Leukaemia is the most common cancer of childhood. The body produces lymphocytes to protect the body from infection, in leukaemia these cells do not mature properly and become too numerous in the blood and bone marrow. Leukaemias may be acute or chronic. The most common type is acute lymphoblastic leukaemia (ALL). There are a number of other less common acute types which may be grouped together as acute non-lymphoblastic leukaemia (ANLL), this includes acute myeloid leukaemia (AML).
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Targeting cancer genes to treat childhood leukaemia
Leukaemia & Lymphoma Research Dr Owen Williams talks about developing new drugs to treat childhood leukaemia. Dr Williams is from the UCL Institute of Child Health and Great Ormond Street Hospital for children NHS Trust.
The NCLF is a non-profit organization providing services, support, and referrals for leukemia patients and their families.The site provides details of their telephone help line, and information on various topics related to childhood leukemia.
PubMed Central search for free-access publications about Childhood Leukaemia MeSH term: Leukemia US National Library of Medicine PubMed has over 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Constantly updated.
SEER, National Cancer Institute Part of a SEER report on statistical trends and risk factors associated with childhood cancers. From: Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995. (PDF)
This list of publications is regularly updated (Source: PubMed).
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.
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.
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.
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.
Bari R, Rujkijyanont P, Sullivan E, et al. Effect of donor KIR2DL1 allelic polymorphism on the outcome of pediatric allogeneic hematopoietic stem-cell transplantation. J Clin Oncol. 2013; 31(30):3782-90 [PubMed] Article available free on PMC after 20/10/2014 Related Publications
PURPOSE: Killer-cell immunoglobulin-like receptors (KIRs) that regulate natural-killer cells are highly polymorphic. Some KIR2DL1 alleles encode receptors that have stronger signaling function than others. We tested the hypothesis that the clinical outcomes of allogeneic hematopoietic stem-cell transplantation (HSCT) could be affected by donor KIR2DL1 polymorphism. PATIENTS AND METHODS: All 313 pediatric patients received allogeneic HSCT at a single institution. Donor KIR2DL1 functional allele typing was retrospectively performed using single nucleotide polymorphism assay. RESULTS: Patients who received a donor graft containing the functionally stronger KIR2DL1 allele with arginine at amino acid position 245 (KIR2DL1-R(245)) had better survival (P = .0004) and lower cumulative incidence of disease progression (P = .001) than those patients who received a donor graft that contained only the functionally weaker KIR2DL1 allele with cysteine at the same position (KIR2DL1-C(245)). The effect of KIR2DL1 allelic polymorphism was similar in patients with acute myeloid leukemia or acute lymphoblastic leukemia among all allele groups (P ≥ .71). Patients who received a KIR2DL1-R(245)-positive graft with HLA-C receptor-ligand mismatch had the best survival (P = .00003) and lowest risk of leukemia progression (P = .0005) compared with those who received a KIR2DL1-C(245) homozygous graft. CONCLUSION: Donor KIR2DL1 allelic polymorphism affects recipient outcomes after allogeneic HSCT. These findings have substantial implications for prognostication and donor selection.
Kersten E, Scanlan P, Dubois SG, Matthay KK Current treatment and outcome for childhood acute leukemia in Tanzania. Pediatr Blood Cancer. 2013; 60(12):2047-53 [PubMed] Related Publications
BACKGROUND: In order to understand the disparity in childhood leukemia survival in low-income countries (LICs) compared to high-income countries (HICs), we evaluated the resources available at Tanzania's national pediatric oncology ward, and clinical characteristics, disease course and outcomes of children diagnosed with acute leukemia from 2008 through 2010. PROCEDURES: A chart review and assessment of services was performed to assess childhood leukemia diagnoses, treatment, and outcomes in Tanzania at the Ocean Road Cancer Institute (ORCI) from January 1, 2008 to December 31, 2010. Results were compared to those from a 2005 evaluation that showed only one of 20 children with leukemia surviving at 1 year. RESULTS: During the study period, 106 patients presented with leukemia, including 81 patients with acute lymphoblastic leukemia (ALL) and 25 with acute myeloid leukemia (AML). Forty-nine of 58 (84%) patients with ALL, and six of 17 (35%) with AML who received therapy and had complete data, achieved complete remission. Estimated 2-year event-free survival for all patients with ALL was 33%; for AML it was 0%. Ten patients died prior to initiation of therapy, 19 died of toxicity, and eight abandoned therapy. CONCLUSIONS: Though leukemia survival in Tanzania remains far below that in HICs, survival rates for ALL have significantly improved in recent years due to standardization of treatment regimens and better staff, though AML outcome remains dismal. Ongoing improvements in pediatric leukemia outcomes will require strategies to improve awareness and early access to treatment coupled with improvements in diagnostic capabilities, supportive care, and training.
Johnston DL, Alonzo TA, Gerbing RB, et al. Outcome of pediatric patients with acute myeloid leukemia (AML) and -5/5q- abnormalities from five pediatric AML treatment protocols: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2013; 60(12):2073-8 [PubMed] Related Publications
BACKGROUND: Abnormalities of chromosome 5q (-5/5q-) are associated with poor prognosis in adults with acute myeloid leukemia (AML). However, there are no large studies on outcomes of children with -5/5q- AML. To determine the disease correlates of this group, we retrospectively analyzed cytogenetic data from five studies of childhood AML. PROCEDURE: Data from patients whose cytogenetic clones included -5/5q-, with the exception of those with acute promyelocytic leukemia or Down syndrome, were included. RESULTS: Of the 2,240 patients with cytogenetic data available, 26 (1.2%) had -5 or 5q-. A significant number of these patients were age 11-21 (61.5%, P = 0.031) and had M0 morphology compared with patients without -5/5q- (24.0% vs. 2.8%, P < 0.001). Twenty-two of the 26 patients had a complete remission (CR) response to induction chemotherapy. The 5-year overall survival (OS) from the time of diagnosis for the -5/5q- patients was significantly lower than for patients without -5/5q- (27 ± 17% vs. 50 ± 2%, P = 0.027). Similarly, from induction CR, patients with -5/5q- had significantly worse disease free survival, OS and relapse risk than those without this abnormality (27 ± 19% vs. 46 ± 2%, P = 0.035, 32 ± 20% vs. 57 ± 2%, P = 0.025, 68 ± 21% vs. 45 ± 2%, P = 0.01, respectively). CONCLUSIONS: Pediatric patients with AML and -5/5q- had a very poor outcome. These findings support the need for new or novel therapies for these patients.
Molgaard-Hansen L, Skou AS, Juul A, et al. Pubertal development and fertility in survivors of childhood acute myeloid leukemia treated with chemotherapy only: a NOPHO-AML study. Pediatr Blood Cancer. 2013; 60(12):1988-95 [PubMed] Related Publications
BACKGROUND: More than 60% of children with acute myeloid leukemia (AML) become long-term survivors. Most are cured using chemotherapy without hematopoietic stem cell transplantation (HSCT). We report on pubertal development and compare self-reported parenthood among AML survivors and their siblings. PROCEDURE: We included 137 children treated for AML according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO)-AML-84, -88, and -93 trials, who were alive by June 2007. Patients with relapse or treated with HSCT were excluded. AML survivors participated in a physical and biochemical examination (n = 102) and completed a questionnaire (n = 101). One of their siblings completed an identical questionnaire (n = 84). RESULTS: At a median follow-up of 11 years (range 5-25) after diagnosis of AML the survivors (median age 16 years, range 5-36) were either prepubertal or had entered puberty normally. Serum levels of FSH, LH, testosterone, estradiol, sex hormone binding globulin (SHBG), inhibin A and B, and testicular volumes were within normal ranges. Anti-Müllerian hormone (AMH) levels were decreased in 5 of 40 postpubertal females. Mean reported age at menarche was 13.1 (range 11-17) years. Among survivors 15 years of age or older 31% of females reported pregnancies and 9% of males reported pregnancies in their partners, rates comparable with the frequency reported by their siblings. CONCLUSIONS: Most AML survivors treated with chemotherapy had normal pubertal development and fertility, however, AMH levels were decreased in 13% of postpubertal females. Longer follow-up is necessary to evaluate possible risk of premature ovarian failure.
Lustfeld I, Altvater B, Ahlmann M, et al. High proportions of CD4⁺ T cells among residual bone marrow T cells in childhood acute lymphoblastic leukemia are associated with favorable early responses. Acta Haematol. 2014; 131(1):28-36 [PubMed] Related Publications
Residual nonmalignant T cells in the bone marrow of patients with acute leukemias may be involved in active immune responses to leukemic cells. Here, we investigated the phenotypic signature of T cells present at diagnosis in 39 pediatric patients with acute lymphoblastic leukemia (ALL) treated within standardized ALL-BFM study protocols. Previously described age associations of lymphocyte subpopulations in the peripheral blood of healthy children were reproduced in leukemic bone marrow. Analysis of individual lymphocyte parameters and risk-associated variables using univariate linear regression models revealed a correlation of higher CD4/CD8 ratios at diagnosis with a favorable bone marrow response on day 15. Separate analysis of CD4⁺ cells with the CD4⁺CD25(hi)FoxP3⁺ T(reg) cell phenotype showed that the association was caused by non-T(reg) CD4⁺ cells. The association of higher CD4/CD8 ratios with a favorable bone marrow response on day 15 of treatment persisted in a cohort extended to 69 patients. We conclude that CD4⁺ non-T(reg) cells in leukemic bone marrow at diagnosis may have a role in early response to treatment. Prospective analysis of the CD4/CD8 ratio in a large cohort of pediatric patients is now needed. Moreover, future experiments will establish the functional role of the individual T cell subsets in immune control in pediatric ALL.
Migliorini G, Fiege B, Hosking FJ, et al. Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype. Blood. 2013; 122(19):3298-307 [PubMed] Related Publications
Acute lymphoblastic leukemia (ALL) is the major pediatric cancer diagnosed in economically developed countries with B-cell precursor (BCP)-ALL, accounting for approximately 70% of ALL. Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence for common inherited susceptibility to BCP-ALL, identifying susceptibility loci at 7p12.2, 9p21.3, 10q21.2, and 14q11.2. To identify additional BCP-ALL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1658 cases and 4723 controls, with validation in 1449 cases and 1488 controls. Combined analysis identified novel loci mapping to 10p12.2 (rs10828317, odds ratio [OR] = 1.23; P = 2.30 × 10(-9)) and 10p14 marked by rs3824662 (OR = 1.31; P = 8.62 × 10(-12)). The single nucleotide polymorphism rs10828317 is responsible for the N215S polymorphism in exon 7 of PIP4K2A, and rs3824662 localizes to intron 3 of the transcription factor and putative tumor suppressor gene GATA3. The rs10828317 association was shown to be specifically associated with hyperdiploid ALL, whereas the rs3824662-associated risk was confined to nonhyperdiploid non-TEL-AML1 + ALL. The risk allele of rs3824662 was correlated with older age at diagnosis (P < .001) and significantly worse event-free survivorship (P < .0001). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to BCP-ALL and the influence of constitutional genotype on disease development.
Niedzielska E, Węcławek-Tompol J, Matkowska-Kocjan A, Chybicka A The influence of genetic RFC1, MS and MTHFR polymorphisms on the risk of acute lymphoblastic leukemia relapse in children and the adverse effects of methotrexate. Adv Clin Exp Med. 2013 Jul-Aug; 22(4):579-84 [PubMed] Related Publications
Polymorphism in genes coding drug-metabolizing enzymes may cause individual differences in the effectiveness and toxicity of many medications, including cytostatics. Although in recent years intensive treatment has positively influenced the prognosis in leukemias, many adverse effects resulting from nonspecific actions and the narrow therapeutic index of anti-cancer drugs are still observed during therapy. Determining selected gene polymorphisms may increase both the safety and the efficacy of treatment, and might help in developing individual therapies.
Coenen EA, Zwaan CM, Reinhardt D, et al. Pediatric acute myeloid leukemia with t(8;16)(p11;p13), a distinct clinical and biological entity: a collaborative study by the International-Berlin-Frankfurt-Munster AML-study group. Blood. 2013; 122(15):2704-13 [PubMed] Related Publications
In pediatric acute myeloid leukemia (AML), cytogenetic abnormalities are strong indicators of prognosis. Some recurrent cytogenetic abnormalities, such as t(8;16)(p11;p13), are so rare that collaborative studies are required to define their prognostic impact. We collected the clinical characteristics, morphology, and immunophenotypes of 62 pediatric AML patients with t(8;16)(p11;p13) from 18 countries participating in the International Berlin-Frankfurt-Münster (I-BFM) AML study group. We used the AML-BFM cohort diagnosed from 1995-2005 (n = 543) as a reference cohort. Median age of the pediatric t(8;16)(p11;p13) AML patients was significantly lower (1.2 years). The majority (97%) had M4-M5 French-American-British type, significantly different from the reference cohort. Erythrophagocytosis (70%), leukemia cutis (58%), and disseminated intravascular coagulation (39%) occurred frequently. Strikingly, spontaneous remissions occurred in 7 neonates with t(8;16)(p11;p13), of whom 3 remain in continuous remission. The 5-year overall survival of patients diagnosed after 1993 was 59%, similar to the reference cohort (P = .14). Gene expression profiles of t(8;16)(p11;p13) pediatric AML cases clustered close to, but distinct from, MLL-rearranged AML. Highly expressed genes included HOXA11, HOXA10, RET, PERP, and GGA2. In conclusion, pediatric t(8;16)(p11;p13) AML is a rare entity defined by a unique gene expression signature and distinct clinical features in whom spontaneous remissions occur in a subset of neonatal cases.
van der Veer A, Waanders E, Pieters R, et al. Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL. Blood. 2013; 122(15):2622-9 [PubMed] Article available free on PMC after 10/10/2014 Related Publications
Most relapses in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are not predicted using current prognostic features. Here, we determined the co-occurrence and independent prognostic relevance of 3 recently identified prognostic features: BCR-ABL1-like gene signature, deletions in IKZF1, and high CRLF2 messenger RNA expression (CRLF2-high). These features were determined in 4 trials representing 1128 children with ALL: DCOG ALL-8, ALL9, ALL10, and Cooperative ALL (COALL)-97/03. BCR-ABL1-like, IKZF1-deleted, and CRLF2-high cases constitute 33.7% of BCR-ABL1-negative, MLL wild-type BCP-ALL cases, of which BCR-ABL1-like and IKZF1 deletion (co)occurred most frequently. Higher cumulative incidence of relapse was found for BCR-ABL1-like and IKZF1-deleted, but not CRLF2-high, cases relative to remaining BCP-ALL cases, reflecting the observations in each of the cohorts analyzed separately. No relapses occurred among cases with CRLF2-high as single feature, whereas 62.9% of all relapses in BCR-ABL1-negative, MLL wild-type BCP-ALL occurred in cases with BCR-ABL1-like signature and/or IKZF1 deletion. Both the BCR-ABL1-like signature and IKZF1 deletions were prognostic features independent of conventional prognostic markers in a multivariate model, and both remained prognostic among cases with intermediate minimal residual disease. The BCR-ABL1-like signature and an IKZF1 deletion, but not CRLF2-high, are prognostic factors and are clinically of importance to identify high-risk patients who require more intensive and/or alternative therapies.
Li X, Li D, Zhuang Y, et al. Overexpression of miR-708 and its targets in the childhood common precursor B-cell ALL. Pediatr Blood Cancer. 2013; 60(12):2060-7 [PubMed] Related Publications
BACKGROUND: The critical function of microRNAs in the pathogenesis and prognosis of hematopoietic cancer has become increasingly apparent. However, only a few miRNAs have been reported to be altered in acute lymphocytic leukemia (ALL). PROCEDURES: To uncover aberrantly expressed miRNAs in pediatric B-cell ALL, our study employed genome-wide miRNA microarray analysis and stem-loop real-time quantitative polymerase chain reaction (qRT-PCR) to examine common precursor B-cell ALL samples. The target genes of miRNA-708 were then identified and verified by bioinformatics, dual-luciferase reporter assay, qRT-PCR, and Western blot. RESULTS: Significant upregulation of miR-708, miR-210, and miR-181b, and downregulation of miR-345 and miR-27a were observed in common precursor B-cell ALL (common-ALL) samples (P < 0.05). In addition, elevated expression of miR-708 and miR-181b were found in high-risk common-ALL compared to standard and intermediate ones. miR-708 inhibited luciferase reporter activity by binding to the 3'-untranslated regions (3'-UTRs) of CNTFR, NNAT, and GNG12 mRNA in HEK-293 cell line and suppressed the protein levels of CNTFR, NNAT, and GNG12 in Jurkat cells. In addition, mRNA levels of CNTFR and NNAT, but not of GNG12, were found to be downregulated in high risk common-ALL samples. Mutational analysis revealed that miR-708 binds to the 394-400 bp sequence region of the 3'-UTR of CNTFR mRNA. CONCLUSION: The expression level of miR-708 reflects differences among the clinical types of common-ALL, and CNTFR, NNAT, and GNG12 were identified as targets of miR-708.
Ho PA, Alonzo TA, Gerbing RB, et al. The prognostic effect of high diagnostic WT1 gene expression in pediatric AML depends on WT1 SNP rs16754 status: report from the Children's Oncology Group. Pediatr Blood Cancer. 2014; 61(1):81-8 [PubMed] Related Publications
BACKGROUND: WT1 is aberrantly over-expressed in most cases of AML. We recently demonstrated that WT1 SNP rs16754 correlates with favorable outcome and high diagnostic WT1 expression in childhood AML. We examined the clinical correlates of diagnostic WT1 expression within a contemporary COG trial and determined whether its prognostic impact differs between SNP+ and SNP- patients. PROCEDURE: WT1 mRNA expression was measured via qRT-PCR in diagnostic specimens obtained from 225 patients enrolled on COG-AAML03P1. Direct sequencing of WT1 exon 7 was performed to determine SNP rs16754 genotype. WT1 expression was correlated with disease characteristics, SNP status, and outcome. RESULTS: Patients were categorized into four groups (quartiles: Q1 through Q4) based on diagnostic WT1 expression for analysis. FLT3/ITD (P = 0.017) and WT1 mutations (P < 0.001) both occurred more frequently in patients with the highest WT1 expression. SNP rs16754 frequency did not vary significantly among the quartiles. When all patients were considered, survival outcomes were similar between quartiles. However, when only SNP- patients (n = 150) were analyzed, those with highest WT1 expression (Q4) had the poorest OS (51% vs. 72% for Q1-Q3, P = 0.006) and EFS (35% vs. 54% for Q1-Q3, P = 0.031). Among SNP+ patients (n = 75), survival did not vary significantly between WT1 expression quartiles. CONCLUSION: Although WT1 expression was not prognostic when all patients were considered together, stratifying patients by SNP rs16754 genotype revealed significant differences in outcome. In SNP- patients, high WT1 expression predicted decreased survival in univariate, but not multivariate, analysis, due to a preponderance of high-risk cyto/molecular abnormalities in the highest expression quartile.
Lothstein K, Fisher B, Li Y, et al. Zoonotic infections in pediatric patients with acute leukemia. Pediatr Blood Cancer. 2013; 60(12):E160-2 [PubMed] Related Publications
Few studies have described the impact of zoonotic diseases in children with leukemia. This study aimed to describe the frequency of and associated demographic factors for zoonotic diseases in pediatric acute leukemia patients. Descriptive and comparative statistics relative to age, sex, and patient region were performed on an assembled 11-year retrospective cohort of acute leukemia patients. Of 10,197 patients, 88 patients (0.86%) were found to have a zoonotic infection. Gastrointestinal diseases were the most commonly (86.4%) identified zoonotic illnesses. Although rare, zoonotic diseases do occur in children with leukemia and frequency varies by age, region, and gender.
Li ZG, Jiao Y, Li WJ, et al. Hypermethylation of two CpG sites upstream of CASP8AP2 promoter influences gene expression and treatment outcome in childhood acute lymphoblastic leukemia. Leuk Res. 2013; 37(10):1287-93 [PubMed] Related Publications
DNA hypermethylation of Caspase 8 associated protein 2 (CASP8AP2) and its role in childhood acute lymphoblastic leukemia (ALL) is unclear. We analyzed methylation status of CpG sites upstream of CASP8AP2 gene in 86 children with ALL by bisulfite sequencing and quantitative PCR. Methylation percentage of two CpG sites at positions of -1189 and -1176 was inversely correlated with mRNA expression (Spearman correlation: -0.333, P=0.002). High methylation was associated with the existence of minimal residual disease (MRD) at day 78 (P=0.035), The patients in high methylation group had a poor treatment outcome. The combination of methylation level and MRD at day 33 might improve current risk stratification.
Gruhn B, Naumann T, Gruner D, et al. The expression of histone deacetylase 4 is associated with prednisone poor-response in childhood acute lymphoblastic leukemia. Leuk Res. 2013; 37(10):1200-7 [PubMed] Related Publications
This study aimed at the identification of histone deacetylase (HDAC) isoforms relevant for childhood acute lymphoblastic leukemia (ALL). Expression of HDAC1-11 was determined in 93 primary ALL and eight healthy donor samples. HDAC1, HDAC2 and HDAC8 showed significantly higher expressions in ALL samples. Correlation analysis of HDAC expression with clinicopathological parameters revealed that high HDAC1, HDAC2, HDAC4 and HDAC11 levels were significantly associated with unfavorable prognostic factors. Particularly, high HDAC4 expression was associated with high initial leukocyte count, T cell ALL and prednisone poor-response. siRNA-mediated inhibition of HDAC4 sensitized a T-ALL cell line to etoposide-induced cell death. In conclusion, our data point to HDAC4 as drug target in childhood ALL, especially in prednisone poor-responders.
Al-Sudairy R, Al-Nasser A, Alsultan A, et al. Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia in Saudi Arabia: a multi-institutional retrospective national collaborative study. Pediatr Blood Cancer. 2014; 61(1):74-80 [PubMed] Related Publications
BACKGROUND: Treatment of childhood acute lymphoblastic leukemia (ALL) has been available in Saudi Arabia (SA) for over 30 years; however, only limited data have been published from there. This study was conducted to establish processes for collaborative data collection and provide clinical characteristics and outcome of children with ALL in SA. PROCEDURE: Clinical data for patients diagnosed from 2004 to 2008 were retrospectively collected at eight institutions and entered remotely into a custom-built database. Statistics regarding clinical and genetic characteristics and treatment outcome were calculated. RESULTS: The 594 evaluable patients had a median age of 4.37 years and 56.4% were boys. Majority of patients had B-precursor ALL while 10.7% had T-ALL. CNS leukemia was present in 5.2% of patients. The distribution of common genetic abnormalities was similar to that reported from western populations, with 24.6% hyperdiploidy, 21% RUNX1-ETV6 positivity, 4.2% BCR-ABL1 positivity, and 2.5% with MLL gene rearrangement. Patients received risk-adapted therapy according to various protocols, although treatment strategies for the majority were similar. Five-year OS, RFS and EFS were 86.9%, 79.1%, and 73.3%, respectively. The OS for patients with pre-B ALL was significantly higher than for T-ALL (88.0% vs. 71.8%; P = 0.019, Log-Rank test). Patients with pre-B ALL categorized as low-risk by NCI/Rome criteria and those with hyperdiploidy had OS of 93.4% and 95.8%, respectively. CONCLUSIONS: The characteristics of childhood ALL in SA are similar to those observed in developed countries. Future prospective studies utilizing unified national protocols are needed to further improve the outcome of our patients.
Escherich G, Zur Stadt U, Zimmermann M, et al. Clofarabine in combination with pegylated asparaginase in the frontline treatment of childhood acute lymphoblastic leukaemia: a feasibility report from the CoALL 08-09 trial. Br J Haematol. 2013; 163(2):240-7 [PubMed] Related Publications
Clofarabine was the latest new drug to be approved, in 2004, for relapsed or refractory acute lymphoblastic leukaemia (ALL). To investigate its value in the frontline treatment of ALL we applied clofarabine 5 × 40 mg/m(2) in combination with pegylated asparaginase (PEG-ASP) 1 × 2500 iu/m(2) in high risk ALL patients as a novel post-induction element in the German Co-operative Study Group for treatment of ALL (CoALL) trial 08-09. Newly diagnosed ALL patients, defined by a significant minimal residual disease (MRD) load at the end of induction (B-progenitor ALL at day 29 ≥ 10(-4) and T-ALL at day 43 ≥ 10(-3) ) were eligible for this phase II trial. All other patients received the standard treatment consisting of high-dose cytarabine (HIDAC) 4 × 3 g/m² in combination with Peg-ASP 2500 iu/m². Forty-two patients (39 B-progenitor; 3 T-ALL) fulfilled the criteria, were stratified and received the clofarabine/PEG-ASP treatment resulting in 24/39 (61%) MRD-negative B-progenitor patients compared to 18/39 (46%) after HIDAC/PEG-ASP in CoALL 07-03. Overall, the toxicity profile of clofarabine/PEG-ASP was similar to HIDAC/PEG-ASP without unexpected severe side effects. Clofarabine combined with PEG-ASP is safe and effective in the frontline treatment of ALL. A prospective, randomized trial is warranted to evaluate the antileukaemic efficacy of clofarabine versus HIDAC combined with PEG-ASP.
Locatelli F, Crotta A, Ruggeri A, et al. Analysis of risk factors influencing outcomes after cord blood transplantation in children with juvenile myelomonocytic leukemia: a EUROCORD, EBMT, EWOG-MDS, CIBMTR study. Blood. 2013; 122(12):2135-41 [PubMed] Article available free on PMC after 19/09/2014 Related Publications
We retrospectively analyzed 110 patients with juvenile myelomonocytic leukemia, given single-unit, unrelated donor umbilical cord blood transplantation. Median age at diagnosis and at transplantation was 1.4 years (age range, 0.1-6.4 years) and 2.2 years (age range, 0.5-7.4 years), respectively. Before transplantation, 88 patients received chemotherapy; splenectomy was performed in 24 patients. Monosomy of chromosome 7 was the most frequent cytogenetic abnormality, found in 24% of patients. All but 8 patients received myeloablative conditioning; cyclosporine plus steroids was the most common graft-versus-host disease prophylaxis. Sixteen percent of units were HLA-matched with the recipient, whereas 43% and 35% had either 1 or 2 to 3 HLA disparities, respectively. The median number of nucleated cells infused was 7.1 × 10(7)/kg (range, 1.7-27.6 × 10(7)/kg). With a median follow-up of 64 months (range, 14-174 months), the 5-year cumulative incidences of transplantation-related mortality and relapse were 22% and 33%, respectively. The 5-year disease-free survival rate was 44%. In multivariate analysis, factors predicting better disease-free survival were age younger than 1.4 years at diagnosis (hazard ratio [HR], 0.42; P = .005), 0 to 1 HLA disparities in the donor/recipient pair (HR, 0.4; P = .009), and karyotype other than monosomy 7 (HR, 0.5; P = .02). Umbilical cord blood transplantation may cure a relevant proportion of children with juvenile myelomonocytic leukemia. Because disease recurrence remains the major cause of treatment failure, strategies to reduce incidence of relapse are warranted.
Zappolo K, DeFeo D, Dang D, Covino J How to recognize and treat childhood leukemia. JAAPA. 2013; 26(7):37-41 [PubMed] Related Publications
Acute leukemia may be difficult to diagnose in children because of the lack of specific findings. The key is to recognize unexplained symptoms and consider leukemia as a differential. Prompt treatment improves outcomes.
Prasad R, Jaiswal BP, Mishra OP, Singh UK Association of possible osteopetrosis with acute myeloid leukaemia in a child. BMJ Case Rep. 2013; 2013 [PubMed] Related Publications
Osteopetrosis is a rare disease characterised by an increase in bone mass, skeletal malformations and bone marrow failure due to defective bone resorption. We report a 3-month-old male child presented with chest infections, failure to thrive and hepatosplenomegaly and diagnosed with osteopetrosis associated with acute myeloid leukaemia M3 type (AML-M3). The patient died on day 7 of admission due to respiratory failure. To our knowledge, this is the first case where both osteopetrosis and AML is diagnosed in a patient.
Figueroa ME, Chen SC, Andersson AK, et al. Integrated genetic and epigenetic analysis of childhood acute lymphoblastic leukemia. J Clin Invest. 2013; 123(7):3099-111 [PubMed] Article available free on PMC after 19/09/2014 Related Publications
Acute lymphoblastic leukemia (ALL) is the commonest childhood malignancy and is characterized by recurring structural genetic alterations. Previous studies of DNA methylation suggest epigenetic alterations may also be important, but an integrated genome-wide analysis of genetic and epigenetic alterations in ALL has not been performed. We analyzed 137 B-lineage and 30 T-lineage childhood ALL cases using microarray analysis of DNA copy number alterations and gene expression, and genome-wide cytosine methylation profiling using the HpaII tiny fragment enrichment by ligation-mediated PCR (HELP) assay. We found that the different genetic subtypes of ALL are characterized by distinct DNA methylation signatures that exhibit significant correlation with gene expression profiles. We also identified an epigenetic signature common to all cases, with correlation to gene expression in 65% of these genes, suggesting that a core set of epigenetically deregulated genes is central to the initiation or maintenance of lymphoid transformation. Finally, we identified aberrant methylation in multiple genes also targeted by recurring DNA copy number alterations in ALL, suggesting that these genes are inactivated far more frequently than suggested by structural genomic analyses alone. Together, these results demonstrate subtype- and disease-specific alterations in cytosine methylation in ALL that influence transcriptional activity, and are likely to exert a key role in leukemogenesis.
Akbari Moqadam F, Lange-Turenhout EA, Ariës IM, et al. MiR-125b, miR-100 and miR-99a co-regulate vincristine resistance in childhood acute lymphoblastic leukemia. Leuk Res. 2013; 37(10):1315-21 [PubMed] Related Publications
MicroRNA-125b (miR-125b), miR-99a and miR-100 are overexpressed in vincristine-resistant acute lymphoblastic leukemia (ALL). Cellular viability of ETV6-RUNX1-positive Reh cells significantly increased in presence of 9 ng/mL vincristine upon co-expression of miR-125b/miR-99a (91 ± 4%), miR-125b/miR-100 (93 ± 5%) or miR-125b/miR-99a/miR-100 (82 ± 17%) compared with miR-125b-transduced cells (38 ± 13%, P<0.05). Co-expression of these miRNAs resulted in downregulation of DNTT, NUCKS1, MALAT1, SNRPE, PNO1, SET, KIF5B, PRPS2, RPS11, RPL38 and RPL23A (fold-change 1.3-1.9, p<0.05). Similarly, 7 out of these genes are lower expressed in vincristine-resistant ALL cells of children (p<0.05). The concerted function of miR-125b in combination with miR-99a and/or miR-100 illustrates the complexity of vincristine-resistant pediatric ALL.
Mir Mazloumi SH, Appaji L, Madhumathi DS, Prasannakumari G-banding and fluorescence in situ hybridization in childhood acute myeloid leukemia from South India. Arch Iran Med. 2013; 16(8):459-62 [PubMed] Related Publications
BACKGROUND: The current WHO classification of hematologic malignancies defines distinct entities of myeloid disorders based on the presence of recurrent cytogenetic abnormalities. Diagnostic clonal chromosomal abnormalities provide important prognostic information and are among the most important factors in predicting initial response to chemotherapy, duration of remission and overall survival. METHODS: This study analyzed chromosomal abnormalities in bone marrow aspirates of 50 children diagnosed with acute myeloid leuckemia (AML). RESULTS: The culture success rate was 94%, clonal chromosomal abnormalities constituted 62% and recurrent chromosomal abnormalities were 56%. In the favorable prognostic category, there were 51.6% of cases with t(8;21)(q22;q22), 16.1% had t(15;17)(q22;q21), and a total of 12.9% had chromosome 16 rearrangement. The adverse risk category showed a low frequency of t(9;11)(p22;q13); t(1;22)(p13;q13); inv(3)( q21q26); add 4(q35) and ring chromosome. According to fluorescent in situ hybridization (FISH) results in 16 cytogenetically normal patients, there were no CBFβ/MYH11 fusion genes observed in chromosome 16 rearrangements. DISCUSSION: Larger studies of this kind may provide more information about chromosome 16 rearrangements in cytogenetically normal patients. The present analysis suggests that both age and cytogenetics are important strategies for risk stratification (outcome). Additional laboratory parameters should also be considered in childhood AML.
Studniak E, Maloney E, Ociepa T, et al. Allelic loss of selected tumor suppressor genes in acute lymphoblastic leukemia in children. Pol J Pathol. 2013; 64(2):121-8 [PubMed] Related Publications
Defect in function of tumor suppressor genes may lead to initiation/progression of leukemias. RB1, CDKN2A and TP53 gene alterations are found in acute lymphoblastic leukemia (ALL) in children. Data showing a contribution of these alterations to the pathomechanism of leukemias are contradictory and their impact on a disease course still remains undefined. The main aim of the study was to identify and the characterize of RB1, CDKN2A and TP53 allele loss in ALL children patients at diagnosis. 46 children with de novo ALL were examined. Fluorescent in situ hybridization was performed on bone marrow smear preparations. We demonstrated that at least one of three investigated deletions occurred statistically more frequently in T-lineage leukemia patients (p = 0.044); this was the most frequent in respect to RB1 gene (p = 0.054). Additionally, at least one of the examined deletions was observed statistically more frequently in patients with WBC above 20 000/µl (p = 0.043), this was the most frequent for CDKN2A gene (p = 0.066). Presented results seem to give an evidence that deletions of RB1 and CDKN2A genes may contribute to the development of hyperleukocytic type of T-lineage ALL in children, nevertheless this observation needs further investigations.
Young B, Hill J, Gravenhorst K, et al. Is communication guidance mistaken? Qualitative study of parent-oncologist communication in childhood cancer. Br J Cancer. 2013; 109(4):836-43 [PubMed] Article available free on PMC after 20/08/2014 Related Publications
BACKGROUND: Guidance encourages oncologists to engage patients and relatives in discussing the emotions that accompany cancer diagnosis and treatment. We investigated the perspectives of parents of children with leukaemia on the role of paediatric oncologists in such discussion. METHODS: Qualitative study comprising 33 audio-recorded parent-oncologist consultations and semi-structured interviews with 67 parents during the year following diagnosis. RESULTS: Consultations soon after the diagnosis were largely devoid of overt discussion of parental emotion. Interviewed parents did not describe a need for such discussion. They spoke of being comforted by oncologists' clinical focus, by the biomedical information they provided and by their calmness and constancy. When we explicitly asked parents 1 year later about the oncologists' role in emotional support, they overwhelmingly told us that they did not want to discuss their feelings with oncologists. They wanted to preserve the oncologists' focus on their child's clinical care, deprecated anything that diverted from this and spoke of the value of boundaries in the parent-oncologist relationship. CONCLUSION: Parents were usually comforted by oncologists, but this was not achieved in the way suggested by communication guidance. Communication guidance would benefit from an enhanced understanding of how emotional support is experienced by those who rely on it.
Hashemi F, Sedghi M, Karimi M The impact of educating parents of leukaemic children on the healthy siblings' quality of life. J Pak Med Assoc. 2013; 63(2):249-52 [PubMed] Related Publications
OBJECTIVE: To study the effect of educational programme for the parents on the quality of life of healthy siblings of children with leukaemia. METHODS: The quasi-experimental study was conducted from January to July 2006 at the Oncology Ward of Shahid Faghihi Hospital, Shiraz University of Medical Sciences, Iran. It involved two groups of siblings of children with leukaemia. Parents of the children participated in 3 educational sessions and the quality of life of their healthy children was surveyed before and after education.The data was collected through a questionnairedeveloped by The Netherlands Organisation for Aplied Scientific Research Academic Medical Centre (TN0-AZ1) which has been specially designed for children aged 7-15 years. In this study, the parent form of the questionnaire, including 7 dimensions, was used. Sampling was done by convenient purposive method. The collected data were analysed using SPSS 11.5. RESULTS: The differences in the quality of life scores of the experimental and control groups before and after education was -28.8 +/- 11.3 and -3.6 +/- 4.5, respectively. Also by regarding the mean difference of the two groups, the independent t-test showed significant difference before and after the education (p < 0.01). There was a significant difference between the two groups on all dimensions (p < 0.01) in such a way that the educational interventions was able to improve the quality of life in terms of physical complaints, autonomy, social, cognitive and motor functioning, positive and negative emotions. CONCLUSION: The educational programme was effective in improving the quality of life and its dimensions among healthy siblings of children with leukaemia.