Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic Leukemia.

Children with Down syndrome have an augmented risk for B-cell acute lymphoblastic leukemia (DS-ALL), which is associated with lower survival than in non-DS-ALL. It is known that cytogenetic abnormalities common in childhood ALL are less frequent in DS-ALL, while other genetic aberrancies (ie, overexpression and deletions) are increased. A possible cause for the lower survival of DS-ALL that we herewith evaluated for the first time was the incidence and prognostic value of the Philadelphia-like (Ph-like) profile and the IKZF1plus pattern.

Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets.

Survival of patients with pediatric acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-SCT) is mainly compromised by leukemia relapse, carrying dismal prognosis. As novel individualized therapeutic approaches are urgently needed, we performed whole-exome sequencing of leukemic blasts of 10 children with post-allo-SCT relapses with the aim of thoroughly characterizing the mutational landscape and identifying druggable mutations. We found that post-allo-SCT ALL relapses display highly diverse and mostly patient-individual genetic lesions.

Relapses and treatment-related events contributed equally to poor prognosis in children with ABL-class fusion positive B-cell acute lymphoblastic leukemia treated according to AIEOP-BFM protocols.

ABL-class fusions other than characterize around 2-3% of precursor B-cell acute lymphoblastic leukemia. Case series indicated that patients suffering from these subtypes have a dismal outcome and may benefit from the introduction of tyrosine kinase inhibitors. We analyzed clinical characteristics and outcome of 46 ABL-class fusion positive cases other than treated according to AIEOP-BFM (Associazione Italiana di Ematologia-Oncologia Pediatrica-Berlin-Frankfurt-Münster) ALL 2000 and 2009 protocols; 13 of them received a tyrosine kinase inhibitor (TKI) during different phases of treatment.

Asparagine levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia treated with pegylated-asparaginase in the induction phase of the AIEOP-BFM ALL 2009 study.

Asparagine levels in cerebrospinal fluid and serum asparaginase activity were monitored in children with acute lymphoblastic leukemia treated with pegylated-asparaginase. The drug was given intravenously at a dose of 2,500 IU/m on days 12 and 26. Serum and cerebrospinal fluid samples obtained on days 33 and 45 were analyzed centrally.

Molecular characterization of acute lymphoblastic leukemia with high CRLF2 gene expression in childhood.

Background: A high-level expression of the CRLF2 gene is frequent in precursor B-cell acute lymphoblastic leukemia (pB-ALL) and can be caused by different genetic aberrations. The presence of the most frequent alteration, the P2RY8/CRLF2 fusion, was shown to be associated with a high relapse incidence in children treated according to ALL-Berlin-Frankfurt-Münster (BFM) protocols, which is poorly understood. Moreover, the frequency of other alterations has not been systematically analyzed yet.

Osteonecrosis develops independently from radiological leukemic infiltration of bone in adolescents with acute lymphoblastic leukemia - first findings of the OPAL trial.

Osteonecrosis (ON) is a debilitating side effect of anti-leukemic treatment. Thus far, the role of leukemic infiltration (LI) of bone is unclear. The first 30 children aged ≥10 years, who were enrolled in the ongoing OPAL trial and had MRI studies at diagnosis and at 6 months, were analyzed.

Implications of delayed bone marrow aspirations at the end of treatment induction for risk stratification and outcome in children with acute lymphoblastic leukaemia.

Minimal residual disease (MRD) at the end of induction therapy is important for risk stratification of acute lymphoblastic leukaemia (ALL), but bone marrow (BM) aspiration is often postponed or must be repeated to fulfil qualitative and quantitative criteria for morphological assessment of haematological remission and/or MRD analysis. The impact of BM aspiration delay on measured MRD levels and resulting risk stratification is currently unknown. We analysed paired MRD data of 289 paediatric ALL patients requiring a repeat BM aspiration.

Influence of Cranial Radiotherapy on Outcome in Children With Acute Lymphoblastic Leukemia Treated With Contemporary Therapy.

Purpose: We sought to determine whether cranial radiotherapy (CRT) is necessary to prevent relapse in any subgroup of children with acute lymphoblastic leukemia (ALL).

Patients And Methods: We obtained aggregate data on relapse and survival outcomes for 16,623 patients age 1 to 18 years old with newly diagnosed ALL treated between 1996 and 2007 by 10 cooperative study groups from around the world. The proportion of patients eligible for prophylactic CRT varied from 0% to 33% by trial and was not related to the proportion eligible for allogeneic stem-cell transplantation in first complete remission.

High proportions of CD4⁺ T cells among residual bone marrow T cells in childhood acute lymphoblastic leukemia are associated with favorable early responses.

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.

High CD45 surface expression determines relapse risk in children with precursor B-cell and T-cell acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol.

Further improvement of outcome in childhood acute lymphoblastic leukemia could be achieved by identifying additional high-risk patients who may benefit from intensified treatment. We earlier identified PTPRC (CD45) gene expression as a potential new stratification marker and now analyzed the prognostic relevance of CD45 protein expression. CD45 was measured by flow cytometry in 1065 patients treated according to the ALL-BFM-2000 protocol.

Effective childhood cancer treatment: the impact of large scale clinical trials in Germany and Austria.

In Germany and Austria, more than 90% of pediatric cancer patients are enrolled into nationwide disease-specific first-line clinical trials or interim registries. Essential components are a pediatric cancer registry and centralized reference laboratories, imaging review, and tumor board assistance. The five-year overall survival rate in countries where such infrastructures are established has improved from <20% before 1950 to >80% since 1995.

Optimizing asparaginase therapy for acute lymphoblastic leukemia.

Asparaginases are important agents used in the treatment of children with acute lymphoblastic leukemia (ALL). Three types of asparaginase are currently available: two are derived from Escherichia coli [native asparaginase and pegylated asparaginase (PEG-asparaginase)] and one from Erwinia chrysanthemi (crisantaspase). All three products share the same mechanism of action but have different pharmacokinetic properties, which do not make them easily interchangeable.

Very early/early relapses of acute lymphoblastic leukemia show unexpected changes of clonal markers and high heterogeneity in response to initial and relapse treatment.

Minimal residual disease (MRD) quantified after induction treatment of childhood acute lymphoblastic leukemia (ALL) predicts risk of relapse. It has been assumed that early relapses derive from a residual population of leukemic cells, which is still present after induction and that relapsed disease will consequently be more resistant to treatment. To test these hypotheses, we performed a prospective study on patients treated according to the frontline-trial ALL-BFM 2000, which used MRD response for risk-group stratification.

Presence of the P2RY8-CRLF2 rearrangement is associated with a poor prognosis in non-high-risk precursor B-cell acute lymphoblastic leukemia in children treated according to the ALL-BFM 2000 protocol.

High-level expression of the cytokine receptor-like factor 2 gene, CRLF2, in precursor B-cell acute lymphoblastic leukemia (pB-ALL) was shown to be caused by a translocation involving the IGH@ locus or a deletion juxtaposing CRLF2 with the P2RY8 promoter. To assess its possible prognostic value, CRLF2 expression was analyzed in 555 childhood pB-ALL patients treated according to the Acute Lymphoblastic Leukemia Berlin-Frankfurt-Münster 2000 (ALL-BFM 2000) protocol. Besides CRLF2 rearrangements, high-level CRLF2 expression was seen in cases with supernumerary copies of the CRLF2 locus.

Acute leukaemias of ambiguous lineage in children: characterization, prognosis and therapy recommendations.

Acute leukaemias of ambiguous lineage (ALAL) represent a rare type of leukaemia, expressing both myeloid and lymphoid markers. This study retrospectively analyzed data from 92 children (biphenotypic n = 78, bilineal n = 6, lineage switch n = 8) with ALAL registered in the Berlin-Frankfürt-Münster (BFM) acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) studies between 1998 and 2006 (2.4% of all cases with acute leukaemia).

Frequency and clinical relevance of DNA microsatellite alterations of the CDKN2A/B, ATM and p53 gene loci: a comparison between pediatric precursor T-cell lymphoblastic lymphoma and T-cell lymphoblastic leukemia.

Although deletions of cell cycle regulatory gene loci have long been reported in various malignancies, little is known regarding their relevance in pediatric T-cell lymphoblastic lymphoma (T-LBL) and T-cell lymphoblastic leukemia (TALL). The current study focused on loss of heterozygosity (LOH) analyses of the CDKN2A/B (chromosome 9p), ATM (chromosome 11q) and p53 (chromosome 17p) gene loci. Frequencies of LOH were compared in 113 pediatric T-LBL and 125 T-ALL who were treated uniformly according to ALL-BFM strategies.

Multifocal osteomyelitis caused by Candida dubliniensis.

Candida dubliniensis is an emerging fungal pathogen, especially in immunodeficient patients. We report what is to the best of our knowledge the first case of multifocal osteomyelitis following disseminated infection in a patient after haematopoietic stem cell transplantation. PFGE for typing of C.

Pediatric precursor T lymphoblastic leukemia and lymphoblastic lymphoma: Differences in the common regions with loss of heterozygosity at chromosome 6q and their prognostic impact.

Deletions on chromosome 6q are frequently reported in hematological malignancies. However, their biological or prognostic impact has not yet been clarified. This study analyzed loss of heterozygosity (LOH) at chromosome 6q and compared the LOH findings in pediatric precursor T lymphoblastic lymphoma (T-LBL) with the LOH findings in precursor-T lymphoblastic leukemia (T-ALL).

Gene expression shift towards normal B cells, decreased proliferative capacity and distinct surface receptors characterize leukemic blasts persisting during induction therapy in childhood acute lymphoblastic leukemia.

In childhood acute lymphoblastic leukemia (ALL), persistence of leukemic blasts during therapy is of crucial prognostic significance. In the present study, we address molecular and cell biologic features of blasts persisting after 1 week of induction glucocorticoid therapy. Genome-wide gene expression analysis of leukemic samples from precursor B-cell ALL patients (n=18) identified a set of genes differentially expressed in blasts at diagnosis day 0 (d0) and persisting on day 8 (d8).