Childhood Leukaemia
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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). This page contains links to information specifically related to Childhood Leukaemia, other relevant resources are available via the Main Menu of Children's Cancer Web

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Childhood Acute lymphoblastic leukaemia
Childhood Acute Myeloid Leukaemia

Information Patients and Family (7 links)


Information for Health Professionals / Researchers (3 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

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.


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.


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.


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.


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.


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.


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.


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.


Loh ML, Zhang J, Harvey RC, et al.
Tyrosine kinome sequencing of pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group TARGET Project.
Blood. 2013; 121(3):485-8 [PubMed] Article available free on PMC after 17/01/2014
One recently identified subtype of pediatric B-precursor acute lymphoblastic leukemia (ALL) has been termed BCR-ABL1-like or Ph-like because of similarity of the gene expression profile to BCR-ABL1 positive ALL suggesting the presence of lesions activating tyrosine kinases, frequent alteration of IKZF1, and poor outcome. Prior studies demonstrated that approximately half of these patients had genomic lesions leading to CRLF2 overexpression, with half of such cases harboring somatic mutations in the Janus kinases JAK1 and JAK2. To determine whether mutations in other tyrosine kinases might also occur in ALL, we sequenced the tyrosine kinome and downstream signaling genes in 45 high-risk pediatric ALL cases with either a Ph-like gene expression profile or other alterations suggestive of activated kinase signaling. Aside from JAK mutations and 1 FLT3 mutation, no somatic mutations were found in any other tyrosine kinases, suggesting that alternative mechanisms are responsible for activated kinase signaling in high-risk ALL.


Joyce MJ, Pollock BH, Devidas M, et al.
Chemotherapy for initial induction failures in childhood acute lymphoblastic leukemia: a Children's Oncology Group Study (POG 8764).
J Pediatr Hematol Oncol. 2013; 35(1):32-5 [PubMed] Article available free on PMC after 01/01/2014
Children with acute lymphocytic leukemia who fail to enter remission have a poor prognosis. In a previous study, 9 of 14 children with induction failure entered remission after teniposide (VM26) plus cytosine arabinoside (Ara-C). We attempted to confirm these results. Twenty children received teniposide (200 mg/m/day IV) for 3 days and cytosine arabinoside (100 mg/m/day continuous IV infusion) for 7 days. There were 3 complete and 3 partial responses. Two additional patients achieved a complete response after a second, shorter course of the same agents. Although VM26 plus Ara-C is an active combination for treatment of acute lymphocytic leukemia induction failure, it does not appear as effective as in the initial report. Better treatments for this problem are needed.


Xu XJ, Feng JH, Tang YM, et al.
Prognostic significance of flow cytometric minimal residual disease assessment after the first induction course in Chinese childhood acute myeloid leukemia.
Leuk Res. 2013; 37(2):134-8 [PubMed]
Flow cytometry based minimal residual disease (MRD) was evaluated for outcome prediction in childhood acute myeloid leukemia (AML). The median levels of MRD in relapsed and nonrelapsed patients were different after the first induction (0.64% vs. 0.18%, P=0.030). A cutoff level of ≥ 0.25% after the first course of induction was correlated with a high risk of relapse in both univariate analysis (5-year cumulative incidence of relapse: 66.8% vs. 21.2%, P=0.002) and multivariate analyses (hazard ratio: 3.70, 95% CI, 1.23-11.08, P=0.020). Our results showed that MRD level after the first induction therapy provides important information for risk assessment in childhood AML.


Mäkitie O, Heikkinen R, Toiviainen-Salo S, et al.
Long-term skeletal consequences of childhood acute lymphoblastic leukemia in adult males: a cohort study.
Eur J Endocrinol. 2013; 168(2):281-8 [PubMed]
OBJECTIVE: Long-term health sequelae of childhood-onset acute lymphoblastic leukemia (ALL) remain largely unknown. Low bone mineral content (BMC) and bone mineral density (BMD) are recognized complications, but it is unknown whether these persist until adulthood. We evaluated skeletal characteristics and their association with ALL therapy in long-term male ALL survivors.
DESIGN: This cross-sectional cohort study included 49 long-term male ALL survivors and 55 age-matched healthy males.
METHODS: BMD and compression fractures were assessed by dual-energy X-ray absorptiometry; blood biochemistry was obtained for parameters of calcium homeostasis.
RESULTS: The ALL survivors (median age 29 years, range 25-38 years), assessed 10-38 years after ALL diagnosis, had lower lumbar spine (P<0.001), femoral neck (P<0.001), and whole-body (P=0.017) BMD than expected based on normative values. When compared with the controls (median age 30 years, range 24-36 years), the ALL survivors had lower lumbar spine BMC (P=0.014), lower whole-body BMC (P<0.001), and lower whole-body BMD (P<0.001), but the differences were partly explained by differences in height. Altogether, 20% of the ALL survivors had spinal compression fractures, but these were equally prevalent in the controls. Males diagnosed with ALL before age 5 years had significantly lower BMD values. Other recognized risk factors included untreated hypogonadism, vitamin D deficiency, hypophosphatemia, low IGF-binding protein-3, and low physical activity.
CONCLUSIONS: At young adulthood, long-term male ALL survivors have significantly reduced BMC and BMD and a high prevalence of spinal compression fractures. Careful follow-up and active treatment of the recognized risk factors are warranted.


Kavcic M, Fisher BT, Torp K, et al.
Assembly of a cohort of children treated for acute myeloid leukemia at free-standing children's hospitals in the United States using an administrative database.
Pediatr Blood Cancer. 2013; 60(3):508-11 [PubMed]
Pediatric Health Information System data were used to establish a multi-center cohort of 1,686 children treated for newly diagnosed acute myeloid leukemia (AML). The cohort assembly process, which included myeloid leukemia ICD-9 discharge diagnosis codes and manual review of induction chemotherapy, was validated by chart review at a single institution. The use of ICD-9 codes alone resulted in a poor positive predictive value (PPV; 31%). Inclusion of the results from the chemotherapy review improved the PPV to 100% without compromising sensitivity (95.7%). This cohort provides a reliable source for future comparative effectiveness and clinical epidemiology studies in pediatric AML.


White AD, Othman D, Dawrant MJ, et al.
Implantable versus cuffed external central venous catheters for the management of children and adolescents with acute lymphoblastic leukaemia.
Pediatr Surg Int. 2012; 28(12):1195-9 [PubMed]
PURPOSE: The aim of this study was to determine if there is a difference between complications for totally implantable central venous catheters (ports) and tunnelled external central venous catheters (external CVCs) that result in early removal of the central venous catheter (CVC) in children and adolescents with acute lymphoblastic leukaemia (ALL).
METHODS: All children hospitalised between November 1996 and December 2007 with ALL who had a CVC were included retrospectively. We analysed data regarding the patient's first CVC.
RESULTS: We included 322 patients. 254 received a port and 68 received an external CVC. There were 102 CVC complications that required removal of the CVC prior to the completion of chemotherapy (65 in patients with ports, 37 in patients with external CVCs). Overall complications requiring CVC removal were significantly less likely to occur in the patient's with ports (p < 0.001). Ports were significantly less likely to require removal prior to the end of treatment overall (p < 0.001) and for specific complications such as infection (p < 0.001) and dislodgement (p = 0.001). However, when adjusted for disease severity there is no difference in premature CVC removal rates.
CONCLUSION: When patients are risk-stratified for disease severity there is no difference in rates of CVC removal prior to completion of treatment.


Chang JS, Tsai YW, Tsai CR, Wiemels JL
Allergy and risk of childhood acute lymphoblastic leukemia: a population-based and record-based study.
Am J Epidemiol. 2012; 176(11):970-8 [PubMed]
A deficit of normal immune stimulation in early childhood is a suspected risk factor for both childhood acute lymphoblastic leukemia (ALL) and allergies. The present study utilized a population-based case-control design using medical claims data from the National Health Insurance Research Database of Taiwan to evaluate the association between allergy and childhood leukemia. Eight hundred forty-six childhood ALL patients who were newly diagnosed during 2000 to 2008 and were older than 1 but less than 10 years of age were individually matched with 3,374 controls based on sex, birth date, and time of diagnosis (reference date for the controls). Conditional logistic regression was performed to assess the association between childhood ALL and allergies. An increased risk of ALL was observed with having an allergy less than 1 year before the case's ALL diagnosis (odds ratio (OR) = 1.7, 95% confidence interval (CI): 1.5, 2.0), more than 1 year before the case's diagnosis (OR = 1.3, 95% CI: 1.1, 1.5), and before the age of 1 year (OR = 1.4, 95% CI: 1.1, 1.7). These results suggest that the pathogenesis of childhood ALL and allergy share a common biologic mechanism.


Linabery AM, Spector LG
Invited commentary: childhood acute lymphoblastic leukemia and allergies: biology or bias?
Am J Epidemiol. 2012; 176(11):979-83; discussion 984-5 [PubMed] Article available free on PMC after 01/12/2013
Previous epidemiologic studies have shown an inverse association between a personal history of atopy/allergies, both overall and among asthma, eczema, and hay fever investigated separately, and childhood acute lymphoblastic leukemia (ALL) with some consistency; however, in most of these studies, exposure data were collected by maternal interview. Now, in a population-based and records-based study in this issue of the Journal (Am J Epidemiol. 2012;176(11):970-978), Chang et al. report an increased risk for allergic conditions across different etiologic time periods, calling the former paradigm into doubt. A review of the basic biology literature shows that proposed mechanisms support either a positive or an inverse association. In light of this ambiguity, it is epidemiology's turn to determine the direction of association.


Lipshultz SE, Miller TL, Lipsitz SR, et al.
Continuous Versus Bolus Infusion of Doxorubicin in Children With ALL: Long-term Cardiac Outcomes.
Pediatrics. 2012; 130(6):1003-11 [PubMed] Article available free on PMC after 01/12/2013
BACKGROUND AND OBJECTIVES: Doxorubicin, effective against many malignancies, is limited by cardiotoxicity. Continuous-infusion doxorubicin, compared with bolus-infusion, reduces early cardiotoxicity in adults. Its effectiveness in reducing late cardiotoxicity in children remains uncertain. We determined continuous-infusion doxorubicin cardioprotective efficacy in long-term survivors of childhood acute lymphoblastic leukemia (ALL).
METHODS: The Dana-Farber Cancer Institute ALL Consortium Protocol 91-01 enrolled pediatric patients between 1991 and 1995. Newly diagnosed high-risk patients were randomly assigned to receive a total of 360 mg/m(2) of doxorubicin in 30 mg/m(2) doses every 3 weeks, by either continuous (over 48 hours) or bolus-infusion (within 15 minutes). Echocardiograms at baseline, during, and after doxorubicin therapy were blindly remeasured centrally. Primary outcomes were late left ventricular (LV) structure and function.
RESULTS: A total of 102 children were randomized to each treatment group. We analyzed 484 serial echocardiograms from 92 patients (n = 49 continuous; n = 43 bolus) with ≥1 echocardiogram ≥3 years after assignment. Both groups had similar demographics and normal baseline LV characteristics. Cardiac follow-up after randomization (median, 8 years) showed changes from baseline within the randomized groups (depressed systolic function, systolic dilation, reduced wall thickness, and reduced mass) at 3, 6, and 8 years; there were no statistically significant differences between randomized groups. Ten-year ALL event-free survival rates did not differ between the 2 groups (continuous-infusion, 83% versus bolus-infusion, 78%; P = .24).
CONCLUSIONS: In survivors of childhood high-risk ALL, continuous-infusion doxorubicin, compared with bolus-infusion, provided no long-term cardioprotection or improvement in ALL event-free survival, hence provided no benefit over bolus-infusion.


Marjerrison S, Antillon F, Fu L, et al.
Outcome of children treated for relapsed acute lymphoblastic leukemia in Central America.
Cancer. 2013; 119(6):1277-83 [PubMed]
BACKGROUND: Outcomes for relapsed childhood acute lymphoblastic leukemia (ALL) have not been documented in resource-limited settings. This study examined survival after relapse for children with ALL in Central America.
METHODS: A retrospective cohort study was performed and included children with first relapse of ALL in Guatemala, Honduras, or El Salvador between 1990 and 2011. Predictors of subsequent event-free survival (EFS) and overall survival (OS) were examined.
RESULTS: There were 755 children identified with relapsed disease. The median time from diagnosis to relapse was 1.7 years (interquartile range, 0.8-3.1 years). Most relapses occurred during (53.9%) or following (24.9%) maintenance chemotherapy, and the majority occurred in the bone marrow (63.1%). Following the initial relapse, subsequent 3-year EFS (± standard error) and OS were 22.0% ± 1.7%, and 28.2% ± 1.9%, respectively. In multivariable analysis, worse postrelapse survival was associated with age ≥ 10 years, white blood cell count ≥ 50 × 10(9) /L, and positive central nervous system status at the original ALL diagnosis, relapse that was not isolated central nervous system or testicular, and relapse < 36 months following diagnosis. Site and time to relapse were used to identify a favorable risk group whose 3-year EFS and OS were 50.0% ± 8.9% and 68.0% ± 8.1%, respectively.
CONCLUSIONS: Prognosis after relapsed ALL in Central America is poor, but a substantial number of those with favorable risk features have prolonged survival, despite lack of access to stem cell transplantation. Stratification by risk factors can guide therapeutic decision-making. Cancer 2013. © 2012 American Cancer Society.


Gruber TA, Larson Gedman A, Zhang J, et al.
An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia.
Cancer Cell. 2012; 22(5):683-97 [PubMed] Article available free on PMC after 13/11/2013
To define the mutation spectrum in non-Down syndrome acute megakaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL samples. Our analysis identified a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)) in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.


Santos RP, Chao J, Nepo AG, et al.
The use of intravenous palivizumab for treatment of persistent RSV infection in children with leukemia.
Pediatrics. 2012; 130(6):e1695-9 [PubMed]
Palivizumab is a humanized monoclonal antibody used to decrease the threat of respiratory syncytial virus (RSV) infection among children at high risk. There are no standard guidelines due to conflicting data on palivizumab's use in the treatment of RSV lower respiratory tract infections. Intravenous (IV) palivizumab was shown to be well tolerated and associated with decreased mortality in high-risk children who have RSV disease. However, it did not prevent lower respiratory tract infections and did not affect the survival rate of allogeneic stem cell transplant recipients who had RSV infection. We present 2 children with acute lymphocytic leukemia (ALL) and persistent RSV infection while receiving chemotherapy. Patient A is a 4-year-old male with Down syndrome, ALL, and persistent RSV infection for at least 3 months. Patient B is a 3-year-old female with pre-B cell ALL whose chemotherapy intensification phase was delayed due to a month-long RSV infection. RSV infections were determined by using real-time polymerase chain reaction assays from nasopharyngeal swabs before IV palivizumab therapy; patient A was positive for RSV at 36 cycles and patient B was positive for RSV at 29 cycles. RSV infection was cleared in both patients within 72 hours after receiving IV palivizumab (patient A: 16 mg/kg; patient B: 15 mg/kg). IV palivizumab may be a treatment option for persistent RSV infection among immunocompromised patients.


O'Neill KA, Bunch KJ, Murphy MF
Intrauterine growth and childhood leukemia and lymphoma risk.
Expert Rev Hematol. 2012; 5(5):559-76 [PubMed]
Leukemias and lymphomas account for nearly half of all childhood cancers. Although there have been major advances in the treatment of these diseases, what causes them remains largely unknown. There is strong evidence to suggest that leukemia originates in utero, and early life factors may play a role in its etiology. A series of reports illustrate a convincing link between the rate of intrauterine growth and the risk of childhood leukemia. Some studies suggest that this risk relationship also extends to non-Hodgkin lymphoma in children, although, overall, the association with childhood lymphoma is less clear. This review discusses the intricacies of these risk relationships and explores potential explanations of how the rate of fetal growth may influence cancer risk.


Koc A, Aycicek A, Ozdemir ZC, et al.
Outcome of modified St Jude total therapy 13A for childhood acute lymphoblastic leukemia in the southeast region of Turkey.
J Pediatr Hematol Oncol. 2013; 35(1):36-41 [PubMed]
OBJECTIVE: To fill the gap in the current data on childhood acute lymphoblastic leukemia (ALL) in low-income and middle-income countries.
METHODS: This study included 106 children between the ages of 1 and 17 years with newly diagnosed ALL monitored between 1999 and 2010. All the patients were treated with the modified St Jude Total 13A treatment plan at the Pediatric Hematology Clinic at Harran University.
RESULTS: Sixty-eight (64.2%) patients were boys and 38 (35.8%) were girls. The median age at diagnosis was 5.9 ± 3.7 years. Thirty-eight (35.8%) children were classified as standard risk, 53 (39.3%) were intermediate risk, and 15 (14.2%) were high risk. Thirteen (12.3%) children died in induction before the remission date (43 d of remission induction). Of all the 93 (100%) patients who completed remission induction therapy and whose bone marrow were in remission, 5 (4.7%) had a bone marrow relapse, 1 (0.9%) had a retinal relapse, and 5 (4.7%) had secondary acute myeloid leukemia. At a median follow-up of 44 months (range, 0.36 to 135.5 mo), the estimated 5-year overall survival and event-free survival were 77.4 ± 5% and 68.9 ± 6.5%, respectively. The estimated 5-year overall survival for boys and girls was 76.5 ± 6% and 65.8 ± 8%, respectively (P = 0.182).
CONCLUSIONS: St Jude Total 13A treatment protocols to treat childhood ALL can be successfully adapted, which suggests that such an approach may be useful in low socioeconomic regions; however, it should be noted that secondary leukemia can occur at a high rate.


Begum M, Jahan S, Tawfique M, Mannan MA
Out come of induction of remission in undernourished children with acute lymphoblastic leukaemia.
Mymensingh Med J. 2012; 21(4):691-5 [PubMed]
Acute lymphoblastic leukaemia (ALL) is the most common childhood leukaemia. On the other hand under-nutrition is a common problem in our country. This prospective study was conducted to see the outcome of induction of remission in undernourished children with acute lymphoblastic leukaemia. This study was carried out in the department of Paediatric hematology and oncology of Bangabandhu Sheikh Mujib Medical University (BSMMU) during the period from November 2002 to October 2004. A total of sixty (60) children who were diagnosed as acute lymphoblastic leukaemia in 1 to 15 years of age were included in this study. But the children with previous history of congenital disease and that of chemotherapy or steroid were excluded from this study. Patients were divided into two groups on the basis of Z score of weight for age. Thirty (30) children those with Z score- 2 or less were classified as undernourished and was labeled as Group A and another thirty (30) patient those Z score above-2 were classified as well nourished and was placed in Group B, After inclusion into the study, completion of induction of remission was monitored by physical examination and laboratory investigations. The result showed that mean age in Group A was 77.16 ± 7.07 months and that in Group B was 74.13 ± 5.09 months with male preponderance in both the groups. Mean body weight in Group A was 14.55 ± 0.76 Kg and that in Group B was 21.40 ± 1.05 kg (p<0.001). Children in Group A required 39.06 ± 0.72 days to complete induction but in Group B it required 31.63 ± 0.17 days (p<0.04). Hospital stay in Group A children was 52.10 ± 1.08 days and in Group B 42.37 ± 0.50 (p<0.002). The result suggested that under nutrition has an influence on the out come of induction of remission in undernourished children with acute lymphoblastic leukaemia. So appropriate measures are essential to improve nutritional status of children for successful management of ALL in children.


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