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).
Mousa S, Mostafa S, Shaheen I, Elnoshokaty E Detection of trisomy 4 and 10 in Egyptian pediatric patients with acute lymphoblastic leukemia. Clin Lab. 2014; 60(4):609-14 [PubMed] Related Publications
BACKGROUND: Improvement in cure rates for children with acute lymphoblastic leukemia (ALL) has focused attention on better methods of identifying patients with increased or decreased risk of treatment failure. Chromosome aberrations have a major role in pediatric ALL risk assessment. The aim of this work is to detect the frequency of trisomy 4 and 10 in Egyptian pediatric ALL patients and to analyze their possible prognostic significance. METHODS: Forty newly diagnosed pediatric ALL patients were subjected to bone marrow aspirate morphological examination and immunophenotyping. Detection of copy number of chromosome 4 and 10 was done using Fluorescence In Situ Hybridization (FISH) technique using whole chromosome painting probes. RESULTS: Combined trisomy 4 and 10 was detected in 7 cases (17.5%), all of them were of B-ALL type. Single trisomy 4 or 10 was not detected in any case. Trisomy positive patients had a statistically significant lower total leucocytic count (p = 0.041), higher platelet count (p = 0.018), and lower blast percentage in peripheral blood (p = 0.016) at diagnosis. CONCLUSIONS: Combined trisomy 4 and 10 identifies a group of ALL patients that have good prognostic indicators. Screening of Egyptian pediatric ALL patients for trisomy 4 and 10 may help in "patients' stratification" aiming to develop a risk-adapted therapy in order to minimize therapy related morbidities particularly in children.
Meulepas JM, Ronckers CM, Smets AM, et al. Leukemia and brain tumors among children after radiation exposure from CT scans: design and methodological opportunities of the Dutch Pediatric CT Study. Eur J Epidemiol. 2014; 29(4):293-301 [PubMed] Related Publications
Computed tomography (CT) scans are indispensable in modern medicine; however, the spectacular rise in global use coupled with relatively high doses of ionizing radiation per examination have raised radiation protection concerns. Children are of particular concern because they are more sensitive to radiation-induced cancer compared with adults and have a long lifespan to express harmful effects which may offset clinical benefits of performing a scan. This paper describes the design and methodology of a nationwide study, the Dutch Pediatric CT Study, regarding risk of leukemia and brain tumors in children after radiation exposure from CT scans. It is a retrospective record-linkage cohort study with an expected number of 100,000 children who received at least one electronically archived CT scan covering the calendar period since the introduction of digital archiving until 2012. Information on all archived CT scans of these children will be obtained, including date of examination, scanned body part and radiologist's report, as well as the machine settings required for organ dose estimation. We will obtain cancer incidence by record linkage with external databases. In this article, we describe several approaches to the collection of data on archived CT scans, the estimation of radiation doses and the assessment of confounding. The proposed approaches provide useful strategies for data collection and confounder assessment for general retrospective record-linkage studies, particular those using hospital databases on radiological procedures for the assessment of exposure to ionizing or non-ionizing radiation.
Abulaban AA, Algahtani HA, Alharthi A A child with leukemia and behavioral changes. Neurosciences (Riyadh). 2014; 19(2):144-5 [PubMed] Related Publications
A 12-year-old Saudi girl, known case of T-cell leukemia with CNS relapse. She was diagnosed 2 years ago. Multiple cycles of chemotherapy had been used (Fludarabine, Cytarabine, Methotrexate, Cyclosporine, and Mercaptopurine). She was admitted electively for cord blood transplantation. Afterward, she developed visual, and behavioral change followed by seizure.
Hiniker SM, Agarwal R, Modlin LA, et al. Survival and neurocognitive outcomes after cranial or craniospinal irradiation plus total-body irradiation before stem cell transplantation in pediatric leukemia patients with central nervous system involvement. Int J Radiat Oncol Biol Phys. 2014; 89(1):67-74 [PubMed] Related Publications
PURPOSE: To evaluate survival and neurocognitive outcomes in pediatric acute lymphoblastic leukemia (ALL) patients with central nervous system (CNS) involvement treated according to an institutional protocol with stem cell transplantation (SCT) and a component of craniospinal irradiation (CSI) in addition to total-body irradiation (TBI) as preparative regimen. METHODS AND MATERIALS: Forty-one pediatric ALL patients underwent SCT with TBI and received additional cranial irradiation or CSI because of CNS leukemic involvement. Prospective neurocognitive testing was performed before and after SCT in a subset of patients. Cox regression models were used to determine associations of patient and disease characteristics and treatment methods with outcomes. RESULTS: All patients received a cranial radiation boost; median total cranial dose was 24 Gy. Eighteen patients (44%) received a spinal boost; median total spinal dose for these patients was 18 Gy. Five-year disease-free survival (DFS) for all patients was 67%. Those receiving CSI had a trend toward superior DFS compared with those receiving a cranial boost alone (hazard ratio 3.23, P=.14). Patients with isolated CNS disease before SCT had a trend toward superior DFS (hazard ratio 3.64, P=.11, 5-year DFS 74%) compared with those with combined CNS and bone marrow disease (5-year DFS 59%). Neurocognitive testing revealed a mean post-SCT overall intelligence quotient of 103.7 at 4.4 years. Relative deficiencies in processing speed and/or working memory were noted in 6 of 16 tested patients (38%). Pre- and post-SCT neurocognitive testing revealed no significant change in intelligence quotient (mean increase +4.7 points). At a mean of 12.5 years after transplant, 11 of 13 long-term survivors (85%) had completed at least some coursework at a 2- or 4-year college. CONCLUSION: The addition of CSI to TBI before SCT in pediatric ALL with CNS involvement is effective and well-tolerated. Craniospinal irradiation plus TBI is worthy of further protocol investigation in children with CNS leukemia.
Mei Y, Gao C, Wang K, et al. Effect of microRNA-210 on prognosis and response to chemotherapeutic drugs in pediatric acute lymphoblastic leukemia. Cancer Sci. 2014; 105(4):463-72 [PubMed] Related Publications
Many studies have demonstrated that microRNA-210 (miR-210) expression is intensively upregulated in hypoxic states and differentially regulated in most types of cancer cells. However, the clinical significance of miR-210 and its effects on the response of leukemic cells to chemotherapeutic drugs in childhood acute lymphoblastic leukemia (ALL) remain unknown. In the current study, using real-time qRT-PCR to detect miR-210 expression in bone marrow samples from 114 children at initial diagnosis of ALL, we investigated the prognostic significance of miR-210 and determined its associations with common clinical characteristics and treatment outcome. We further examined its effect on the response to chemotherapeutic drugs in the Reh and RS4;11 cell lines. Results showed that miR-210 expression was significantly lower in patients suffering from relapse and induction failure than in other patients (P < 0.001). Using the receiver operating characteristic curve, 3.8243 was selected as the cut-off value of miR-210 expression in our test cohort (38 cases). A significantly poorer treatment outcome (P < 0.05) was found in the low-expression group and verified in the validation cohort (76 cases, P < 0.05). Patients with low expression of miR-210 and positive minimal residual disease at the end of induction had a much higher rate of relapse or induction failure (P = 0.001). Increasing/decreasing miR-210 expression using agomir/antagomir could enhance or reduce the response of Reh cells and RS4;11 cells to daunorubicin/dexamethasone/L-asparaginase and daunorubicin/dexamethasone/vincristine, respectively. In conclusion, miR-210 may be a good prognostic factor and a useful predictor of drug sensitivity, and is a potential therapeutic target for pediatric ALL.
Orgel E, Sposto R, Malvar J, et al. Impact on survival and toxicity by duration of weight extremes during treatment for pediatric acute lymphoblastic leukemia: A report from the Children's Oncology Group. J Clin Oncol. 2014; 32(13):1331-7 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
PURPOSE: Previous studies regarding the influence of weight on event-free survival (EFS) and treatment-related toxicity (TRT) in childhood acute lymphoblastic leukemia (ALL) considered only weight at diagnosis. Inasmuch as weight varies substantially over treatment, we hypothesized its impact on EFS is instead determined by cumulative time spent at an extreme weight during therapy and on TRT by weight at the time of toxicity. PATIENTS AND METHODS: In a cohort of 2,008 children treated for high-risk ALL in Children's Oncology Group study CCG-1961, we determined the effect on EFS of cumulative time receiving therapy at an extreme weight (either obese or underweight) between end of induction and start of maintenance therapy. We also evaluated the association between weight category and incidence and patterns of TRT during 13,946 treatment courses. RESULTS: Being obese or underweight at diagnosis and for ≥ 50% of the time between end of induction and start of maintenance therapy resulted in inferior EFS (hazard ratios, 1.43 and 2.30, respectively; global P < .001). Normalization of weight during that period resulted in mitigation of this risk comparable to never being obese or underweight. Obese or underweight status at start of each treatment course was significantly associated with specific patterns of TRT. CONCLUSION: Influence of weight extremes on EFS and TRT is not set at diagnosis as previously reported but is moderated by subsequent weight status during intensive postinduction treatment phases. These observations suggest that weight is a potentially addressable risk factor to improve EFS and morbidity in pediatric ALL.
Dorantes-Acosta E, Medina-Sanson A, Jaimes-García Y, López-Martínez B Clinical features and treatment outcomes of pediatric acute promyelocytic leukemia in a Mexican pediatric hospital. Rev Invest Clin. 2013 Sep-Oct; 65(5):392-8 [PubMed] Related Publications
INTRODUCTION: Acute promyelocytic leukemia (APL) is a distinct type of acute myeloid leukemia (AML) characterized by chromosomal translocations involving the retinoid acid receptor α (RARA) gene on chromosome 17. APL is a relatively rare blood disease that is highly curable with current treatment strategies; however, patient outcomes are heterogeneous in countries with limited resources. Promyelocytic leukemia accounts for 20-25% of all AML cases in Latin American countries. MATERIAL AND METHODS: We conducted a study from July 2007 to July 2012 and applied the IC-APL2006 protocol. This case study reports the results from eleven patients with AML M3 (five males and six females). In all cases, the diagnoses were made by aspirating bone marrow and evaluating the t(15:17) or t(11:17) transcript. In eight cases, the molecular biology-based diagnostics for the PLM-RARa transcript were positive, and they were negative in two cases. One patient was positive for the PLZF-RARa transcript. RESULTS: The mean WBC at the time of diagnosis was 10.1 x 10(9)/L, and the mean platelet count was 17.1 x 10(9)/L. The mean percentage of abnormal promyelocytes in the bone marrow aspirates was 68%. Of the eleven patients, four presented with disseminated intravascular coagulation. All of the patients began treatment with transretinoic acid (ATRA) (45 mg/m(2)/day), which led to 4 cases of ATRA syndrome. There were 2 relapses, and the patient died in one case. The remaining ten patients were alive after the median follow-up period of 33.6 months (range from 11 to 60 months). CONCLUSION: The authors report on a series of cases involving pediatric patients with AML M3 seen at a single institution; the patients were stratified and treated with a standard protocol to obtain satisfactory results. Although the number of patients is limited, the health outcomes are relevant. To our knowledge, this is the first series of pediatric APL patients in Mexico who were treated with the IC-APL2006 protocol.
Shaikh F, Voicu L, Tole S, et al. The risk of traumatic lumbar punctures in children with acute lymphoblastic leukaemia. Eur J Cancer. 2014; 50(8):1482-9 [PubMed] Related Publications
BACKGROUND: Traumatic lumbar punctures with blasts (TLP+) in children with acute lymphoblastic leukaemia (ALL) obscure central nervous system status and are associated with a poorer event-free survival (EFS). METHODS: We conducted a retrospective cohort study of all lumbar punctures (LPs) for children with ALL diagnosed at our institution from 2005 to 2009. We utilised random-effects and fixed-effects repeated-measures logistic regression analyses to identify risk factors for TLPs. Fixed-effects models use each patient as his or her own control. We used survival analysis to describe outcomes after a TLP+. RESULTS: 264 children underwent 5267 evaluable lumbar punctures (LPs), of which 944 (17.9%) were traumatic. In the multivariable random-effects model, variables significantly associated with TLPs were age <1year (odds ratio (OR) 3.46, 95% confidence interval (CI) 2.06-5.81) or age ⩾10years (OR 2.00, CI 1.66-2.40); body mass index percentile ⩾95 (OR 1.44, CI 1.19-1.75); platelet count <100×10(3)/μL (OR 1.49, CI 1.08-20.7); fewer days since previous LP (OR 5.13, CI 2.34-11.25 for ⩾16days versus 0-3days); and a preceding TLP (OR 1.43, CI 1.19-1.73). In the fixed-effects model, image-guidance reduced the odds of TLP (OR 0.55, CI 0.32-0.95). The 5-year EFS (±SE) for children with TLP+ (77±8%) was significantly lower than for children with CNS1 status (93±2%; p=0.002). CONCLUSIONS: The frequency of TLP remains high. Consistent with previous studies, a TLP+ at diagnosis was associated with a poorer EFS. These risk factors can allow identifying interventions to reduce TLPs and directing interventions to those at highest risk.
Sakamoto LH, Andrade RV, Felipe MS, et al. SMYD2 is highly expressed in pediatric acute lymphoblastic leukemia and constitutes a bad prognostic factor. Leuk Res. 2014; 38(4):496-502 [PubMed] Related Publications
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Although several clinical characteristics can be associated with worse prognosis, more robust biological markers still remains uncovered. SMYD2, a member of SMYD protein family, regulates the activity of several proteins through methylation. In this study, we performed quantitative real time PCR to compare the expression of SMYD2 in 83 pediatric ALL patients and non-neoplastic bone marrow samples (BMS). The study revealed that SMYD2 expression is altered in ALL BMS and its high expression was correlated with a bad prognosis. Moreover, we also revealed that SMYD2 expression level significantly decreases in patients that respond to chemotherapy treatment.
Morais EF, Lira JA, Macedo RA, et al. Oral manifestations resulting from chemotherapy in children with acute lymphoblastic leukemia. Braz J Otorhinolaryngol. 2014 Jan-Feb; 80(1):78-85 [PubMed] Related Publications
INTRODUCTION: Acute lymphocytic leukemia is a type of cancer most common in children and it is characterized by excessive and disordered immature leukocytes in the bone marrow. AIM: Identify most frequent oral manifestations in children with acute lymphocytic leukemia under chemotherapy treatment. METHODOLOGy: The research was conducted on the electronic database PubMed/Medline, Science Direct, Scielo and Scopus. It has been sought papers with full presentation, wrote in Portuguese, English and Spanish, published between January 1992 and April 2013. RESULTS: From studies primarily selected, only eight met the criteria of inclusion. All studies performed intraoral examinations to diagnose oral lesions. According to results, the most frequent lesions were mucositis, candidiasis, periodontitis and gingivitis. The oral health condition from acute lymphocytic leukemia carriers varied according oral hygiene of the patient. CONCLUSION: The results of studies identified such a great part of patients with ALL presented some lesion in oral cavity during or after chemotherapy treatment. The dentist surgeon needs to recognize oral manifestations and intervene in the oral health of patients with ALL, contributing and helping with treatment.
Shah A, Diggens N, Stiller C, et al. Recruitment of childhood leukaemia patients to clinical trials in Great Britain during 1980-2007: variation by birth weight, congenital malformation, socioeconomic status and ethnicity. Arch Dis Child. 2014; 99(5):407-12 [PubMed] Related Publications
OBJECTIVE: To assess recruitment of children to national clinical trials for acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) in Great Britain during 1980-2007 and describe variation by some factors that might influence trial entry. DESIGN AND SETTING: Records of leukaemia patients aged 0-14 years at diagnosis were identified in the National Registry of Childhood Tumours and linked to birth registrations, Children's Cancer and Leukaemia Group records, Hospital Episode Statistics and Medical Research Council clinical trial registers. Trial entry rates were compared between categories of birth weight, congenital malformation, socioeconomic status and ethnicity. RESULTS: 9147 ALL and 1466 AML patients were eligible for national clinical trials during 1980-2007. Overall recruitment rates were 81% and 60% respectively. For ALL, rates varied significantly with congenital malformation (Down syndrome 61%, other malformations 80%, none 82%; p<0.001) and ethnicity (South Asian 78%, other minority groups 80%, white 85%; p<0.001). For AML, rates varied with birth weight (< 2500 g 48%, 2500-4000 g 69%, >4000 g 67%; p=0.001) and congenital malformation (Down syndrome 28%, other malformations 56%, none 63%; p<0.001). CONCLUSIONS: Although recruitment rates to clinical trials for childhood leukaemia are high, future trials should monitor possible variation by birth weight, ethnicity and presence of congenital malformations.
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.
Pietras W, Chaber R, Pela H, et al. The recovery of immune system parameters in children following lymphoblastic leukemia therapy - preliminary report. Adv Clin Exp Med. 2014 Jan-Feb; 23(1):97-102 [PubMed] Related Publications
BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common pediatric neoplasm. Long-term survival is achieved in approximately 80% of patients. One of the more common complications of ALL treatment is immunosuppression. OBJECTIVES: The aim of the study is to assess the reconstruction rate of the most important immune system parameters in children after ALL treatment. MATERIAL AND METHODS: The study included 47 children (22 boys, 25 girls) diagnosed and treated for ALL in Department of Pediatric Hematology and Oncology at Wroclaw Medical University. The study used peripheral blood collected at the time treatment was completed and in the first, second, third and sixth months following treatment, then at yearly intervals up to 10 years after treatment. In order to determine the immune status of the tested samples the following parameters were assessed: white blood cell count, absolute lymphocyte count, the proportions of individual subpopulations of lymphocytes - T (CD3 +), Th (CD4 +), Ts (CD8 +), B (CD19 +), NK (CD16 + 56 +), the concentration of immunoglobulins A, G and M, interleukin 10 activity, as well as the expression of ICAM-1 adhesion molecules. RESULTS: At the end of anti-neoplastic therapy a reduction in both the absolute number leukocytes and various subpopulations of lymphocytes was observed. The lower limits of normal range were achieved about two years after the end of treatment. The concentrations of immunoglobulin IgA, IgG and IgM at the end of treatment were within low normal limits. Normal concentrations of immunoglobulin levels and stability were observed about two years after the end of treatment. There was a slow, steady increase in the production of interleukin-10 and the expression of ICAM-1 adhesion molecules. These results confirm previous observations that after ALL treatment children are in an immunocompromised state for up to 12 months, in terms of both humoral and cellular immunity. CONCLUSIONS: Knowing the average growth trends for the main immune system parameters after ALL treatment can be important in clinical practice for children in whom immune reconstruction proceeds slowly. Predicting the expected time required to restore immune function could be of help, for example in combating infections and planning vaccinations.
Honda Y, Tsuchida M, Zaike Y, et al. Clinical characteristics of 15 children with juvenile myelomonocytic leukaemia who developed blast crisis: MDS Committee of Japanese Society of Paediatric Haematology/Oncology. Br J Haematol. 2014; 165(5):682-7 [PubMed] Related Publications
Juvenile myelomonocytic leukaemia (JMML) is a rare haematopoietic stem cell disease of early childhood, which can progress to blast crisis in some children. A total of 153 children diagnosed with JMML were reported to the Myelodysplastic Syndrome Committee in Japan between 1989 and 2007; 15 of them (9·8%) had 20% or more blasts in the bone marrow (blast crisis) during the disease course. Blast crisis occurred during observation without therapy (n = 3) or with oral 6-mercaptopurine treatment (n = 9) and in relapse after haematopoietic stem cell transplantation (HSCT; n = 3). Six patients had a complex karyotype (5 including monosomy 7) and an additional three patients had isolated monosomy 7 at blast crisis. Seven patients received HSCT after blast crisis and four of them achieved remission. Eleven out of the 15 patients died; the cause of death was disease progression in 10 patients and transplant-related complication in one patient. In summary, patients with blast crisis have poor prognosis and can be cured only by HSCT. The emergence of monosomy 7 and complex karyotype may be characteristic of blast crisis in a substantial subset of children.
Gurney JG, Kaste SC, Liu W, et al. Bone mineral density among long-term survivors of childhood acute lymphoblastic leukemia: results from the St. Jude Lifetime Cohort Study. Pediatr Blood Cancer. 2014; 61(7):1270-6 [PubMed] Related Publications
BACKGROUND: The prevalence of low bone mineral density (BMD) in adult survivors of childhood acute lymphoblastic leukemia (ALL), and the degree of recovery or decline, are not well elucidated. PROCEDURE: Study subjects (age ≥ 18 years and ≥10 years post-diagnosis) participated in an institutional follow-up protocol and risk-based clinical evaluation based on Children's Oncology Group guidelines. Trabecular volumetric BMD was ascertained using quantitative computed tomography, reported as age- and sex-specific Z-scores. RESULTS: At median age 31 years, 5.7% of 845 subjects had a BMD Z-score of ≤-2 and 23.8% had a Z-score of -1 to -2. Cranial radiation dose of ≥24 Gy, but not cumulative methotrexate or prednisone equivalence doses, was associated with a twofold elevated risk of a BMD Z-score of ≤-1. The cranial radiation effect was stronger in females than in males. In a subset of 400 subjects, 67% of those who previously had a BMD Z-score of ≤-2 improved by one or more categories a median of 8.5 years later. CONCLUSIONS: Very low BMD was relatively uncommon in this sample of adult survivors of childhood ALL, and BMD Z-scores tended to improve from adolescence to young adulthood. High-dose cranial or craniospinal radiation exposure was the primary predictor of suboptimal BMD in our study. Given that cranial radiation treatment for childhood ALL is used far more sparingly now than in earlier treatment eras, concerns about persistently low BMD among most current childhood ALL patients may be unwarranted.
Erdmann F, Kaatsch P, Zeeb H, et al. Survival from childhood acute lymphoblastic leukaemia in West Germany: does socio-demographic background matter? Eur J Cancer. 2014; 50(7):1345-53 [PubMed] Related Publications
BACKGROUND: Sex, age, immunophenotype and white blood cell count at diagnosis are well accepted predictors of survival from acute lymphoblastic leukaemia (ALL) in children. Less is known about the relationship between socio-economic determinants and survival from paediatric ALL, studied here for the first time in German children. METHODS: ALL cases were diagnosed between 1992 and 1994 and their parents interviewed during a previous nationwide case-control study. Children were followed-up for 10 years after diagnosis by the German Childhood Cancer Registry. Cox proportional hazards models estimating hazard ratios (HRs) were calculated to assess the impact of selected socio-demographic characteristics on overall and event-free survival. RESULTS: Overall survival was 82.5%, with a higher proportion of girls than boys surviving (85% versus 81%). We found a non-linear relationship between age at diagnosis and survival, with poorer survival in infants and children aged >5 years. There was no association between socio-economic factors and survival or risk of relapse. For five levels of increasing family income, all HRs were close to one. No relationship was seen with parental educational level. CONCLUSION: Socio-economic determinants did not affect ALL survival in West German children, in contrast to studies from some other countries. Dissimilarities in social welfare systems, including access to health care, lifestyle and differences in treatment may contribute to these differences in findings. Our observation of no social inequalities in paediatric ALL survival is reassuring, but needs continued monitoring to assess the potential impact of evolvement of treatment options and changes in paediatric health service.
Avila ML, Macartney CA, Hitzler JK, et al. Assessment of the outcomes associated with periprocedural anticoagulation management in children with acute lymphoblastic leukemia. J Pediatr. 2014; 164(5):1201-7 [PubMed] Related Publications
OBJECTIVE: To report the outcomes of an institutional protocol for periprocedural anticoagulant (AC) management in children with acute lymphoblastic leukemia (ALL). STUDY DESIGN: Children being treated for ALL who received full-dose (therapeutic) anticoagulation before undergoing at least 1 lumbar puncture (LP) were included in this retrospective cohort study. The main outcome was the risk of traumatic LP; exploratory analysis included the risks of symptomatic spinal hematoma and progression/recurrence of the thrombotic event. Analyses were conducted using logistic regression analysis with a generalized estimating equation approach. RESULTS: Twenty-two children with ALL receiving an AC underwent a total of 396 LPs. Although traumatic LP was associated with full-dose AC therapy in univariable analysis, a multiple logistic regression model controlling for other risk factors for traumatic LP showed that AC therapy was not significantly associated with the risk of traumatic LP when the ACs were held as per the institutional protocol. No patient developed symptomatic spinal hematoma. Exploratory analysis revealed that AC dose, a likely marker of thrombus burden, was significantly associated with progression/recurrence of the thrombotic event in univariable analysis. CONCLUSION: In our cohort, recent AC therapy was not statistically associated with an increased risk of bleeding after LP when following a specific protocol for periprocedural AC management. The risk associated with the progression/recurrence of thromboembolic events requires further evaluation.
Knight S, McCarthy M, Anderson V, et al. Visuomotor function in children treated for acute lymphoblastic leukaemia with chemotherapy only. Dev Neuropsychol. 2014; 39(2):101-12 [PubMed] Related Publications
This study aimed to evaluate visuomotor function in children treated for acute lymphoblastic leukaemia (ALL). The performance of 64 children, 1-7 years post-chemotherapy for ALL, was compared to that of their healthy peers (n = 56) on visuomotor integration (VMI) and motor coordination (MC) tasks. Children posttreatment for ALL displayed significantly reduced VMI, but not MC, performances as compared to controls. Children treated on chemotherapy-only ALL regimes are at heightened risk for visuomotor integration deficits. Monitoring of visuomotor skills and implementation of appropriate interventions targeting higher level visuomotor integration skills should form an important component of any ALL long-term effects program.
Kriner P, Lopez K, Leung J, et al. Notes from the field: varicella-associated death of a vaccinated child with leukemia - California, 2012. MMWR Morb Mortal Wkly Rep. 2014; 63(7):161 [PubMed] Related Publications
Varicella, a contagious viral disease, is typically self-limited but can result in serious complications, especially among persons who are immunocompromised. On April 10, 2012, a girl aged 4 years with acute lymphoblastic leukemia (ALL) was exposed to a mildly ill cousin who developed a varicella rash 2 days later. The episode was reported to the child's oncologist after 13 days. The girl was prescribed 7 days of oral acyclovir for prophylaxis and concurrently began her scheduled chemotherapy, which included a 5-day course of dexamethasone (prednisone equivalent dose of 23 mg/day). Twenty-two days after her varicella exposure, the girl was taken to an emergency department for fever and abdominal pain. She was treated symptomatically; her caretakers were instructed to discontinue chemotherapy and to follow up with her oncologist. Two days later, the girl returned to the emergency department with a generalized rash. She was hospitalized and treated with intravenous acyclovir and antibiotics. However, she developed multiorgan failure and died on May 7. Varicella was confirmed by polymerase chain reaction testing, and no alternative diagnoses were found for her acute illness.
Bhojwani D, Sabin ND, Pei D, et al. Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol. 2014; 32(9):949-59 [PubMed] Article available free on PMC after 20/03/2015 Related Publications
PURPOSE: Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. PATIENTS AND METHODS: Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. RESULTS: Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity. CONCLUSION: MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.
Zhang FF, Kelly MJ, Saltzman E, et al. Obesity in pediatric ALL survivors: a meta-analysis. Pediatrics. 2014; 133(3):e704-15 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND AND OBJECTIVE: Previous studies of survivors of pediatric acute lymphoblastic leukemia (ALL) have drawn heterogeneous conclusions regarding the prevalence of obesity and risk factors for developing obesity in pediatric ALL survivors. We sought to determine the prevalence of obesity in pediatric ALL survivors and examine risk factors for obesity through a systematic review and meta-analysis. METHODS: A MEDLINE search was performed from its inception through 2013. Studies met the inclusion criteria if they (1) included at least 10 survivors of pediatric ALL; (2) assessed the prevalence or indicators of obesity; and (3) compared obesity among ALL survivors to a reference population or external control group. Extracted data included patient and treatment characteristics, study design, population used for comparison, and prevalence of obesity. RESULTS: Forty-seven studies met the inclusion criteria. Despite significant heterogeneity among the studies (I(2) = 96%), the mean BMI z score in 1742 pediatric ALL survivors was 0.83 (95% confidence interval: 0.60-1.06), which corresponds to the 80th BMI percentile, indicating a significantly higher BMI in pediatric ALL survivors than the reference population. Subgroup analyses found a high prevalence of obesity in ALL survivors regardless of survivors' receipt of cranial irradiation, gender, or age at diagnosis. CONCLUSIONS: Obesity is prevalent in pediatric ALL survivors and is independent of patient- and treatment-related characteristics. Clinicians need to screen for obesity and its associated health conditions early in survivorship.
Warris LT, van den Heuvel-Eibrink MM, den Hoed MA, et al. Does dexamethasone induce more neuropsychological side effects than prednisone in pediatric acute lymphoblastic leukemia? A systematic review. Pediatr Blood Cancer. 2014; 61(7):1313-8 [PubMed] Related Publications
Steroid-induced neuropsychological side effects impact quality of life in children with acute lymphoblastic leukemia. Dexamethasone induces more metabolic side effects than prednisone. To evaluate whether dexamethasone also leads to more neuropsychological side effects, we reviewed all available literature. Randomized controlled trials with neuropsychological function as the primary or secondary outcome did not show clinically meaningful differences between dexamethasone and prednisone on cognition, mood or behavior.
Oliveira JC, Pezuk JA, Brassesco MS, et al. PLK1 expression and BI 2536 effects in childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2014; 61(7):1227-31 [PubMed] Related Publications
BACKGROUND: Polo-like kinase 1 (PLK1) is a conserved kinase that mediates various mitotic events. Compelling data have repeatedly demonstrated its upregulation in different neoplasia, being frequently associated with poor prognosis. However, in childhood acute lymphoblastic leukemia (ALL), no studies have yet been conducted. PROCEDURE: PLK1 expression and association with biological features were evaluated in 65 consecutively diagnosed childhood ALL samples by quantitative real-time PCR. Moreover, the effects of a specific PLK1 inhibitor, BI 2536, was tested against a panel of nine ALL cell lines at nanomolar concentrations (10, 50, 100 nM). RESULTS: The mRNA expression of PLK1 showed great variability in pediatric ALL, but no difference was evidenced compared to normal bone marrow. Additionally, no association was found between PLK1 mRNA expression with any clinical or biological features. Alternatively, high mRNA expression of PLK1 was present in ALL cell lines. In vitro treatment with BI 2536 strongly diminished growth, while presenting significant reduction in colony formation capacity and increased apoptosis rates. Moreover, strong G2/M arrest was detected suggesting important impaired proliferation after treatment. CONCLUSIONS: PLK1 mRNA expression level is not associated with prognosis in childhood ALL; however, considering the great variability observed in the sample and the in vitro experiments presented herein, BI 2536 treatment might serve as a promising therapeutic to enhance the efficacy of conventional treatment modalities in some childhood ALL cases.
de Smith AJ, Walsh KM, Ladner MB, et al. The role of KIR genes and their cognate HLA class I ligands in childhood acute lymphoblastic leukemia. Blood. 2014; 123(16):2497-503 [PubMed] Article available free on PMC after 17/04/2015 Related Publications
Killer cell immunoglobulin-like receptors (KIRs), via interaction with their cognate HLA class I ligands, play a crucial role in the development and activity of natural killer cells. Following recent reports of KIR gene associations in childhood acute lymphoblastic leukemia (ALL), we present a more in-depth investigation of KIR genes and their cognate HLA ligands on childhood ALL risk. Genotyping of 16 KIR genes, along with HLA class I groups C1/C2 and Bw4 supertype ligands, was carried out in 212 childhood ALL cases and 231 healthy controls. Frequencies of KIR genes, KIR haplotypes, and combinations of KIR-HLA ligands were tested for disease association using logistic regression analyses. KIR A/A genotype frequency was significantly increased in cases (33.5%) compared with controls (24.2%) (odds ratio [OR] = 1.57; 95% confidence interval [CI], 1.04-2.39). Stratifying analysis by ethnicity, a significant difference in KIR genotype frequency was demonstrated in Hispanic cases (34.2%) compared with controls (21.9%) (OR = 1.86; 95% CI, 1.05-3.31). Homozygosity for the HLA-Bw4 allele was strongly associated with increased ALL risk exclusively in non-Hispanic white children (OR = 3.93; 95% CI, 1.44-12.64). Our findings suggest a role for KIR genes and their HLA ligands in childhood ALL etiology that may vary among ethnic groups.
Douer D, Aldoss I, Lunning MA, et al. Pharmacokinetics-based integration of multiple doses of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute lymphoblastic leukemia. J Clin Oncol. 2014; 32(9):905-11 [PubMed] Related Publications
PURPOSE: Asparaginase treatment is standard in all pediatric acute lymphoblastic leukemia (ALL) regimens, whereas in adults, it is either excluded or administered for a shorter duration. Several adult ALL protocols are adapting pediatric regimens, but the optimal implementation of asparaginase is not well studied, considering its potential higher toxicity. We studied a pegaspargase dosing strategy based on its pharmacokinetic characteristics in adults. PATIENTS AND METHODS: Between 2004 and 2009, 51 adults age 18 to 57 years with newly diagnosed ALL were treated with a regimen adapted from a pediatric trial that included six doses of intravenous pegaspargase at 2,000 IU/m(2) per dose. Intervals between doses were longer than 4 weeks and rationally synchronized with other chemotherapy drugs to prevent overlapping toxicities. Pegaspargase was administered with steroids to reduce hypersensitivity. Asparaginase-related toxicities were monitored after 173 pegaspargase doses. RESULTS: The most common grade 3/4 asparaginase-related toxicities were lengthy hyperbilirubinemia and transaminitis, occasionally resulting in subsequent treatment delays. All toxicities resolved spontaneously. Forty-five percent of patients were able to receive all six doses of pegaspargase, and 61% received ≥ three doses. In only 20% of patients, the drug was discontinued after pegaspargase-related serious toxicity. Ninety-six percent achieved complete remission, almost all within 4 weeks, and a low induction death rate was seen. Seven-year disease-free and overall survival were 58% and 51%, respectively. CONCLUSION: Our dose and schedule of pegaspargase, based on its pharmacokinetics, and our detailed toxicity profile could be applied for safer adaptation of pediatric ALL protocols in adults.
Bunch KJ, Keegan TJ, Swanson J, et al. Residential distance at birth from overhead high-voltage powerlines: childhood cancer risk in Britain 1962-2008. Br J Cancer. 2014; 110(5):1402-8 [PubMed] Article available free on PMC after 04/03/2015 Related Publications
BACKGROUND: We extend our previous study of childhood leukaemia and proximity to high-voltage powerlines by including more recent data and cases and controls from Scotland, by considering 132-kV powerlines as well as 275 and 400 kV and by looking at greater distances from the powerlines. METHODS: Case-control study using 53,515 children from the National Registry of Childhood Tumours 1962-2008, matched controls, and calculated distances of mother's address at child's birth to powerlines at 132, 275, and 400 kV in England, Wales and Scotland. RESULTS: Our previous finding of an excess risk for leukaemia at distances out to 600 m declines over time. Relative risk and 95% confidence interval for leukaemia, 0-199 m compared with>1000 m, all voltages: 1960s 4.50 (0.97-20.83), 2000s 0.71 (0.49-1.03), aggregate over whole period 1.12 (0.90-1.38). Increased risk, albeit less strong, may also be present for 132-kV lines. Increased risk does not extend beyond 600 m for lines of any voltage. CONCLUSIONS: A risk declining over time is unlikely to arise from any physical effect of the powerlines and is more likely to be the result of changing population characteristics among those living near powerlines.
Jeha S, Coustan-Smith E, Pei D, et al. Impact of tyrosine kinase inhibitors on minimal residual disease and outcome in childhood Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2014; 120(10):1514-9 [PubMed] Related Publications
BACKGROUND: Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) tyrosine kinase inhibitors (TKIs) improve the outcome of patients with childhood Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) when they are incorporated into postremission induction chemotherapy. To date, no data are available on the impact of TKIs on minimal residual disease (MRD) at the end of induction therapy among patients who have a poor early response to 2 weeks of induction therapy that does not include TKIs. METHODS: The authors analyzed the early response to TKIs during remission induction in children with Ph-positive ALL who were treated at St. Jude Children's Research Hospital. MRD was measured on days 15 and 42 of induction. TKIs were incorporated into induction therapy on day 22 in the post-TKI era. RESULTS: TKIs produced a marked drop in MRD levels: at the end of remission induction, 9 of 11 patients who received imatinib or dasatinib and conventional induction chemotherapy achieved MRD-negative status compared with only 2 of 16 patients who received chemotherapy alone (P < .001). The 5-year event-free survival rate (± standard deviation) was 68.6% ± 19.2% for the 11 patients who received TKIs versus 31.6% ± 9.9% for the 19 patients who did not (P = .022); notably, 2 of the former group underwent hematopoietic stem cell transplantation versus 15 of the latter group (P = .002). MRD levels and outcomes did not differ significantly among 498 patients with standard-risk/high-risk, Ph-negative ALL who were treated in the pre-TKI or post-TKI eras. CONCLUSIONS: TKIs administered in the early phases of therapy can dramatically reduce MRD and improve the outcome of childhood Ph-positive ALL.
Pulsipher MA, Langholz B, Wall DA, et al. The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children's Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial. Blood. 2014; 123(13):2017-25 [PubMed] Article available free on PMC after 27/03/2015 Related Publications
Sirolimus has activity against acute lymphoblastic leukemia (ALL) in xenograft models and efficacy in preventing acute graft-versus-host disease (aGVHD). We tested whether addition of sirolimus to GVHD prophylaxis of children with ALL would decrease aGVHD and relapse. Patients were randomized to tacrolimus/methotrexate (standard) or tacrolimus/methotrexate/sirolimus (experimental). The study met futility rules for survival after enrolling 146 of 259 patients. Rate of Grade 2-4 aGVHD was 31% vs 18% (standard vs experimental, P = .04), however, grade 3-4 aGVHD was not different (13% vs 10%, P = .28). Rates of veno-occlusive disease (VOD) and thrombotic microangiopathy (TMA) were lower in the nonsirolimus arm (9% vs 21% VOD, P = .05; 1% vs 10% TMA, P = .06). At 2 years, event free survival (EFS) and overall survival (OS) were 56% vs 46%, and 65% vs 55% (standard vs experimental), respectively (P = .28 and .23). Multivariate analysis showed increased relapse risk in children with ≥0.1% minimal residual disease (MRD) pretransplant, and decreased risk in patients with grades 1-3 aGVHD (P = .04). Grades 1-3 aGVHD were associated with improved EFS (P = .02), whereas grade 4 aGVHD and extramedullary disease at diagnosis led to inferior OS. Although addition of sirolimus decreased aGVHD, survival was not improved. This study is registered with ClinicalTrials.gov as #NCT00382109.
Myers RM, Balsamo L, Lu X, et al. A prospective study of anxiety, depression, and behavioral changes in the first year after a diagnosis of childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. Cancer. 2014; 120(9):1417-25 [PubMed] Related Publications
BACKGROUND: The authors prospectively assessed anxiety, depression, and behavior in children with standard-risk acute lymphoblastic leukemia (SR-ALL) during the first year of therapy and identified associated risk factors. METHODS: A cohort study was performed of 159 children (aged 2 years-9.99 years) with SR-ALL who were enrolled on Children's Oncology Group protocol AALL0331 at 31 sites. Parents completed the Behavior Assessment System for Children, the General Functioning Scale of the Family Assessment Device, and the Coping Health Inventory for Parents at approximately 1, 6, and 12 months after diagnosis. RESULTS: Overall, mean scores for anxiety, depression, aggression, and hyperactivity were similar to population norms. However, more children scored in the at-risk/clinical range for depression than the expected 15% at 1 month (21.7%; P= .022), 6 months (28.6%; P< .001), and 12 months (21.1%; P= .032). For anxiety, more children scored in the at-risk/clinical range at 1 month (25.2% vs 15%; P= .001), but then reverted to expected levels. On adjusted analysis, unhealthy family functioning was found to be predictive of anxiety (odds ratio [OR], 2.24; P= .033) and depression (OR, 2.40; P= .008). Hispanic ethnicity was associated with anxiety (OR, 3.35; P= .009). Worse physical functioning (P= .049), unmarried parents (P= .017), and less reliance on social support (P= .004) were found to be associated with depression. Emotional distress at 1 month predicted anxiety (OR, 7.11; P= .002) and depression (OR, 3.31; P= .023) at 12 months. CONCLUSIONS: Anxiety is a significant problem in a subpopulation of patients with SR-ALL immediately after diagnosis, whereas depression remains a significant problem for at least 1 year. Children of Hispanic ethnicity or those with unhealthy family functioning may be particularly vulnerable. These data suggest that clinicians should screen for anxiety and depression throughout the first year of therapy.