maintenance of lymphoid transformation. Finally, we identified aberrant methylation in multiple genes also targeted by recurring DNA copy number alterations in ALL, suggesting that these genes are inactivated far more frequently than suggested by structural genomic analyses alone. Together, these results demonstrate subtype- and disease-specific alterations in cytosine methylation in ALL that influence transcriptional activity, and are likely to exert a key role in leukemogenesis.
Akbari Moqadam F, Lange-Turenhout EA, Ariës IM, et al. MiR-125b, miR-100 and miR-99a co-regulate vincristine resistance in childhood acute lymphoblastic leukemia. Leuk Res. 2013; 37(10):1315-21 [PubMed] Related Publications
MicroRNA-125b (miR-125b), miR-99a and miR-100 are overexpressed in vincristine-resistant acute lymphoblastic leukemia (ALL). Cellular viability of ETV6-RUNX1-positive Reh cells significantly increased in presence of 9 ng/mL vincristine upon co-expression of miR-125b/miR-99a (91 ± 4%), miR-125b/miR-100 (93 ± 5%) or miR-125b/miR-99a/miR-100 (82 ± 17%) compared with miR-125b-transduced cells (38 ± 13%, P<0.05). Co-expression of these miRNAs resulted in downregulation of DNTT, NUCKS1, MALAT1, SNRPE, PNO1, SET, KIF5B, PRPS2, RPS11, RPL38 and RPL23A (fold-change 1.3-1.9, p<0.05). Similarly, 7 out of these genes are lower expressed in vincristine-resistant ALL cells of children (p<0.05). The concerted function of miR-125b in combination with miR-99a and/or miR-100 illustrates the complexity of vincristine-resistant pediatric ALL.
Mir Mazloumi SH, Appaji L, Madhumathi DS, Prasannakumari G-banding and fluorescence in situ hybridization in childhood acute myeloid leukemia from South India. Arch Iran Med. 2013; 16(8):459-62 [PubMed] Related Publications
BACKGROUND: The current WHO classification of hematologic malignancies defines distinct entities of myeloid disorders based on the presence of recurrent cytogenetic abnormalities. Diagnostic clonal chromosomal abnormalities provide important prognostic information and are among the most important factors in predicting initial response to chemotherapy, duration of remission and overall survival. METHODS: This study analyzed chromosomal abnormalities in bone marrow aspirates of 50 children diagnosed with acute myeloid leuckemia (AML). RESULTS: The culture success rate was 94%, clonal chromosomal abnormalities constituted 62% and recurrent chromosomal abnormalities were 56%. In the favorable prognostic category, there were 51.6% of cases with t(8;21)(q22;q22), 16.1% had t(15;17)(q22;q21), and a total of 12.9% had chromosome 16 rearrangement. The adverse risk category showed a low frequency of t(9;11)(p22;q13); t(1;22)(p13;q13); inv(3)( q21q26); add 4(q35) and ring chromosome. According to fluorescent in situ hybridization (FISH) results in 16 cytogenetically normal patients, there were no CBFβ/MYH11 fusion genes observed in chromosome 16 rearrangements. DISCUSSION: Larger studies of this kind may provide more information about chromosome 16 rearrangements in cytogenetically normal patients. The present analysis suggests that both age and cytogenetics are important strategies for risk stratification (outcome). Additional laboratory parameters should also be considered in childhood AML.
Studniak E, Maloney E, Ociepa T, et al. Allelic loss of selected tumor suppressor genes in acute lymphoblastic leukemia in children. Pol J Pathol. 2013; 64(2):121-8 [PubMed] Related Publications
Defect in function of tumor suppressor genes may lead to initiation/progression of leukemias. RB1, CDKN2A and TP53 gene alterations are found in acute lymphoblastic leukemia (ALL) in children. Data showing a contribution of these alterations to the pathomechanism of leukemias are contradictory and their impact on a disease course still remains undefined. The main aim of the study was to identify and the characterize of RB1, CDKN2A and TP53 allele loss in ALL children patients at diagnosis. 46 children with de novo ALL were examined. Fluorescent in situ hybridization was performed on bone marrow smear preparations. We demonstrated that at least one of three investigated deletions occurred statistically more frequently in T-lineage leukemia patients (p = 0.044); this was the most frequent in respect to RB1 gene (p = 0.054). Additionally, at least one of the examined deletions was observed statistically more frequently in patients with WBC above 20 000/µl (p = 0.043), this was the most frequent for CDKN2A gene (p = 0.066). Presented results seem to give an evidence that deletions of RB1 and CDKN2A genes may contribute to the development of hyperleukocytic type of T-lineage ALL in children, nevertheless this observation needs further investigations.
Young B, Hill J, Gravenhorst K, et al. Is communication guidance mistaken? Qualitative study of parent-oncologist communication in childhood cancer. Br J Cancer. 2013; 109(4):836-43 [PubMed] Article available free on PMC after 20/08/2014 Related Publications
BACKGROUND: Guidance encourages oncologists to engage patients and relatives in discussing the emotions that accompany cancer diagnosis and treatment. We investigated the perspectives of parents of children with leukaemia on the role of paediatric oncologists in such discussion. METHODS: Qualitative study comprising 33 audio-recorded parent-oncologist consultations and semi-structured interviews with 67 parents during the year following diagnosis. RESULTS: Consultations soon after the diagnosis were largely devoid of overt discussion of parental emotion. Interviewed parents did not describe a need for such discussion. They spoke of being comforted by oncologists' clinical focus, by the biomedical information they provided and by their calmness and constancy. When we explicitly asked parents 1 year later about the oncologists' role in emotional support, they overwhelmingly told us that they did not want to discuss their feelings with oncologists. They wanted to preserve the oncologists' focus on their child's clinical care, deprecated anything that diverted from this and spoke of the value of boundaries in the parent-oncologist relationship. CONCLUSION: Parents were usually comforted by oncologists, but this was not achieved in the way suggested by communication guidance. Communication guidance would benefit from an enhanced understanding of how emotional support is experienced by those who rely on it.
Hashemi F, Sedghi M, Karimi M The impact of educating parents of leukaemic children on the healthy siblings' quality of life. J Pak Med Assoc. 2013; 63(2):249-52 [PubMed] Related Publications
OBJECTIVE: To study the effect of educational programme for the parents on the quality of life of healthy siblings of children with leukaemia. METHODS: The quasi-experimental study was conducted from January to July 2006 at the Oncology Ward of Shahid Faghihi Hospital, Shiraz University of Medical Sciences, Iran. It involved two groups of siblings of children with leukaemia. Parents of the children participated in 3 educational sessions and the quality of life of their healthy children was surveyed before and after education.The data was collected through a questionnairedeveloped by The Netherlands Organisation for Aplied Scientific Research Academic Medical Centre (TN0-AZ1) which has been specially designed for children aged 7-15 years. In this study, the parent form of the questionnaire, including 7 dimensions, was used. Sampling was done by convenient purposive method. The collected data were analysed using SPSS 11.5. RESULTS: The differences in the quality of life scores of the experimental and control groups before and after education was -28.8 +/- 11.3 and -3.6 +/- 4.5, respectively. Also by regarding the mean difference of the two groups, the independent t-test showed significant difference before and after the education (p < 0.01). There was a significant difference between the two groups on all dimensions (p < 0.01) in such a way that the educational interventions was able to improve the quality of life in terms of physical complaints, autonomy, social, cognitive and motor functioning, positive and negative emotions. CONCLUSION: The educational programme was effective in improving the quality of life and its dimensions among healthy siblings of children with leukaemia.
Yan-Fang T, Jian N, Jun L, et al. The promoter of miR-663 is hypermethylated in Chinese pediatric acute myeloid leukemia (AML). BMC Med Genet. 2013; 14:74 [PubMed] Article available free on PMC after 20/08/2014 Related Publications
BACKGROUND: There is growing evidence supporting a role for microRNAs (miRNA) as targets in aberrant mechanisms of DNA hypermethylation. Epigenetic silencing of tumor suppressor miRNAs, including miR-663, which has recently been reported to be inactivated by hypermethylation in several cancers, may play important roles in pediatric acute myeloid leukemia (AML). However, expression of miR-663 and its promoter methylation remain status unclear in childhood leukemia. METHODS: Promoter methylation status of miR-663 was investigated by methylation specific PCR (MSP) and bisulfate genomic sequencing (BGS). Transcriptional expression of miR-663 was evaluated by semi-quantitative and real-time PCR, and the relationship between expression of miR-663 and promoter methylation was confirmed using 5-aza-2'-deoxycytidine (5-Aza) demethylation reagent. RESULTS: MiR-663 was aberrantly methylated in 45.5% (5/11) leukemia cell lines; BGS showed that the promoter was significantly methylated in three AML cell lines; methylation of miR-663 was significantly higher in Chinese pediatric AML patients [41.4% (29/70)] compared to normal bone marrow (NBM) control samples [10.0% (3/30)]. These results were confirmed by both BGS and 5-Aza demethylation analysis. In addition, miR-663 transcript expression was significantly lower in AML patients, both with and without miR-663 methylation, compared to controls; however, there were no significant differences in clinical features or French-American-British (FAB) classification between patients with and without miR-663 methylation. CONCLUSIONS: Expression of miR-663 was significantly lower in pediatric AML cells compared to NBM controls; furthermore, a high frequency of miR-663 promoter hypermethylation was observed in both AML cell lines and pediatric AML samples. Inactivation of miR-663 by promoter hypermethylation could be affected by 5-Aza demethylation. These findings suggest that hypermethylation of the miR-663 promoter may be an early event in the development of pediatric AML.
Kumar KR, Koduru P, Timmons C, et al. Myelodysplastic syndrome (MDS)-associated cytogenetic abnormalities in pediatric chronic myelogenous leukemia. Pediatr Blood Cancer. 2013; 60(11):E146-8 [PubMed] Related Publications
Chronic myelogenous leukemia (CML) is very rare in the pediatric population. We report the case of a 2-year-old female with CML and concurrent myelodysplastic syndrome (MDS) associated cytogenetic abnormalities. The co-existence of t(9;22) and chromosomal deletions that are associated with MDS poses a unique diagnostic challenge. Given the reported association of t(9;22) and genomic instability, we hypothesize that the chromosomal deletions represent clonal evolution of the CML.
Carranza C, Granados L, Morales O, et al. Frequency of the ETV6-RUNX1, BCR-ABL1, TCF3-PBX1, and MLL-AFF1 fusion genes in Guatemalan pediatric acute lymphoblastic leukemia patients and their ethnic associations. Cancer Genet. 2013; 206(6):227-32 [PubMed] Related Publications
Fusion genes involved in acute lymphoblastic leukemia (ALL) occur mostly due to genetic and environmental factors, and only a limited number of studies have reported any ethnic influence. This study assesses whether an ethnic influence has an effect on the frequency of any of the four fusion genes: BCR-ABL1, ETV6-RUNX1, TCF3-PBX1, and MLL-AFF1 found in ALL. To study this ethnic influence, mononuclear cells were obtained from bone marrow samples from 143 patients with ALL. We performed RNA extraction and reverse transcription, then assessed the quality of the cDNA by amplifying the ABL1 control gene, and finally evaluated the presence of the four transcripts by multiplex polymerase chain reaction. We found 10 patients who had the BCR-ABL1 fusion gene (7%); 3 patients (2%) were TCF3-PBX1 positive; and 6 patients (4.5%) were ETV6-RUNX1 positive. The incidence of this last fusion gene is quite low when compared to the values reported in most countries. The low incidence of the ETV6-RUNX1 fusion gene found in Guatemala matches the incidence rates that have been reported in Spain and Indian Romani. Since it is known that an ethnic resemblance exists among these three populations, as shown by ancestral marker studies, the ALL data suggests an ethnic influence on the occurrence and frequency of this particular fusion gene.
Joshi S, Hegde AM, Rai K, Shetty S Evaluation of salivary sialic acid levels in acute lymphoblastic leukemic children and its correlation with dental caries experience. J Clin Pediatr Dent. 2013; 37(3):309-13 [PubMed] Related Publications
AIM: The aim of present study was to evaluate the salivary sialic acid levels in Acute Lymphoblastic Leukemic (ALL) children and to correlate it with dental caries experience. METHOD: A total of 120 children aged 4-10 yrs were divided into 4 groups of 30 each. Dental caries experience was recorded followed by un-stimulated saliva collection. RESULTS: The mean salivary sialic acid levels of the study group were much higher when compared with the control group, which was statistically significant. A linear relationship between salivary sialic acid levels and dental caries in leukemic children was observed. CONCLUSION: The findings of our study conclude that salivary sialic acid levels may have a potent activity in dental caries process and can be used as a useful marker in cancer
Allen A, Sireci A, Colovai A, et al. Early T-cell precursor leukemia/lymphoma in adults and children. Leuk Res. 2013; 37(9):1027-34 [PubMed] Related Publications
Early T-cell precursor-ALL (ETP-ALL) is a subtype of T-ALL with a poor prognosis in children. We analyzed ETP-ALL compared to conventional T-ALL/LBL in both adults and children to determine any differences in clinical outcomes, based on the following parameters: induction failure, relapse, and survival. Patients with ETP-ALL have a higher risk of relapse, especially in children (in all patients, HR=4.08, p=0.127, and children, HR=11.63, p=0.025). ETP-ALL seems to have an increased risk of adverse outcomes, particularly in children. Larger studies are needed to better determine the prognosis of this subtype of T-ALL.
Teachey DT, Hunger SP Predicting relapse risk in childhood acute lymphoblastic leukaemia. Br J Haematol. 2013; 162(5):606-20 [PubMed] Related Publications
Intensive multi-agent chemotherapy regimens and the introduction of risk-stratified therapy have substantially improved cure rates for children with acute lymphoblastic leukaemia (ALL). Current risk allocation schemas are imperfect, as some children are classified as lower-risk and treated with less intensive therapy relapse, while others deemed higher-risk are probably over-treated. Most cooperative groups previously used morphological clearance of blasts in blood and marrow during the initial phases of chemotherapy as a primary factor for risk group allocation; however, this has largely been replaced by the detection of minimal residual disease (MRD). Other than age and white blood cell count (WBC) at presentation, many clinical variables previously used for risk group allocation are no longer prognostic, as MRD and the presence of sentinel genetic lesions are more reliable at predicting outcome. Currently, a number of sentinel genetic lesions are used by most cooperative groups for risk stratification; however, in the near future patients will probably be risk-stratified using genomic signatures and clustering algorithms, rather than individual genetic alterations. This review will describe the clinical, biological, and response-based features known to predict relapse risk in childhood ALL, including those currently used and those likely to be used in the near future to risk-stratify therapy.
Liang Y, Ca Q, Zhai ZM, Wang NL A practical strategy of monitoring minimal residue disease and intervention for central nervous system relapse of childhood acute lymphoblastic leukemia: a single Chinese center's experience. J Pediatr Hematol Oncol. 2013; 35(5):388-93 [PubMed] Related Publications
OBJECTIVE: To investigate monitoring minimal residual disease (MRD) using cerebral spinal fluid for predicting central nervous system leukemia (CNSL) and treatment. OBSERVATIONS: There is no survival difference between enhanced triple intrathecal therapy (ETIT) and cranial radiation for CNSL patients with positive morphology and MRD. Positive MRD correlated with CNSL, whereas negative MRD indicated a lower chance of CNSL recurrence. Altogether 79 cerebral spinal fluid specimens indicating negative morphology but positive MRD were given either ETIT or conventional triple intrathecal therapy. The ETIT group indicated lower relapse. CONCLUSION: Flow cytometry is sensitive to predict CNSL and ETIT is a potent intervention.
Moreno RB, Rives S, Justicia A, et al. Successful port-a-cath salvage using linezolid in children with acute leukemia. Pediatr Blood Cancer. 2013; 60(9):E103-5 [PubMed] Related Publications
Central venous catheter (CVC) removal is indicated when persistent catheter-related bloodstream infection (CRBSI) occurs. This is a retrospective study to analyze the use of linezolid as a salvage therapy for CRBSIs due to coagulase-negative Staphylococci in children diagnosed with acute leukemia. Seven treatment courses of linezolid were administrated to six patients with port-type-CRBSI after non-effective intravenous vancomycin or teicoplanin treatment. Simultaneous lock and systemic therapy with linezolid avoided the removal of port-type-CVC in all cases. Treatment with linezolid was an alternative to catheter removal in these patients. Prospective studies are needed to confirm linezolid effectiveness as a salvage treatment in CRBSI.
Edelmann MN, Ogg RJ, Scoggins MA, et al. Dexamethasone exposure and memory function in adult survivors of childhood acute lymphoblastic leukemia: A report from the SJLIFE cohort. Pediatr Blood Cancer. 2013; 60(11):1778-84 [PubMed] Related Publications
BACKGROUND: Dexamethasone is used in acute lymphoblastic leukemia (ALL) treatment, though long-term impact on central nervous system (CNS) function is unclear. As glucocorticoids influence hippocampal function, we investigated memory networks in survivors of childhood ALL treated with dexamethasone or prednisone. PROCEDURE: Neurocognitive assessment and functional magnetic resonance imaging (fMRI) were conducted in 38 adult survivors randomly recruited from cohorts treated on one of two standard treatment protocols, which differed primarily in the glucocorticoid administered during continuation therapy (dexamethasone [n = 18] vs. prednisone [n = 20]). Groups did not differ in age at diagnosis, age at evaluation, or cumulative intravenous or intrathecal methotrexate exposure. RESULTS: Survivors treated with dexamethasone demonstrated lower performance on multiple memory-dependent measures, including story memory (P = 0.01) and word recognition (P = 0.04), compared to survivors treated with only prednisone. Dexamethasone treatment was associated with decreased fMRI activity in the left retrosplenial brain region (effect size = 1.3), though the small sample size limited statistical significance (P = 0.08). Story memory was associated with altered activation in left inferior frontal-temporal brain regions (P = 0.007). CONCLUSIONS: Results from this pilot study suggest that adult survivors of ALL treated with dexamethasone are at increased risk for memory deficits and altered neural activity in specific brain regions and networks associated with memory function.
Gramatges MM, Rabin KR The adolescent and young adult with cancer: state of the art-- acute leukemias. Curr Oncol Rep. 2013; 15(4):317-24 [PubMed] Article available free on PMC after 01/08/2014 Related Publications
Despite survival gains over the past several decades, adolescent and young adult (AYA) patients with both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) demonstrate a consistent survival disadvantage. The AYA population exhibits unique disease and host characteristics, and further study is needed to improve their outcomes. This review will highlight distinctive aspects of disease biology in this population, as well as salient treatment-related toxicities including osteonecrosis, pancreatitis, thromboembolism, hyperglycemia, and infections. The impact of obesity and differences in drug metabolism and chemotherapy resistance will also be discussed, as well as optimal treatment considerations for the AYA population.
Ramzan M, Yadav SP, Dinand V, Sachdeva A Dengue fever causing febrile neutropenia in children with acute lymphoblastic leukemia: an unknown entity. Hematol Oncol Stem Cell Ther. 2013; 6(2):65-7 [PubMed] Related Publications
Dengue fever is endemic in many parts of the world but it has not been described as a cause of febrile neutropenia. We describe here clinical features, laboratory values and outcome in 10 children with acute lymphoblastic leukemia (ALL) and with dengue fever as a cause of febrile neutropenia. These data are compared to an age-matched control population of 22 children with proven dengue infection without ALL. Except for fever in all patients and plethoric face in one patient, typical symptoms of dengue such as abdominal pain, myalgias, and headaches, were absent. Mean duration of hospital stay was 6.3±2.0 days in ALL patients vs. 5.0±2.0 in controls (p=0.096). Median platelet count was 13,000/cmm (range 1000-28,000) in cases vs. 31,500 (range 13,000-150,000) in controls (p=0.018). Mean time for recovery for platelet was 6.0±1.3days in ALL patients vs. 2.5±0.9days in controls (p<0.001). All 10 patients survived. In endemic areas, high suspicion of dengue fever should be maintained in children with ALL and febrile neutropenia although typical symptoms may be lacking. Platelet recovery may be significantly delayed.
Krull KR, Zhang N, Santucci A, et al. Long-term decline in intelligence among adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiation. Blood. 2013; 122(4):550-3 [PubMed] Article available free on PMC after 25/07/2014 Related Publications
Survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation therapy (CRT) are at risk for cognitive impairment, although whether impairment progresses with age into adulthood is unknown. We report change in intelligence for 102 adult survivors of childhood ALL (age range, 26.6-54.7 years) during a median interval of 28.5 years. Survivors demonstrated lower Performance intelligence (mean, 95.3; standard deviation, 16.5; P = .005) but not Verbal IQ (mean, 97.4; standard deviation, 15.44; P = .09) at initial testing. Verbal intelligence declined an average of 10.3 points (P < .0001) during the follow-up interval with no decline in Performance intelligence. Decline was associated with current attention problems (P = .002) but not gender, CRT dose, age at CRT exposure, or years between testing. Results suggest long-term survivors of childhood ALL treated with CRT are at risk for progressive decline in verbal intellect, which may be driven by attention deficits. This trial was registered at clinicaltrials.gov as no. NCT00760656.
La Starza R, Lettieri A, Pierini V, et al. Linking genomic lesions with minimal residual disease improves prognostic stratification in children with T-cell acute lymphoblastic leukaemia. Leuk Res. 2013; 37(8):928-35 [PubMed] Related Publications
Multiple lesions in genes that are involved in cell cycle control, proliferation, survival and differentiation underlie T-cell acute lymphoblastic leukaemia (T-ALL). We translated these biological insights into clinical practice to improve diagnostic work-ups and patient management. Combined interphase fluorescence in situ hybridization (CI-FISH), single nucleotide polymorphism (SNP), and gene expression profiles (GEP) were applied in 51 children with T-ALL who were stratified according to minimal residual disease (MRD) risk categories (AIEOP-BFM ALL2000). CI-FISH identified type A abnormalities in 90% of patients. Distribution of each was in line with the estimated incidence in childhood T-ALL: 37.5% TAL/LMO, 22.5% HOXA, 20% TLX3, 7.5% TLX1, and 2.5% NKX2-1. GEP predictions concurred. SNP detected type B abnormalities in all cases, thus linking type A and B lesions. This approach provided an accurate, comprehensive genomic diagnosis and a complementary GEP-based classification of T-ALL in children. Dissecting primary and secondary lesions within MRD categories could improve prognostic criteria for the majority of patients and be a step towards personalized diagnosis.
Patel SK, Lo TT, Dennis JM, et al. Neurocognitive and behavioral outcomes in Latino childhood cancer survivors. Pediatr Blood Cancer. 2013; 60(10):1696-702 [PubMed] Article available free on PMC after 01/10/2014 Related Publications
BACKGROUND: Children with brain tumors and leukemia are at risk for neurocognitive and behavioral late effects due to central nervous system-directed therapies. Few studies have examined these outcomes in ethnic minority samples, despite speculation that socio-demographic factors may increase vulnerability for adverse neurobehavioral outcomes. We evaluated the neurocognitive and behavioral outcomes and their impact on the health-related quality of life in survivors of childhood cancer drawn from Latino families in the Los Angeles region. PROCEDURE: Using culturally-relevant recruitment strategies, 73 predominantly Spanish-speaking parents of pediatric brain tumor or leukemia survivors completed standardized questionnaires, including the Conners parent-report and the Bidimensional Acculturation Scales. Clinical and socio-demographic factors influencing the development of neurocognitive and behavioral dysfunction were examined. RESULTS: Approximately 50% of the children placed at or above the "elevated" level for difficulties with attention, school-based learning, and peer relations. Younger age at diagnosis significantly predicted dysfunction in inattention, learning problems, and hyperactivity/impulsivity. Children whose parents were less adherent to the non-Hispanic white culture were more likely to have problems with peer relations and executive functioning. HRQL was significantly lower in survivors with neurocognitive and behavioral dysfunction relative to those with normal range scores on the Conners scale. CONCLUSIONS: In addition to the child's age at diagnosis, acculturation appears to predict select neurocognitive and behavioral outcomes in this socio-demographically homogeneous sample of Latino families. Further research is needed to understand the interaction of ethnic and cultural factors with therapeutic exposures in determining the adverse neurobehavioral outcomes, so as to optimally design interventions.
Sitaresmi MN, Mostert S, Gundy CM, et al. A medication diary-book for pediatric patients with acute lymphoblastic leukemia in Indonesia. Pediatr Blood Cancer. 2013; 60(10):1593-7 [PubMed] Related Publications
BACKGROUND: Event-free survival of pediatric patients with acute lymphoblastic leukemia (ALL) in Yogyakarta, Indonesia was low (20%). The aim of the study was to evaluate the effectiveness of using a medication diary-book on the treatment outcome of childhood ALL. PROCEDURE: A randomized study was conducted with 109 pediatric patients with ALL in a pediatric oncology center in Yogyakarta, Indonesia. Both intervention and control groups received a structured parental education program and donated chemotherapy. The intervention group received a medication diary-book to remind parents and families to take oral chemotherapy and present for scheduled appointments or admissions. Event-free survival estimate (EFS) at 3 years was assessed. RESULTS: Among pediatric patients with ALL with highly educated mothers (senior high school or higher), the EFS-estimate at 3 years of the intervention group was significantly higher than the EFS-estimate at 3 years of the control group (62% vs. 29%, P = 0.04). Among pediatric patients with ALL with low-educated mothers, no significant difference was found in the EFS-estimates at 3 years between the intervention and control group (26% vs. 18%, P = 0.86). CONCLUSIONS: We conclude that a medication diary-book might be useful to improve the survival of pediatric patients with ALL in resource-limited settings, particularly in patients with highly educated mothers.
Mateos MK, O'Brien TA, Oswald C, et al. Transplant-related mortality following allogeneic hematopoeitic stem cell transplantation for pediatric acute lymphoblastic leukemia: 25-year retrospective review. Pediatr Blood Cancer. 2013; 60(9):1520-7 [PubMed] Article available free on PMC after 01/10/2014 Related Publications
BACKGROUND: Over the last 25 years, donor source, conditioning, graft-versus-host disease prevention and supportive care for children undergoing hematopoeitic stem cell transplantation (HSCT) have changed dramatically. HSCT indications for acute lymphoblastic leukemia (ALL) now include high-risk patients in first and subsequent remission. There is a large burden of infectious and pre-HSCT morbidities, due to myelosuppressive therapy required for remission induction. We hypothesized that, despite these trends, overall survival (OS) had increased. PROCEDURE: A retrospective audit of allogeneic pediatric HSCT for ALL was performed in our institution over 25 years. Outcomes for 136 HSCTs were analyzed in three consecutive 8-year periods (Period 1: 1/1/1984-31/8/1992, Period 2: 1/9/1992-30/4/2001, Period 3: 1/5/2001-31/12/2009). RESULTS: Despite a significant increase in unrelated donor HSCT, event-free and OS over 25 years improved significantly. (EFS 31.6-64.8%, P = 0.0027; OS 41.8-78.9%, P < 0.0001) Concurrently, TRM dropped from 33% to 5% (P = 0.0004) whilst relapse rate was static (P = 0.07). TRM reduced significantly for matched sibling and unrelated cord blood transplantation (UCT) in Period 3 compared with earlier periods (P = 0.036, P = 0.0098, respectively). Factors leading to improved survival in patients undergoing UCT include better matching, higher total nucleated cell doses, and significantly faster neutrophil engraftment. Length of initial HSCT admission was similar over time. CONCLUSION: EFS and OS have increased significantly despite heightened HSCT complexity. This survival gain was due to TRM reduction. Contemporary patients have benefited from refined donor selection and improved supportive care. Overall rates of leukemic relapse post-HSCT are unchanged, and remain the focus for improvement.
Miligi L, Benvenuti A, Mattioli S, et al. Risk of childhood leukaemia and non-Hodgkin's lymphoma after parental occupational exposure to solvents and other agents: the SETIL Study. Occup Environ Med. 2013; 70(9):648-55 [PubMed] Related Publications
AIM: In the context of the Italian Multicentric Epidemiological Study on Risk Factors for Childhood Leukaemia and Non-Hodgkin's Lymphoma (SETIL), the risk of childhood cancer was investigated in relation to parental occupational exposures. METHODS: All cases of childhood leukaemia and non-Hodgkin's lymphoma (NHL) in children aged 0-10 years were identified. Controls were chosen at random from the local population in each region. Parents were interviewed using a structured questionnaire. The collected data were blindly reviewed by expert industrial hygienists in order to estimate exposure to a list of agents. Statistical analyses were performed for each agent using unconditional multivariable logistic regression models, taking into account timing of exposure. RESULTS: 683 cases of acute childhood leukaemia, 97 cases of NHL and 1044 controls were identified. Increased risk of childhood leukaemia was found for maternal exposure to aliphatic (OR 4.3) or aromatic hydrocarbons (OR 3.8) in the preconception period, and for paternal exposure to diesel exhaust (OR 1.4), lead exposure (OR 1.4) and mineral oils (OR 1.7). Risk of NHL appeared to be related to paternal exposure to oxygenated solvents (OR 2.5) and petrol exhaust (OR 2.2). CONCLUSIONS: We found increased risk for childhood leukaemia associated with maternal occupational exposure to aromatic and aliphatic hydrocarbons, particularly in the preconception period; increased risks were also observed for paternal exposure to diesel exhaust fumes, mineral oils and lead. The risk of NHL appeared to be related to paternal exposure to oxygenated solvent and petrol exhausts.
Gupta S, Pole JD, Guttmann A, Sung L Validation of a registry-derived risk algorithm based on treatment protocol as a proxy for disease risk in childhood acute lymphoblastic leukemia. BMC Med Res Methodol. 2013; 13:68 [PubMed] Article available free on PMC after 01/10/2014 Related Publications
BACKGROUND: Administrative databases and cancer registries are frequently used to conduct population-based research, but often lack clinical data necessary for risk stratification. Our objective was to determine the criterion validity of a risk-stratification algorithm based on treatment characteristics available from a pediatric cancer registry as a proxy for disease risk, by comparing it to traditional biology-based risk classifications. METHODS: We identified all children with acute lymphoblastic leukemia diagnosed at a single institution between January 2000 and June 2011, and linked them to a population-based cancer registry. Several risk algorithms were then constructed using disease risk variables collected through chart review by a pediatric oncologist, and compared to a risk algorithm based on treatment protocol name and age, available from the registry. RESULTS: Of 596 patients identified, 579 (97.1%) met inclusion criteria and were successfully linked. The registry-based algorithm showed almost perfect agreement with a biology-based algorithm based on age, initial white blood cell count, immunophenotype and cytogenetics (kappa=0.85, 95th confidence interval 0.81-0.90). Discrepant cases were often due to the presence of unusual high risk features not captured by standard disease-risk variables but reflected in clinicians' choices of higher intensity treatment protocols. CONCLUSIONS: Protocol name represents a valid proxy of disease risk, allowing for risk stratification while conducting comparative effectiveness research using cancer registries and health services data. Future studies should examine the validity of treatment-based risk algorithms in other malignancies and using other treatment characteristics commonly found in health services data, such as the receipt of specific chemotherapeutic agents.
Zwaan CM, Rizzari C, Mechinaud F, et al. Dasatinib in children and adolescents with relapsed or refractory leukemia: results of the CA180-018 phase I dose-escalation study of the Innovative Therapies for Children with Cancer Consortium. J Clin Oncol. 2013; 31(19):2460-8 [PubMed] Related Publications
PURPOSE: Dasatinib is a potent BCR-ABL inhibitor with proven efficacy in adults with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) and in imatinib-resistant/intolerant disease. This phase I study of the Innovative Therapies for Children with Cancer Consortium assessed dasatinib safety and efficacy in pediatric patients. PATIENTS AND METHODS: Escalating once-daily dasatinib doses (60 to 120 mg/m(2)) were administered to children (n = 58) with (i) imatinib-pretreated CML or Philadelphia chromosome (Ph)-positive acute lymhoblastic leukemia (ALL) and (ii) treatment-refractory Ph-negative ALL or acute myeloid leukemia (AML). RESULTS: Dasatinib safety and efficacy profiles compared favorably with those in adults. The most common drug-related nonhematologic adverse events were nausea (31%, all grades; 2%, grade 3 to 4), headache (22%, 3%), diarrhea (21%, 0%), and vomiting (17%, 2%). Of 17 patients with CML-CP, 14 (82%) achieved complete cytogenetic response (CCyR) and eight (47%) achieved major molecular response. After ≥ 24 months of follow-up, median complete hematologic response (CHR) and major cytogenetic response (MCyR) durations were not reached. Of 17 patients with advanced-phase CML or Ph-positive ALL, six (35%) achieved confirmed CHR and 11 (65%) achieved CCyR. Median MCyR duration was 4.6 months (95% CI, 2.1 to 17.4 months). No patient with Ph-negative ALL or AML responded. Dasatinib pediatric pharmacokinetic parameters were comparable with those in adult studies, showing rapid absorption (time to reach maximum concentration, 0.5 to 6.0 hours) and elimination (mean half-life, 3.0 to 4.4 hours). CONCLUSION: Dasatinib 60 mg/m(2) and 80 mg/m(2) once-daily dosing were selected for phase II studies in children with Ph-positive leukemias.