Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R) and 20 older children (MLL-R cases) with leukemia. Our data demonstrated infant MLL-R ALL to have one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite the paucity of mutations, activating mutations in kinase/PI3K/RAS signaling pathways were detected in 47%. Surprisingly, however, these mutations were often sub-clonal and frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (a mean of 6.5/case versus 1.3/case, P=7.15×10−5) and contained frequent mutations (45%) in epigenetic regulators, a category of genes that with the exception of MLL was rarely mutated in infant MLL-R ALL.

An expert panel was convened to provide specific, expert consensus guidelines for the use of glucarpidase in patients who develop high‐dose methotrexate (HDMTX)‐induced nephrotoxicity and delayed methotrexate excretion. This guideline provides recommendations to identify the population of patients who would benefit from glucarpidase rescue by more precisely defining the absolute methotrexate concentrations associated with risk for severe or life‐threatening toxicity at several time points after the start of a HDMTX infusion.

The NOPHO-AML 2004 induction strategy gives an excellent remission rate with low toxic mortality in an unselected population. Outcome is worse in patients with intermediate response but may be improved by intensifying consolidation in this group using SCT.

High hyperdiploid acute lymphoblastic leukemia (ALL) is one of the most common malignancies in children. It is characterized by gain of chromosomes, typically +X, +4, +6, +10, +14, +17, +18, and +21, +21; little is known about additional genetic aberrations. Approximately 20% of the patients relapse; therefore it is clinically important to identify risk-stratifying markers. We used SNP array analysis to investigate a consecutive series of 74 cases of high hyperdiploid ALL. We show that the characteristic chromosomal gains are even more frequent than previously believed, indicating that karyotyping mistakes are common, and that almost 80% of the cases display additional abnormalities detectable by SNP array analysis. Subclonality analysis strongly implied that the numerical aberrations were primary and arose before structural events, suggesting that step-wise evolution of the leukemic clone is common. An association between duplication of 1q and +5 was seen (P = 0.003). Other frequent abnormalities included whole-chromosome uniparental isodisomies (wUPIDs) 9 and 11, gain of 17q not associated with isochromosome formation, extra gain of part of 21q, deletions of ETS variant 6 (ETV6), cyclin-dependent kinase inhibitor 2A (CKDN2A) and paired box 5 (PAX5), and PAN3 poly(A) specific ribonuclease subunit homolog (PAN3) microdeletions. Comparison of whole-chromosome and partial UPID9 suggested different pathogenetic outcomes, with the former not involving CDKN2A. Finally, two cases had partial deletions of AT rich interactive domain 5B (ARID5B), indicating that acquired as well as constitutional variants in this locus may be associated with pediatric ALL. Here we provide a comprehensive characterization of the genetic landscape of high hyperdiploid childhood ALL, including the heterogeneous pattern of secondary genetic events.

Summary To determine the epidemiology and outcome of children with Down syndrome (DS) diagnosed with acute leukaemia in the Nordic countries, data registered in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) population‐based leukaemia registry were analysed. Of 3494 children with acute leukaemia diagnosed between July 1984 and December 2001, 136 patients (3·9%) with DS were identified. 2·1% of the children with acute lymphoid leukaemia (ALL) and 14·0% of the children with acute myeloid leukaemia (AML) had DS. In ALL, DS patients had similar age and sex distribution and no major differences in blood counts compared with non‐DS children. None of the DS patients had T cell leukaemia. Outcome was inferior to that of non‐DS children and treatment results did not improve over time. In AML, DS patients showed a significant female predominance and all but one were <5 years old. DS patients with AML had significantly lower platelet and white blood cell counts and two‐thirds were type M7 as according to the French–American–British classification. None of the patients <5 years of age had typical AML cytogenetic aberrations. Outcome was far better in the DS group. DS patients treated for AML after 1992 had an excellent outcome (probability of event‐free survival, 83 ± 6%). The high proportion of female DS patients with AML is unexplained. The differing treatment results in AML versus ALL need further evaluation and represent a challenge for the coming years.

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Summary In the Nordic Society for Paediatric Haematology and Oncology paediatric study acute myeloid leukaemia (AML) 93, event‐free survival was 50% and overall survival was 66%, indicating that many patients were cured following relapse. Factors influencing outcome in children with relapsed AML were investigated. The study included all 146 children in the Nordic countries diagnosed with AML between 1988 and 2003, who relapsed. Data on disease characteristics and relapse treatment were related to outcome. Sixty‐six percentage achieved remission with survival after relapse (5 years) 34 ± 4%. Of 122 patients who received re‐induction therapy, 77% entered remission with 40 ± 5% survival. Remission rates were similar for different re‐induction regimens but fludarabine, cytarabine, granulocyte colony‐stimulating factor‐based therapy had low treatment‐related mortality. Prognostic factors for survival were duration of first complete remission (CR1) and stem cell transplantation (SCT) in CR1. In early relapse (<1 year in CR1), survival was 21 ± 5% compared with 48 ± 6% in late relapse. For children receiving re‐induction therapy, survival in early relapse was 29 ± 6% and 51 ± 6% in late. Patients treated in CR1 with SCT, autologous SCT or chemotherapy had a survival of 18 ± 9, 5 ± 5 and 41 ± 5%, respectively. Survival was 62 ± 6% in 64 children given SCT as part of their relapse therapy. A significant proportion of children with relapsed AML can be cured, even those with early relapse. Children who receive re‐induction therapy, enter remission and proceed to SCT can achieve a cure rate of 60%.

Global expression profiles of a consecutive series of 121 childhood acute leukemias (87 B lineage acute lymphoblastic leukemias, 11 T cell acute lymphoblastic leukemias, and 23 acute myeloid leukemias), six normal bone marrows, and 10 normal hematopoietic subpopulations of different lineages and maturations were ascertained by using 27K cDNA microarrays. Unsupervised analyses revealed segregation according to lineages and primary genetic changes, i.e., TCF3(E2A)͞PBX1, IGH@͞MYC, ETV6(TEL)͞RUNX1(AML1), 11q23͞MLL, and hyperdiploidy (>50 chromosomes). Supervised discriminatory analyses were used to identify differentially expressed genes correlating with lineage and primary genetic change. The gene-expression profiles of normal hematopoietic cells were also studied. By using principal component analyses (PCA), a differentiation axis was exposed, reflecting lineages and maturation stages of normal hematopoietic cells. By applying the three principal components obtained from PCA of the normal cells on the leukemic samples, similarities between malignant and normal cell lineages and maturations were investigated. Apart from showing that leukemias segregate according to lineage and genetic subtype, we provide an extensive study of the genes correlating with primary genetic changes. We also investigated the expression pattern of these genes in normal hematopoietic cells of different lineages and maturations, identifying genes preferentially expressed by the leukemic cells, suggesting an ectopic activation of a large number of genes, likely to reflect regulatory networks of pathogenetic importance that also may provide attractive targets for future directed therapies.