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
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).
Ibrahem WN, Hasony HJ, Hassan JG Human parvovirus B19 in childhood acute lymphoblastic leukaemia in Basrah. J Pak Med Assoc. 2014; 64(1):9-12 [PubMed] Related Publications
OBJECTIVE: To investigate the association of human parvovirus B19 infection with the onset of acute lymphoblastic leukaemia and its effect on TEL-AML-1 fusion gene and the presence of mutant P53. METHODS: The case-control study was conducted at Basrah Hospital for Paediatrics and Gynaecology, Basrah, Iraq, from May 2009 to April 2010. A total of 100 blood samples were collected from 40 newly diagnosed cases and 60 healthy children to serve as control matched by age and gender. Human parvovirus B19-IgG and anti-P53 antibody were detected by enzyme-linked immunosorbent assay and TEL-AML-1 fusion gene was detected by reverse transcriptase-polymerase chain reaction on extracted ribonucleic acid from fresh blood samples using specified primers. SPSS 15 was used for statistical analysis. RESULTS: A higher proportion of human parvovirus B19-positive cases was found in leukaemic patients (n=19; 47.5%) compared to 12 (20%) in the control group (p<0.05). There was significant association between TEL-AML-1 translocation and human parvovirus-B19 infection as 10 (71.4%) of TEL-AML-1 translocation-positive cases had human parvovirus-B19 IgG. On the other hand, there was no association between such infections and P53 gene mutation in the patients. CONCLUSION: Human parvovirus-B19 infection is common in the population, with higher prevalence among leukaemic patients with significant association between human parvovirus-B19 and TEL-AML-1 fusion gene in patients of acute lymphoblastic leukaemia.
Abdelmalak CA, Yahya RS, Elghannam DM, et al. PRAME gene expression in childhood acute lymphoblastic leukemia: impact on prognosis. Clin Lab. 2014; 60(1):55-61 [PubMed] Related Publications
BACKGROUND: The PRAME (preferentially expressed antigen of melanoma) gene is frequently overexpressed in a wide variety of malignant diseases, including acute myeloid leukemia (AML) and acute B-cell malignancies. AIM: To study the expression of PRAME gene and clarify its prognostic impact on disease outcome. METHODS: Screening for PRAME gene expression was assessed using real-time reverse transcriptase polymerase chain reaction in 55 pretreated ALL bone marrow samples. RESULTS: PRAME positivity was found in 14 (31.3%) of 45 patients. No significant correlation could be observed between PRAME expression and clinical characteristics. Positive PRAME expressers had a statistically higher CR (p = 0.001), lower relapse (p = 0.02), lower mortality (p < 0.001), a trend towards lower Refractory disease (p = 0.10), and a statistically longer DFS and OS (p < 0.001, < 0.001, respectively) in comparison to negative PRAME expressers. CONCLUSIONS: Our results suggested that PRAME was a predictor for better outcome, could be a useful target for immunotherapy, and might represent a candidate marker for the monitoring of minimal residual disease.
Genomic aberrations affecting genes in B cell differentiation are hallmarks of B-precursor acute lymphoblastic leukemia (ALL). A new whole-genome sequencing study of ETV6-RUNX1-positive ALL has now identified RAG-mediated recombination, which specifically targets genes and regulatory elements active during B cell differentiation, as the underlying mechanism.
Fogelstrand L, Staffas A, Wasslavik C, et al. Prognostic implications of mutations in NOTCH1 and FBXW7 in childhood T-ALL treated according to the NOPHO ALL-1992 and ALL-2000 protocols. Pediatr Blood Cancer. 2014; 61(3):424-30 [PubMed] Related Publications
BACKGROUND: In children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis. PROCEDURE: We analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes. RESULTS: Forty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P = 0.14) or event-free survival (EFS) (P = 0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.2 ± 1.9 (mean ± SEM), MYB 8.7 ± 0.8 (mean ± SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 ± 0.7, MYB 5.1 ± 1.2, P = 0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P = 0.02) and EFS (P = 0.028) was seen. CONCLUSIONS: Increased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated.
Mushtaq N, Fadoo Z, Naqvi A Childhood acute lymphoblastic leukaemia: experience from a single tertiary care facility of Pakistan. J Pak Med Assoc. 2013; 63(11):1399-404 [PubMed] Related Publications
OBJECTIVE: To evaluate the demographic features, outcome and prognostic factors seen in children with acute lymphoplastic leukaemia at a tertiary care hospital. METHODS: The retrospective descriptive study was conducted at Aga Khan University Hospital, Karachi, comprising data related to children below 15 years of age and treated between January 1997 and December 2006. Kaplan Meir survival curves were used to describe overall and event-free survival rates. Cox Proportional Hazards model was used to describe factors associated with death and relapse. SPSS 16 was the main statistical tool. RESULTS: Of the total 121 children diagnosed with the condition, 79 (65.3%) were males; 86 (71.1%) patients were between 1-9 years of age; Immunophenotyping was done in 99 (81.81%) patients: 86 (87%) cases had precursor B and 13 (13.13%) had precursor T. Of the total, 106 (87.6%) patients opted for treatment, while 15 (11.6%) were lost to follow-up. Besides, 26 (21.7%) patients had at least one relapse; the most common site being bone marrow in 13 (50%) followed by central nervous system in 9 (36.6%). There were 20 (16.5%) deaths in the sample. Infection was the most frequent cause of death. The event-free survival and overall survival was 63% (n = 76) and 65% (n = 79) respectively. CONCLUSION: Through the clinical characteristics of children with acute lymphoblastic leukamia were similar to those reported in literature, the outcomes were inferior. The high rate of infections and relapse warrant better supportive care and risk-based approach.
Duffner PK, Armstrong FD, Chen L, et al. Neurocognitive and neuroradiologic central nervous system late effects in children treated on Pediatric Oncology Group (POG) P9605 (standard risk) and P9201 (lesser risk) acute lymphoblastic leukemia protocols (ACCL0131): a methotrexate consequence? A report from the Children's Oncology Group. J Pediatr Hematol Oncol. 2014; 36(1):8-15 [PubMed] Related Publications
Concerns about long-term methotrexate (MTX) neurotoxicity in the 1990s led to modifications in intrathecal (IT) therapy, leucovorin rescue, and frequency of systemic MTX administration in children with acute lymphoblastic leukemia. In this study, neurocognitive outcomes and neuroradiologic evidence of leukoencephalopathy were compared in children treated with intense central nervous system (CNS)-directed therapy (P9605) versus those receiving fewer CNS-directed treatment days during intensive consolidation (P9201). A total of 66 children from 16 Pediatric Oncology Group institutions with "standard-risk" acute lymphoblastic leukemia, 1.00 to 9.99 years at diagnosis, without evidence of CNS leukemia at diagnosis were enrolled on ACCL0131: 28 from P9201 and 38 from P9605. Magnetic resonance imaging scans and standard neuropsychological tests were performed ≥2.6 years after the end of treatment. Significantly more P9605 patients developed leukoencephalopathy compared with P9201 patients (68%, 95% confidence interval 49%-83% vs. 22%, 95% confidence interval 5%-44%; P=0.001) identified as late as 7.7 years after the end of treatment. Overall, 40% of patients scored <85 on either Verbal or Performance IQ. Children on both studies had significant attention problems, but P9605 children scored below average on more neurocognitive measures than those treated on P9201 (82%, 14/17 measures vs. 24%, 4/17 measures). This supports ongoing concerns about intensive MTX exposure as a major contributor to CNS late effects.
Stary J, Zimmermann M, Campbell M, et al. Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol. 2014; 32(3):174-84 [PubMed] Related Publications
PURPOSE: From 2002 to 2007, the International Berlin-Frankfurt-Münster Study Group conducted a prospective randomized clinical trial (ALL IC-BFM 2002) for the management of childhood acute lymphoblastic leukemia (ALL) in 15 countries on three continents. The aim of this trial was to explore the impact of differential delayed intensification (DI) on outcome in all risk groups. PATIENTS AND METHODS: For this trial, 5,060 eligible patients were divided into three risk groups according to age, WBC, early treatment response, and unfavorable genetic aberrations. DI was randomized as follows: standard risk (SR), two 4-week intensive elements (protocol III) versus one 7-week protocol II; intermediate risk (IR), protocol III × 3 versus protocol II × 1; high risk (HR), protocol III × 3 versus either protocol II × 2 (Associazione Italiana Ematologia Oncologia Pediatrica [AIEOP] option), or 3 HR blocks plus single protocol II (Berlin-Frankfurt-Münster [BFM] option). RESULTS: At 5 years, the probabilities of event-free survival and survival were 74% (± 1%) and 82% (± 1%) for all 5,060 eligible patients, 81% and 90% for the SR (n = 1,564), 75% and 83% for the IR (n = 2,650), and 55% and 62% for the HR (n = 846) groups, respectively. No improvement was accomplished by more intense and/or prolonged DI. CONCLUSION: The ALL IC-BFM 2002 trial is a good example of international collaboration in pediatric oncology. A wide platform of countries able to run randomized studies in ALL has been established. Although the alternative DI did not improve outcome compared with standard treatment and the overall results are worse than those achieved by longer established leukemia groups, the national results have generally improved.
Baker JM, To T, Beyene J, et al. Influence of length of time to diagnosis and treatment on the survival of children with acute lymphoblastic leukemia: a population-based study. Leuk Res. 2014; 38(2):204-9 [PubMed] Related Publications
The objectives were to describe times to diagnosis and initiation of treatment in pediatric ALL in Ontario from 1997 to 2007, and to measure their impact on OS and EFS. In 1000 children, the median times to diagnosis and treatment were both 1 day (IQR = 1-2). Those who began treatment >3 days after diagnosis had inferior OS (AHR = 2.49; 95% CI = 1.40-4.43; p = 0.002), and inferior EFS (AHR = 1.73; 95% CI = 1.01-2.96; p = 0.047) compared to those who began treatment ≤ 3 days after diagnosis. There was no statistically significant relationship between time to diagnosis and survival. Longer time to treatment was associated with worse survival in pediatric ALL; reasons for this relationship may be multi-factorial.
Pei JS, Lee YM, Lo HH, et al. Association of X-ray repair cross-complementing-6 genotypes with childhood leukemia. Anticancer Res. 2013; 33(12):5395-9 [PubMed] Related Publications
BACKGROUND: The Non-homologous end-joining repair gene XRCC6/Ku70 plays an important role in the repair of DNA double-strand breaks (DSBs), and has been found to be involved in the carcinogenesis of many types of cancers including oral, prostate, breast and bladder cancer. However, the contribution of XRCC6 to childhood leukemia has yet to be studied. In the present study, we investigated the association of XRCC6 genotypes with the risk of childhood leukemia. MATERIALS AND METHODS: Two hundred and sixty-six patients with childhood leukemia and an equal number of age-matched healthy controls recruited in Central Taiwan, were genotyped investigating these polymorphisms' association with childhood leukemia. RESULTS: As for XRCC6 promoter T-991C, patients carrying the TC genotype had a significantly increased risk of childhood leukemia compared with the TT wild-type genotype [odds ratio (OR)=2.30, 95% confidence interval (CI)=1.38-3.84, p=0.0047]. Meanwhile, the genotypes of XRCC6 promoter C-57G, A-31G and intron3 were not statistically associated with childhood leukemia risk. CONCLUSION: Our findings suggest that the XRCC6 genotype could serve as a predictor of childhood leukemia risk and XRCC6 could serve as a target for personalized medicine and therapy.
Pállinger E, Kovács G, Horváth Z, et al. Changes in the hormone (ACTH, insulin,epinephrine) content of immune cells in children having acute lymphocytic leukemia (ALL). Acta Microbiol Immunol Hung. 2013; 60(4):423-31 [PubMed] Related Publications
Immune cells synthesize, store and secrete hormones, the level of which changes in ALL. In previous experiments the level of histamine, serotonin and triiodothyronine (T3)was studied, while at present that of ACTH, insulin and epinephrine, using flow cytometric analysis for the determination of cell subsets and detection of hormone content. The measurements were done in children at the time of diagnosis. ACTH was significantly elevated in each T cell subsets (total T, Th, Tc, activated T), while B and NK cells were not touched. The alterations in the insulin content (decrease in Tc and activated T cells) were uncertain, and NK cells contained significantly less insulin. The disease did not influence the cells' epinephrine content. There is not clear explanation for the importance of changes in the cells' hormone content, however, it is discussed in the text.
Bansal M, Sharma KK, Bakhshi S, Vatsa M Perception of Indian parents on health-related quality of life of children during maintenance therapy of acute lymphoblastic leukemia: a comparison with siblings and healthy children. J Pediatr Hematol Oncol. 2014; 36(1):30-6 [PubMed] Related Publications
BACKGROUND: Advancements in treatment have improved the prognosis of children with acute lymphoblastic leukemia (ALL). Therefore, there is a need to explore health-related quality of life (HRQOL) in depth, specifically in maintenance therapy, where the available data are minimal. This study was conducted to assess the varied items listed in the domains of HRQOL of Children with ALL during maintenance therapy from a parent's perspective. METHODS: Forty children on the maintenance therapy of ALL, 40 siblings, and 40 healthy children were enrolled, and the HRQOL was assessed by parent proxy reports and child self-reports using PedsQL generic core 4.0 in local language. RESULTS: Parents significantly overrated the HRQOL of ALL patients, their siblings, and healthy children in comparison with child self-report in all domains of health. The HRQOL of children with ALL on maintenance therapy was significantly poorer than siblings and healthy children, but their ability to self-care, household work, attentiveness, and ability to do homework were not affected as per parents' reports. Parents reported that absenteeism because of sickness and hospital visits was more among children with ALL than siblings and healthy children. Children with ALL had emotional problems such as fear, anger, sleeping problems, and worries. In a social health domain, parents reported difficulty in competing among children with ALL. The HRQOL of siblings was as good as healthy children in physical, social, and school health domains as per parents' reports. CONCLUSIONS: In our cohort, parents overrated HRQOL in all groups of children. The study identified the various items in each domain of HRQOL that were affected in children with ALL from parents' perspective; this would guide health care professionals to focus on these specific items so as to improve the overall HRQOL of children with ALL.
Pastorczak A, Fendler W, Zalewska-Szewczyk B, et al. Asparagine synthetase (ASNS) gene polymorphism is associated with the outcome of childhood acute lymphoblastic leukemia by affecting early response to treatment. Leuk Res. 2014; 38(2):180-3 [PubMed] Related Publications
The polymorphism of 14-bp tandem repeat sequence located in the ASNS gene probably acts as a transcriptional enhancer element and leads to higher expression of the gene in carriers of more than 2 repeats (>R2). We searched for an association with disease outcome in 264 children with ALL. A multivariate proportional hazard regression model adjusted for age at diagnosis (HR (95%CI)=1.05 (1.04-1.09)) and high-risk group (HR(95%CI)=3.47 (1.74-6.88)) revealed that R3 carriers with a poor response at day 15 had an increased risk of events, HR (95%CI)=2.72 (1.06-6.96). These results suggest a conditional interaction between the ASNS polymorphism and an early response to chemotherapy among pediatric patients with ALL.
Schuback HL, Arceci RJ, Meshinchi S Somatic characterization of pediatric acute myeloid leukemia using next-generation sequencing. Semin Hematol. 2013; 50(4):325-32 [PubMed] Related Publications
Acute myeloid leukemia (AML) is a complex and heterogeneous disease with distinct age-associated genomic and epigenomic alterations. A large number of somatic karyotypic and molecular alterations have been identified in AML to date; however, very few predict outcome or identify potential therapeutic targets. Here we describe the current state of known molecular and genetic alterations in pediatric AML. Further, as recent advances in sequencing technologies have revolutionized our ability to interrogate cancer genome, transcriptome, and epigenome, we will also review the emerging genomic data identified by next-generation sequencing and discuss their potential impact as tools for therapeutic interventions in the near future. In coming years, a wealth of data from large-scale discovery phase projects such as the Children's Oncology Group/ National Cancer Institute (COG/NCI) TARGET AML initiative will be available to researchers to discover new biomarkers for risk and target identification in pediatric AML.
Mullighan CG Genomic characterization of childhood acute lymphoblastic leukemia. Semin Hematol. 2013; 50(4):314-24 [PubMed] Article available free on PMC after 04/10/2014 Related Publications
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and a leading case of childhood cancer death. The last decade has witnessed a transformation in our understanding of the genetic basis of ALL due to detailed integrative genomic profiling of large cohorts of childhood ALL. Initially using microarray based approaches, and more recently with next-generation sequencing, these studies have enabled more precise subclassification of ALL, and have shown that each ALL entity is characterized by constellations of structural and sequence mutations that typically perturb key cellular pathways including lymphoid development, cell cycle regulation, tumor suppression, Ras- and tyrosine kinase-driven signaling, and epigenetic regulation. Importantly, several of the newly identified genetic alterations have entered the clinic to improve diagnosis and risk stratification, and are being pursued as new targets for therapeutic intervention. Studies of ALL have also led the way in dissecting the subclonal heterogeneity of cancer, and have shown that individual patients commonly harbor multiple related but genetically distinct subclones, and that this genetically determined clonal heterogeneity is an important determinant of relapse. In addition, genome-wide profiling has identified inherited genetic variants that influence ALL risk. Ongoing studies are deploying detailed integrative genetic transcriptomic and epigenetic sequencing to comprehensively define the genomic landscape of ALL. This review describes the recent advances in our understanding of the genetics of ALL, with an emphasis on those alterations of key pathogenic or therapeutic importance.
Kiyokawa N, Iijima K, Tomita O, et al. Significance of CD66c expression in childhood acute lymphoblastic leukemia. Leuk Res. 2014; 38(1):42-8 [PubMed] Related Publications
Upon analyzing 696 childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cases, we identified the characteristics of CD66c expression. In addition to the confirmation of strong correlation with BCR-ABL positivity and hyperdiploid, we further observed that CD66c is frequently expressed in CRLF2-positive (11/15, p<0.01 against chimeric gene-negative) as well as hypodiploid cases (3/4), whereas it is never expressed in ETV6-RUNX1, MLL-AF4, MLL-AF9, MLL-ENL, and E2A-PBX1-positive cases. Although the expression of CD66c itself is not directly linked to the prognosis, the accompanying genetic abnormalities are important prognostic factors for BCP-ALL, indicating the importance of CD66c expression in the initial diagnosis of BCP-ALL.
Buitenkamp TD, Izraeli S, Zimmermann M, et al. Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group. Blood. 2014; 123(1):70-7 [PubMed] Article available free on PMC after 04/10/2014 Related Publications
Children with Down syndrome (DS) have an increased risk of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The prognostic factors and outcome of DS-ALL patients treated in contemporary protocols are uncertain. We studied 653 DS-ALL patients enrolled in 16 international trials from 1995 to 2004. Non-DS BCP-ALL patients from the Dutch Child Oncology Group and Berlin-Frankfurt-Münster were reference cohorts. DS-ALL patients had a higher 8-year cumulative incidence of relapse (26% ± 2% vs 15% ± 1%, P < .001) and 2-year treatment-related mortality (TRM) (7% ± 1% vs 2.0% ± <1%, P < .0001) than non-DS patients, resulting in lower 8-year event-free survival (EFS) (64% ± 2% vs 81% ± 2%, P < .0001) and overall survival (74% ± 2% vs 89% ± 1%, P < .0001). Independent favorable prognostic factors include age <6 years (hazard ratio [HR] = 0.58, P = .002), white blood cell (WBC) count <10 × 10(9)/L (HR = 0.60, P = .005), and ETV6-RUNX1 (HR = 0.14, P = .006) for EFS and age (HR = 0.48, P < .001), ETV6-RUNX1 (HR = 0.1, P = .016) and high hyperdiploidy (HeH) (HR = 0.29, P = .04) for relapse-free survival. TRM was the major cause of death in ETV6-RUNX1 and HeH DS-ALLs. Thus, while relapse is the main contributor to poorer survival in DS-ALL, infection-associated TRM was increased in all protocol elements, unrelated to treatment phase or regimen. Future strategies to improve outcome in DS-ALL should include improved supportive care throughout therapy and reduction of therapy in newly identified good-prognosis subgroups.
Liew E, Thyagu S, Atenafu EG, et al. Quality of life following completion of treatment for adult acute lymphoblastic leukemia with a pediatric-based protocol. Leuk Res. 2013; 37(12):1632-5 [PubMed] Related Publications
Using multiple validated self-report instruments, we evaluated the health-related quality of life (HRQoL) of 29 adult ALL patients a median of 28 months after completing a pediatric-based treatment regimen. Global health was similar to normative data, but leukemia survivors had lower cognitive and social function, and reported more financial difficulty. Fatigue and pain affected 83% and 53% of patients, respectively, and both showed significant inverse correlation with overall health and all functional scales. Vincristine-related peripheral neuropathy was reported by 43%. Although therapy-related symptoms were persistent, long-term ALL survivors have a global HRQoL similar to the general population.
Mao J, Zhang L, Shen H, et al. Creatinine clearance rate and serum creatinine concentration are related to delayed methotrexate elimination in children with lymphoblastic malignancies. Neoplasma. 2014; 61(1):77-82 [PubMed] Related Publications
Methotrexate (MTX) is an effective treatment for childhood acute lymphoblastic leukemia (ALL) or Non-Hodgkin lymphoma (NHL); however, toxicity can arise with high doses MTX (HDMTX), especially in patients with delayed MTX elimination. Routine monitoring of plasma MTX concentrations is clinically important, but unfortunately is not always feasible. The aim of this study was to examine the relationship between MTX elimination and renal function to identify parameters that may be useful for predicting delayed MTX elimination in Chinese children with ALL and NHL. A total of 105 children with ALL and NHL were included in the study. Each patient received HDMTX (3 or 5 g/m2) over 24 hours. Plasma MTX concentrations were measured at 24, 48, and 96 hours. Delayed elimination was indicated by plasma MTX concentrations ≥1.0 at 48 hours or ≥0.1 μmol/L at 96 hours. Creatinine clearance rate (CCr) and serum Cr concentrations were measured at 0, 24, and 48 hours. There were 39 patients (37.1%) with delayed MTX elimination. For patients with delayed MTX elimination, the 24 hour plasma MTX concentration was negatively correlated with the 24 hour CCr (P=0.019). The 48 hour plasma MTX concentration was positively correlated with 24 and 48 hour serum Cr concentrations (P=0.001 and P<0.001, respectively), and negatively correlated with the 24 and 48 CCr (both P<0.001). Both MTX concentrations and elimination time decreased with increasing CCr (P<0.05 and P<0.001, respectively). Receiver operating characteristic curves revealed that the best predictors of delayed MTX elimination were 24 hour CCr 36 mmol/L (sensitivity: 64.7%; specificity: 77.4%) (both P < 0.001). CCr and serum Cr concentration may be useful for monitoring plasma MTX concentrations in children receiving HDMTX for ALL and NHL and for predicting delayed MTX elimination.
Krull KR, Brinkman TM, Li C, et al. Neurocognitive outcomes decades after treatment for childhood acute lymphoblastic leukemia: a report from the St Jude lifetime cohort study. J Clin Oncol. 2013; 31(35):4407-15 [PubMed] Article available free on PMC after 10/12/2014 Related Publications
PURPOSE: To determine rates, patterns, and predictors of neurocognitive impairment in adults decades after treatment for childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Survivors of childhood ALL treated at St Jude Children's Research Hospital who were still alive at 10 or more years after diagnosis and were age ≥ 18 years were recruited for neurocognitive testing. In all, 1,014 survivors were eligible, 738 (72.8%) agreed to participate, and 567 (76.8%) of these were evaluated. Mean age was 33 years; mean time since diagnosis was 26 years. Medical record abstraction was performed for data on doses of cranial radiation therapy (CRT) and cumulative chemotherapy. Multivariable modeling was conducted and glmulti package was used to select the best model with minimum Akaike information criterion. RESULTS: Impairment rates across neurocognitive domains ranged from 28.6% to 58.9%, and those treated with chemotherapy only demonstrated increased impairment in all domains (all P values < .006). In survivors who received no CRT, dexamethasone was associated with impaired attention (relative risk [RR], 2.12; 95% CI, 1.11 to 4.03) and executive function (RR, 2.42; 95% CI, 1.20 to 4.91). The impact of CRT was dependent on young age at diagnosis for intelligence, academic, and memory functions. Risk for executive function problems increased with survival time in a CRT dose-dependent fashion. In all survivors, self-reported behavior problems increased by 5% (RR, 1.05; 95% CI, 1.01 to 1.09) with each year from diagnosis. Impairment was associated with reduced educational attainment and unemployment. CONCLUSION: This study demonstrates persistent and significant neurocognitive impairment in adult survivors of childhood ALL and warrants ongoing monitoring of brain health to facilitate successful adult development and to detect early onset of decline as survivors mature.
Xu WQ, Zhang LY, Chen XY, et al. Serum creatinine and creatinine clearance for predicting plasma methotrexate concentrations after high-dose methotrexate chemotherapy for the treatment for childhood lymphoblastic malignancies. Cancer Chemother Pharmacol. 2014; 73(1):79-86 [PubMed] Related Publications
PURPOSE: Monitoring of plasma methotrexate (MTX) concentrations allows for therapeutic adjustments in treating childhood acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) with high-dose MTX (HDMTX). We tested the hypothesis that assessment of creatinine clearance (CrCl) and/or serum Cr may be a suitable means of monitoring plasma MTX concentrations. METHODS: All children in the study had ALL or NHL, were in complete remission, and received HDMTX (3 or 5 g/m(2))+leucovorin. Plasma MTX concentrations were measured at 24, 48, and 96 h. CrCl was determined at 24 and 48 h. Correlations between 24- and 48-h plasma MTX concentrations and CrCl and serum Cr concentrations were determined. CrCl and serum Cr concentrations were compared over time between children who had delayed and non-delayed MTX elimination. RESULTS: A total of 105 children were included. There were significant negative correlations between CrCl at 24 and 48 h and plasma MTX concentrations at 24 (both p < 0.001) and 48 h (both p < 0.001). There were significant positive correlations between serum Cr concentrations at both 24 and 48 h and plasma MTX concentrations at 24 (both p < 0.001) and 48 h (both p < 0.001). There were 88 (30.2 %) instances of elimination delay. Children with elimination delay had significantly lower CrCl and higher Cr concentrations at 24 and 48 h compared with children without elimination delay (all p < 0.05). CONCLUSION: Our findings suggest that, with further refinement, assessment of renal function may be a useful means of monitoring plasma MTX concentrations during HDMTX for ALL and NHL.
Badaloni C, Ranucci A, Cesaroni G, et al. Air pollution and childhood leukaemia: a nationwide case-control study in Italy. Occup Environ Med. 2013; 70(12):876-83 [PubMed] Related Publications
OBJECTIVES: Leukaemia is the most common cancer in children, but its aetiology is still poorly understood. We tested the hypothesis that traffic-related air pollution is associated with paediatric leukaemia because of chronic exposure to several potential carcinogens. METHODS: The Italian SETIL study (Study on the aetiology of lymphohematopoietic malignancies in children) was conducted in 14 Italian regions. All incident cases of leukaemia in children aged ≤10 years from these regions (period 1998-2001) were eligible for enrolment. Two controls per case, matched on birth date, gender and region of residence were randomly selected from the local population registries. Exposure assessment at birth residence included traffic indicators (distance to main roads and length of main roads within 100 m) and estimates of pollutants concentrations (particulate matter -PM2.5 and PM10- and gases -NO2 and O3-) from national dispersion model and land use regression models. The association between the exposure variables and leukaemia was assessed by logistic regression analyses. RESULTS: Participation rates were 91.4% among cases and 69.2% in controls; 620 cases (544 acute lymphocytic and 76 acute non-lymphocytic leukaemia) and 957 controls were included. Overall, when considering the residence at birth, 35.6% of cases and 42.4% of controls lived along busy roads, and the mean annual PM10 levels were 33.3 (SD=6.3) and 33.4 µg/m(3) (SD=6.5), respectively. No association was found, and all ORs, independent of the method of assessment and the exposure windows, were close to the null value. CONCLUSIONS: Using various exposure assessment strategies, air pollution appears not to affect the incidence of childhood leukaemia.
Perez-Andreu V, Roberts KG, Harvey RC, et al. Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse. Nat Genet. 2013; 45(12):1494-8 [PubMed] Related Publications
Recent genomic profiling of childhood acute lymphoblastic leukemia (ALL) identified a high-risk subtype with an expression signature resembling that of Philadelphia chromosome-positive ALL and poor prognosis (Ph-like ALL). However, the role of inherited genetic variation in Ph-like ALL pathogenesis remains unknown. In a genome-wide association study (GWAS) of 511 ALL cases and 6,661 non-ALL controls, we identified a susceptibility locus for Ph-like ALL (GATA3, rs3824662; P = 2.17 × 10(-14), odds ratio (OR) = 3.85 for Ph-like ALL versus non-ALL; P = 1.05 × 10(-8), OR = 3.25 for Ph-like ALL versus non-Ph-like ALL), with independent validation. The rs3824662 risk allele was associated with somatic lesions underlying Ph-like ALL (CRLF2 rearrangement, JAK gene mutation and IKZF1 deletion) and with variation in GATA3 expression. Finally, genotype at the GATA3 SNP was also associated with early treatment response and risk of ALL relapse. Our results provide insights into interactions between inherited and somatic variants and their role in ALL pathogenesis and prognosis.
Hyakuna N, Shimomura Y, Watanabe A, et al. Assessment of corticosteroid-induced osteonecrosis in children undergoing chemotherapy for acute lymphoblastic leukemia: a report from the Japanese Childhood Cancer and Leukemia Study Group. J Pediatr Hematol Oncol. 2014; 36(1):22-9 [PubMed] Article available free on PMC after 10/12/2014 Related Publications
Steroid-induced osteonecrosis (ON) is a challenging complication encountered during modern chemotherapy for childhood acute lymphoblastic leukemia (ALL). We retrospectively assessed the incidence of ON and its risk factors in a total of 1095 patients enrolled in 3 consecutive Japanese Children's Cancer and Leukemia Study Group ALL studies (ALL941 [1994 to 2000], n=464; ALL2000 [2000 to 2004], n=305; and ALL2004 [2004 to 2010], n=326). ON was diagnosed in 16 patients, of whom 15 were symptomatic. The cumulative incidence of ON was 0.76% in ALL941, 0.35% in ALL2000, and 3.6% in ALL2004. The incidence of ON in ALL941/2000, in which only prednisolone was administered as a steroid, was significantly lower than that in ALL2004, in which dexamethasone was used as a partial substitute for prednisolone (P<0.01). In ALL2004, sex and age were significantly correlated with the incidence of ON (1.3% in boys vs. 6.7% in girls, P=0.0132; 0.42% for age <10 y vs. 15.6% for age ≥10 y, P<0.0001), suggesting that girls aged 10 years and above are at a greater risk of ON onset. These results indicate that the risk of ON should be considered when administering dexamethasone as part of ALL protocol treatment in girls aged 10 years and above.
Shukla N, Kobos R, Renaud T, et al. Phase II trial of clofarabine with topotecan, vinorelbine, and thiotepa in pediatric patients with relapsed or refractory acute leukemia. Pediatr Blood Cancer. 2014; 61(3):431-5 [PubMed] Related Publications
BACKGROUND: Outcomes for children with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) are dismal. In an effort to improve outcomes, we performed a phase I/II study of a novel clofarabine based combination regimen called TVTC. Herein, we report the response rates of patients in the phase II portion of the study. PROCEDURE: Seventeen patients with R/R ALL, AML, or biphenotypic leukemia were enrolled. Sixteen patients were evaluable for response. Patients were treated at the maximum tolerated dose (MTD) from the phase I portion of the study (clofarabine 40 mg/m(2) /day IV × 5 days, topotecan 1 mg/m(2) /day IV continuous infusion × 5 days, vinorelbine 20 mg/m(2) /week IV × 3 weeks, thiotepa 15 mg/m(2)/day IV × 1 day). The primary endpoint was overall response rate (ORR), defined as CR or CR without platelet recovery (CRp). RESULTS: The ORR was 69% (10 CR, 1 CRp). Among the 11 responders, 9 (82%) proceeded to hematopoietic stem cell transplantation. The most common grade 3+ non-hematologic toxicities were febrile neutropenia (82%) and transient transaminase elevation (47%). CONCLUSIONS: TVTC demonstrates significant activity in patients with R/R acute leukemia. The activity in R/R AML patients was very encouraging, with 8 of 12 (67%) patients achieving a CR/CRp. Patients with high risk de novo AML may benefit from incorporation of TVTC therapy into frontline treatment regimens. This regimen warrants further exploration in a larger cohort of patients with R/R leukemia.
Leone M, Viret P, Bui HT, et al. Assessment of gross motor skills and phenotype profile in children 9-11 years of age in survivors of acute lymphoblastic leukemia. Pediatr Blood Cancer. 2014; 61(1):46-52 [PubMed] Related Publications
BACKGROUND: The purpose of this study was to evaluate the usefulness of a new gross motor skill test battery in acute lymphoblastic leukemia (ALL) children who have been off therapy for at least 1 year and to assess its discriminatory power (discriminant analysis) from healthy children. PROCEDURE: Twenty children (10 males and 10 females) 9-11 years of age (median age = 10.6 years) were assessed by the UQAC-UQAM test battery and then compared to recent provincial norms. This pilot study was also an opportunity to validate this test battery as a reliable tool for clinical or research purposes in the area of chronic or disabling diseases in children. Eleven motor skill variables grouped into five factors have been measured (speed, agility, balance, coordination, and reaction time). RESULTS: Scores from 10 of the 11 motor skill tests showed significant differences when compared to the control group (P ≤ 0.05). Nearly 50% of patients obtained an average score below the 15th percentile. Furthermore, stepwise discriminant analysis allowed classifying successfully 88.4% of children in the correct group (ALL or Control). The normal development of GMS among children affected by ALL appears to have been compromised. The UQAC-UQAM test battery seems to be sensitive enough to quantify with precision the extent of the motor impairment in these children. CONCLUSION: The UQAC-UQAM test battery appears to be a useful tool to evaluate the extent to which ALL survivors are affected. Early motor intervention should be considered for those patients even during the treatment periods.
Millot F, Claviez A, Leverger G, et al. Imatinib cessation in children and adolescents with chronic myeloid leukemia in chronic phase. Pediatr Blood Cancer. 2014; 61(2):355-7 [PubMed] Related Publications
Imatinib can be safely discontinued in adults with chronic myeloid leukemia (CML) where there is a prolonged complete molecular response (CMR). No data are available in the pediatric population. Six children with CML discontinued imatinib by themselves. Only three of them were in CMR but for <2 years. A significant increase in transcript level was observed in all six patients after cessation of imatinib and five patients lost the major molecular response (MMR). Four patients regained the MMR within 3 months. Cessation of imatinib in children is not recommended outside a trial, particularly in patients without prolonged CMR.
Canner J, Alonzo TA, Franklin J, et al. Differences in outcomes of newly diagnosed acute myeloid leukemia for adolescent/young adult and younger patients: a report from the Children's Oncology Group. Cancer. 2013; 119(23):4162-9 [PubMed] Related Publications
BACKGROUND: Studies comparing survival of adolescent and young adult (AYA) patients to that of younger patients with newly diagnosed acute myeloid leukemia (AML) have yielded conflicting results. In order to more accurately characterize relative survival and other outcomes of AYA patients, a cross-study analysis was conducted using data from recent trials conducted by the Children's Cancer Group (CCG) and Children's Oncology Group (COG). METHODS: Data were combined from the CCG-2891, CCG-2941, CCG-2961, and AAML03P1 trials. The data set included 1840 patients, comprising 238 AYA and 1602 younger patients. RESULTS: Overall survival was not significantly different in the 2 groups (AYA, 49% ± 7% versus younger, 54% ± 3% (± 2 standard errors), P = .058). Relapse was lower in AYA patients (30% ± 7% versus 41% ± 3%, P = .002), but treatment-related mortality (TRM) was higher (25% ± 6% versus 12% ± 2%, P < .001). After adjustment for other factors, older age remained strongly associated with TRM (hazard ratio = 2.30, 95% CI = 1.59-3.33, P < .001). Infection accounted for the excess TRM in AYA patients. CONCLUSIONS: Survival in AYA and younger patients with newly diagnosed AML is similar; however, older patients are at higher risk for TRM. More effective strategies for preventing mortality from infection in AYA patients are needed.
Jaffe JD, Wang Y, Chan HM, et al. Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia. Nat Genet. 2013; 45(11):1386-91 [PubMed] Related Publications
Epigenetic dysregulation is an emerging hallmark of cancers. We developed a high-information-content mass spectrometry approach to profile global histone modifications in human cancers. When applied to 115 lines from the Cancer Cell Line Encyclopedia, this approach identified distinct molecular chromatin signatures. One signature was characterized by increased histone 3 lysine 36 (H3K36) dimethylation, exhibited by several lines harboring translocations in NSD2, which encodes a methyltransferase. A previously unknown NSD2 p.Glu1099Lys (p.E1099K) variant was identified in nontranslocated acute lymphoblastic leukemia (ALL) cell lines sharing this signature. Ectopic expression of the variant induced a chromatin signature characteristic of NSD2 hyperactivation and promoted transformation. NSD2 knockdown selectively inhibited the proliferation of NSD2-mutant lines and impaired the in vivo growth of an NSD2-mutant ALL xenograft. Sequencing analysis of >1,000 pediatric cancer genomes identified the NSD2 p.E1099K alteration in 14% of t(12;21) ETV6-RUNX1-containing ALLs. These findings identify NSD2 as a potential therapeutic target for pediatric ALL and provide a general framework for the functional annotation of cancer epigenomes.
Jaing TH, Yang CP, Hung IJ, et al. Phyllodes tumor in survivors of childhood osteosarcoma: a single institution's experience. J Pediatr Hematol Oncol. 2014; 36(1):e36-8 [PubMed] Related Publications
We evaluate the incidence of second neoplasms in 86 patients with osteosarcoma (OS) of the extremities treated with different protocols of adjuvant chemotherapy. Three patients developed phyllodes tumors as the second neoplasm. One of these patients simultaneously developed a third cancer with therapy-related acute myeloid leukemia. The sites of primary OS were the tibia (2) and humerus (1). None had received prior radiotherapy before excision of phyllodes tumor. All the patients were female with a median age of 21.7 years at the time of presentation. As yet, that precise causation is unclear, but it can increase our understanding of carcinogenic processes, in general.
Cheng J, Su H, Zhu R, et al. Maternal coffee consumption during pregnancy and risk of childhood acute leukemia: a metaanalysis. Am J Obstet Gynecol. 2014; 210(2):151.e1-151.e10 [PubMed] Related Publications
OBJECTIVE: This study was undertaken to explore the association between maternal coffee consumption during pregnancy and childhood acute leukemia (AL). STUDY DESIGN: The PubMed database was used to search studies up to May 5, 2013, and the lists of references of retrieved articles were also screened to identify additional relevant studies. Studies were included if they reported the odds ratio and corresponding 95% confidence interval (CI) of childhood AL, including childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), with respect to maternal coffee consumption during pregnancy. RESULTS: Compared with non/lowest drinkers, the combined odds ratio regarding the relationship of maternal coffee consumption during pregnancy and childhood AL was 1.22 (95% CI, 1.04-1.43) for ever drinkers, 1.16 (95% CI, 1.00-1.34) for low to moderate-level drinkers, and 1.72 (95% CI, 1.37-2.16) for high-level drinkers. When analysis was conducted by subtypes of childhood AL, maternal coffee consumption (high-level drinkers vs non/lowest drinkers) was statistically significantly associated with childhood ALL (1.65; 95% CI, 1.28-2.12) and childhood AML (1.58; 95% CI, 1.20-2.08). We observed the linear dose-response relationship of coffee consumption and childhood AL (P for nonlinearity = .68), including childhood ALL and childhood AML; with increased coffee consumption, the risk of childhood AL increased. CONCLUSION: The findings of the metaanalysis suggest that maternal coffee consumption during pregnancy may increase the risk of childhood AL. Because of limited studies, further prospective studies are urgently needed to explore the adverse effect of coffee consumption on childhood AL.