35 results on '"Stary, J."'
Search Results
2. Long-term follow up of pediatric Philadelphia positive acute lymphoblastic leukemia treated with the EsPhALL2004 study: High white blood cell count at diagnosis is the strongest prognostic factor
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Biondi, A, Cario, G, De Lorenzo, P, Castor, A, Conter, V, Leoni, V, Gandemer, V, Pieters, R, Stary, J, Escherich, G, Campbell, M, Attarbaschi, A, Li, C, Vora, A, Bradtke, J, Saha, V, Valsecchi, M, Schrappe, M, Biondi, Andrea, Cario, Gunnar, De Lorenzo, Paola, Castor, Anders, Conter, Valentino, Leoni, Veronica, Gandemer, Virginie, Pieters, Rob, Stary, Jan, Escherich, Gabriele, Campbell, Myriam, Attarbaschi, Andishe, Li, Chi-Kong, Vora, Ajay, Bradtke, Jutta, Saha, Vaskar, Valsecchi, Maria Grazia, Schrappe, Martin, Biondi, A, Cario, G, De Lorenzo, P, Castor, A, Conter, V, Leoni, V, Gandemer, V, Pieters, R, Stary, J, Escherich, G, Campbell, M, Attarbaschi, A, Li, C, Vora, A, Bradtke, J, Saha, V, Valsecchi, M, Schrappe, M, Biondi, Andrea, Cario, Gunnar, De Lorenzo, Paola, Castor, Anders, Conter, Valentino, Leoni, Veronica, Gandemer, Virginie, Pieters, Rob, Stary, Jan, Escherich, Gabriele, Campbell, Myriam, Attarbaschi, Andishe, Li, Chi-Kong, Vora, Ajay, Bradtke, Jutta, Saha, Vaskar, Valsecchi, Maria Grazia, and Schrappe, Martin
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- 2019
3. Predictive value of minimal residual disease in philadelphia-chromosome-positive acute lymphoblastic leukemia treated with imatinib in the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia, based on immunoglobulin/T-cell receptor and BCR/ABL1 methodologies
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Cazzaniga, G, De Lorenzo, P, Alten, J, Röttgers, S, Hancock, J, Saha, V, Castor, A, Madsen, H, Gandemer, V, Cavé, H, Leoni, V, Köhler, R, Ferrari, G, Bleckmann, K, Pieters, R, Van Der Velden, V, Stary, J, Zuna, J, Escherich, G, Stadt, U, Aricò, M, Conter, V, Schrappe, M, Valsecchi, M, Biondi, A, Röttgers, Si, Madsen, HO, Ferrari, GM, Stadt, UZ, Conter, Valentino, Valsecchi, MG, Cazzaniga, G, De Lorenzo, P, Alten, J, Röttgers, S, Hancock, J, Saha, V, Castor, A, Madsen, H, Gandemer, V, Cavé, H, Leoni, V, Köhler, R, Ferrari, G, Bleckmann, K, Pieters, R, Van Der Velden, V, Stary, J, Zuna, J, Escherich, G, Stadt, U, Aricò, M, Conter, V, Schrappe, M, Valsecchi, M, Biondi, A, Röttgers, Si, Madsen, HO, Ferrari, GM, Stadt, UZ, Conter, Valentino, and Valsecchi, MG
- Abstract
The prognostic value of minimal residual disease (MRD) in Philadelphia-chromosome-positive (Ph+) childhood acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors is not fully established. We detected MRD by real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes (IG/TR) and/or BCR/ABL1 fusion transcript to investigate its predictive value in patients receiving Berlin-Frankfurt-MÃ1⁄4nster (BFM) high-risk (HR) therapy and post-induction intermittent imatinib (the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia (EsPhALL) study). MRD was monitored after induction (time point (TP)1), consolidation Phase IB (TP2), HR Blocks, reinductions, and at the end of therapy. MRD negativity progressively increased over time, both by IG/TR and BCR/ABL1. Of 90 patients with IG/TR MRD at TP1, nine were negative and none relapsed, while 11 with MRD<5Ã10â4and 70 with MRDâ¥5Ã10â4had a comparable 5-year cumulative incidence of relapse of 36.4 (15.4) and 35.2 (5.9), respectively. Patients who achieved MRD negativity at TP2 had a low relapse risk (5-yr cumulative incidence of relapse (CIR)=14.3[9.8]), whereas those who attained MRD negativity at a later date showed higher CIR, comparable to patients with positive MRD at any level. BCR/ABL1 MRD negative patients at TP1 had a relapse risk similar to those who were IG/TR MRD negative (1/8 relapses). The overall concordance between the two methods is 69%, with significantly higher positivity by BCR/ABL1. In conclusion, MRD monitoring by both methods may be functional not only for measuring response but also for guiding biological studies aimed at investigating causes for discrepancies, although from our data IG/TR MRD monitoring appears to be more reliable. Early MRD negativity is highly predictive of favorable outcome. The earlier MRD negativity is achieved, the better the prognosis.
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- 2018
4. Loss of B cells and their precursors is the most constant feature of GATA-2 deficiency in childhood myelodysplastic syndrome
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Novakova, M, Zaliova, M, Sukova, M, Wlodarski, M, Janda, A, Fronkova, E, Campr, V, Lejhancova, K, Zapletal, O, Pospisilova, D, Cerna, Z, Kuhn, T, Svec, P, Pelkova, V, Zemanova, Z, Kerndrup, G, Van den Heuvel - Eibrink, Marry, van der Velden, Vincent, Niemeyer, C, Kalina, T, Trka, J, Stary, J, Hrusak, O, Mejstrikova, E, and Immunology
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B-Lymphocytes ,Adolescent ,Precursor Cells, B-Lymphoid ,Anemia, Aplastic ,Infant ,Bone Marrow Cells ,Article ,Immunophenotyping ,Diagnosis, Differential ,GATA2 Transcription Factor ,Young Adult ,Phenotype ,ROC Curve ,Bone Marrow ,T-Lymphocyte Subsets ,hemic and lymphatic diseases ,Child, Preschool ,Lymphopenia ,Myelodysplastic Syndromes ,Mutation ,Humans ,Myeloid Cells ,Lymphocyte Count ,Child ,Biomarkers - Abstract
GATA-2 deficiency was recently described as common cause of overlapping syndromes of immunodeficiency, lymphedema, familiar myelodysplastic syndrome or acute myeloid leukemia. The aim of our study was to analyze bone marrow and peripheral blood samples of children with myelodysplastic syndrome or aplastic anemia to define prevalence of the GATA2 mutation and to assess whether mutations in GATA-2 transcription factor exhibit specific immunophenotypic features. The prevalence of a GATA2 mutation in a consecutively diagnosed cohort of children was 14% in advanced forms of myelodysplastic syndrome (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and myelodysplasia-related acute myeloid leukemia), 17% in refractory cytopenia of childhood, and 0% in aplastic anemia. In GATA-2-deficient cases, we found the most profound B-cell lymphopenia, including its progenitors in blood and bone marrow, which correlated with significantly diminished intronRSS-Kde recombination excision circles in comparison to other myelodysplastic syndrome/aplastic anemia cases. The other typical features of GATA-2 deficiency (monocytopenia and natural killer cell lymphopenia) were less discriminative. In conclusion, we suggest screening for GATA2 mutations in pediatric myelodysplastic syndrome, preferentially in patients with impaired B-cell homeostasis in bone marrow and peripheral blood (low number of progenitors, intronRSS-Kde recombination excision circles and naïve cells).
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- 2016
5. Characterization of leukemias with ETV6-ABL1 fusion
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Zaliova, M, Moorman, A, Cazzaniga, G, Stanulla, M, Harvey, R, Roberts, K, Heatley, S, Loh, M, Konopleva, M, Chen, I, Zimmermannova, O, Schwab, C, Smith, O, Mozziconacci, M, Chabannon, C, Kim, M, Frederik Falkenburg, J, Norton, A, Marshall, K, Haas, O, Starkova, J, Stuchly, J, Hunger, S, White, D, Mullighan, C, Willman, C, Stary, J, Trka, J, Zuna, J, Moorman, AV, Harvey, RC, Roberts, KG, Heatley, SL, Loh, ML, Chen, IM, Mozziconacci, MJ, Frederik Falkenburg, JH, Haas, OA, Hunger, SP, Mullighan, CG, Willman, CL, Zaliova, M, Moorman, A, Cazzaniga, G, Stanulla, M, Harvey, R, Roberts, K, Heatley, S, Loh, M, Konopleva, M, Chen, I, Zimmermannova, O, Schwab, C, Smith, O, Mozziconacci, M, Chabannon, C, Kim, M, Frederik Falkenburg, J, Norton, A, Marshall, K, Haas, O, Starkova, J, Stuchly, J, Hunger, S, White, D, Mullighan, C, Willman, C, Stary, J, Trka, J, Zuna, J, Moorman, AV, Harvey, RC, Roberts, KG, Heatley, SL, Loh, ML, Chen, IM, Mozziconacci, MJ, Frederik Falkenburg, JH, Haas, OA, Hunger, SP, Mullighan, CG, and Willman, CL
- Abstract
To characterize the incidence, clinical features and genetics of ETV6-ABL1 leukemias, representing targetable kinase-activating lesions, we analyzed 44 new and published cases of ETV6-ABL1-positive hematologic malignancies [22 cases of acute lymphoblastic leukemia (13 children, 9 adults) and 22 myeloid malignancies (18 myeloproliferative neoplasms, 4 acute myeloid leukemias)]. The presence of the ETV6-ABL1 fusion was ascertained by cytogenetics, fluorescence in-situ hybridization, reverse transcriptase-polymerase chain reaction and RNA sequencing. Genomic and gene expression profiling was performed by single nucleotide polymorphism and expression arrays. Systematic screening of more than 4,500 cases revealed that in acute lymphoblastic leukemia ETV6-ABL1 is rare in childhood (0.17% cases) and slightly more common in adults (0.38%). There is no systematic screening of myeloproliferative neoplasms; however, the number of ETV6-ABL1-positive cases and the relative incidence of acute lymphoblastic leukemia and myeloproliferative neoplasms suggest that in adulthood ETV6-ABL1 is more common in BCR-ABL1-negative chronic myeloid leukemia-like myeloproliferations than in acute lymphoblastic leukemia. The genomic profile of ETV6-ABL1 acute lymphoblastic leukemia resembled that of BCR-ABL1 and BCR-ABL1- like cases with 80% of patients having concurrent CDKN2A/B and IKZF1 deletions. In the gene expression profiling all the ETV6-ABL1-positive samples clustered in close vicinity to BCR-ABL1 cases. All but one of the cases of ETV6- ABL1 acute lymphoblastic leukemia were classified as BCR-ABL1-like by a standardized assay. Over 60% of patients died, irrespectively of the disease or age subgroup examined. In conclusion, ETV6-ABL1 fusion occurs in both lymphoid and myeloid leukemias; the genomic profile and clinical behavior resemble BCR-ABL1-positive malignancies, including the unfavorable prognosis, particularly of acute leukemias. The poor outcome suggests that treatment with tyros
- Published
- 2016
6. Predictive value of minimal residual disease in Philadelphia-chromosome-positive acute lymphoblastic leukemia treated with imatinib in the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia, based on immunoglobulin/T-cell receptor and BCR/ABL1 methodologies
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Virginie Gandemer, Kirsten Bleckmann, Giovanni Cazzaniga, Anders Castor, Martin Schrappe, Rob Pieters, Andrea Biondi, Maria Grazia Valsecchi, Giulia Maria Ferrari, Valentino Conter, Hélène Cavé, Maurizio Aricò, Hans O. Madsen, Jan Stary, Silja Röttgers, Veronica Leoni, Vincent H.J. van der Velden, Rolf Köhler, Udo zur Stadt, Jan Zuna, Paola De Lorenzo, Vaskar Saha, Gabriele Escherich, Jeremy Hancock, Julia Alten, Cazzaniga, G, De Lorenzo, P, Alten, J, Röttgers, S, Hancock, J, Saha, V, Castor, A, Madsen, H, Gandemer, V, Cavé, H, Leoni, V, Köhler, R, Ferrari, G, Bleckmann, K, Pieters, R, Van Der Velden, V, Stary, J, Zuna, J, Escherich, G, Stadt, U, Aricò, M, Conter, V, Schrappe, M, Valsecchi, M, Biondi, A, and Immunology
- Subjects
Oncology ,medicine.medical_specialty ,Neoplasm, Residual ,Receptors, Antigen, T-Cell ,Immunoglobulins ,Article ,Chromosomes ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Cumulative incidence ,Childhood Acute Lymphoblastic Leukemia ,Survival analysis ,Philadelphia ,Hematology ,ABL ,Manchester Cancer Research Centre ,business.industry ,ResearchInstitutes_Networks_Beacons/mcrc ,breakpoint cluster region ,Imatinib ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Acute Lymphoblastic Leukemia ,Minimal residual disease ,body regions ,030220 oncology & carcinogenesis ,Immunology ,Imatinib Mesylate ,business ,030215 immunology ,medicine.drug - Abstract
The prognostic value of minimal residual disease (MRD) in Philadelphia-chromosome-positive (Ph+) childhood acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors is not fully established. We detected MRD by real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes (IG/TR) and/or BCR/ABL1 fusion transcript to investigate its predictive value in patients receiving Berlin-Frankfurt-Münster (BFM) high-risk (HR) therapy and post-induction intermittent imatinib (the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia (EsPhALL) study). MRD was monitored after induction (time point (TP)1), consolidation Phase IB (TP2), HR Blocks, reinductions, and at the end of therapy. MRD negativity progressively increased over time, both by IG/TR and BCR/ABL1. Of 90 patients with IG/TR MRD at TP1, nine were negative and none relapsed, while 11 with MRD
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- 2018
7. 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
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Arend von Stackelberg, Rosanna Parasole, Martin Zimmermann, Jan Stary, Maria Grazia Valsecchi, Valentino Conter, Luciana Vinti, Anja Moericke, Cristina Matteo, Elena Barisone, Andishe Attarbaschi, David C. Kasper, Daniela Silvestri, Sabine Legien, Andrea Ballerini, Martin Schrappe, Joachim Gerss, Antonella Colombini, Carmelo Rizzari, Bettina Reismüller, Christin Linderkamp, Concetta Micalizzi, Joachim Boos, Gudrun Wuerthwein, Massimo Zucchetti, Andrea Biondi, Petr Smisek, Michael C. Frühwald, Claudia Lanvers-Kaminsky, Rizzari, C, Lanvers-Kaminsky, C, Valsecchi, M, Ballerini, A, Matteo, C, Gerss, J, Wuerthwein, G, Silvestri, D, Colombini, A, Conter, V, Biondi, A, Schrappe, M, Moericke, A, Zimmermann, M, Von Stackelberg, A, Linderkamp, C, Frühwald, M, Legien, S, Attarbaschi, A, Reismüller, B, Kasper, D, Smisek, P, Stary, J, Vinti, L, Barisone, E, Parasole, R, Micalizzi, C, Zucchetti, M, and Boos, J
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Male ,Study phase ,Asparaginase ,medicine.medical_specialty ,Adolescent ,Lymphoblastic Leukemia ,Pharmacokinetic ,Induction Phase ,Article ,Polyethylene Glycols ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cerebrospinal fluid ,Pharmacokinetics ,Internal medicine ,Germany ,Medicine ,Humans ,Pediatric Acute Lymphoblastic Leukemia ,ddc:610 ,Asparagine ,Child ,Czech Republic ,Pharmacology ,business.industry ,Infant ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Acute Lymphoblastic Leukemia ,Endocrinology ,chemistry ,Italy ,Austria ,Child, Preschool ,Female ,Drug Monitoring ,business ,Pegylated asparaginase ,030215 immunology - Abstract
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/m2 on days 12 and 26. Serum and cerebrospinal fluid samples obtained on days 33 and 45 were analyzed centrally. Since physiological levels of asparagine in the cerebrospinal fluid of children and adolescents are 4-10 μmol/L, in this study asparagine depletion was considered complete when the concentration of asparagine was ≤0.2 μmol/L, i.e. below the lower limit of quantification of the assay used. Over 24 months 736 patients (AIEOP n=245, BFM n=491) and 903 cerebrospinal fluid samples (n=686 on day 33 and n=217 on day 45) were available for analysis. Data were analyzed separately for the AIEOP and BFM cohorts and yielded superimposable results. Independently of serum asparaginase activity levels, cerebrospinal fluid asparagine levels were significantly reduced during the investigated study phase but only 28% of analyzed samples showed complete asparagine depletion while relevant levels, ≥1 μmol/L, were still detectable in around 23% of them. Complete cerebrospinal fluid asparagine depletion was found in around 5-6% and 33-37% of samples at serum asparaginase activity levels
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- 2019
8. Characterization of leukemias with ETV6-ABL1 fusion
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Kathryn G. Roberts, Marina Konopleva, Jan Stuchly, Anthony V. Moorman, Marie-Joelle Mozziconacci, Jan Stary, Jan Zuna, Stephen P. Hunger, Charles G. Mullighan, Cheryl L. Willman, J.H. Frederik Falkenburg, Owen P. Smith, Giovanni Cazzaniga, Julia Starkova, I-Ming Chen, Deborah L. White, Claire Schwab, Susan L. Heatley, Myungshin Kim, Alice Norton, Oskar A. Haas, Mignon L. Loh, Martin Stanulla, Olga Zimmermannova, Marketa Zaliova, Richard C. Harvey, Jan Trka, Karen E. Marshall, Christian Chabannon, Zaliova, M, Moorman, A, Cazzaniga, G, Stanulla, M, Harvey, R, Roberts, K, Heatley, S, Loh, M, Konopleva, M, Chen, I, Zimmermannova, O, Schwab, C, Smith, O, Mozziconacci, M, Chabannon, C, Kim, M, Frederik Falkenburg, J, Norton, A, Marshall, K, Haas, O, Starkova, J, Stuchly, J, Hunger, S, White, D, Mullighan, C, Willman, C, Stary, J, Trka, J, and Zuna, J
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Adult ,Male ,Myeloid ,DNA Copy Number Variations ,Adolescent ,Oncogene Proteins, Fusion ,MED/03 - GENETICA MEDICA ,Immunology ,Biology ,Bioinformatics ,Biochemistry ,Polymorphism, Single Nucleotide ,Translocation, Genetic ,Fusion gene ,Young Adult ,CDKN2A ,hemic and lymphatic diseases ,Protein-Tyrosine Kinase ,medicine ,Cluster Analysis ,Humans ,Child ,Myeloproliferative neoplasm ,In Situ Hybridization, Fluorescence ,Aged ,DNA Copy Number Variation ,ABL ,Cluster Analysi ,Leukemia ,Gene Expression Profiling ,Myeloid leukemia ,Infant ,Articles ,Cell Biology ,Hematology ,Protein-Tyrosine Kinases ,Middle Aged ,medicine.disease ,ETV6 ,Alternative Splicing ,medicine.anatomical_structure ,Phenotype ,Fusion transcript ,Child, Preschool ,Cancer research ,Female ,Transcriptome ,Human - Abstract
Introduction The ETV6-ABL1 (TEL-ABL) fusion gene is a rare but recurrent genetic aberration found in various hematological malignancies in children and adults. Due to the inverse orientation of ETV6 (12p13) and ABL1 (9q34) an in-frame fusion cannot be produced by a simple balanced translocation and thus results from a complex rearrangement. Alternative splicing generates two fusion transcripts - type A and B without and with ETV6 exon 5, respectively. Both transcripts encode a constitutively active chimeric tyrosine kinase. The effect of ETV6-ABL1 on cellular proliferation, cell survival and transforming capacity mirrors that seen in BCR-ABL1-positive cases. There is a renewed interest in ETV6-ABL1 since the discovery of a "BCR-ABL1-like" (or "Ph-like") gene expression profile (GEP) among B-cell precursor (BCP) ALL cases lacking an established chromosomal abnormality (so-called "B-other ALL"). The BCR-ABL1-like GEP resembles the BCR-ABL1 GEP because both are driven by the activation of kinase signaling. In vitro studies suggest that many of these kinase fusions, including ETV6-ABL1, are sensitive to specific tyrosine kinase inhibitors (TKI), thus representing a promising and relevant therapeutic target, especially given the reported unfavorable prognosis of BCR-ABL1-like ALL. The aim of this study was to characterize the incidence, clinical features and genetic profile of ETV6-ABL1 leukemias with a focus on ALL as an example of a targetable kinase-activating lesion. Patients and methods The cohort totals 44 ETV6-ABL1 patients and comprises newly identified cases (n=9), published cases with additional new data (n=11) and cases with re-examined published data (n=24). Half of the patients (n=22) was diagnosed with ALL (13 children, 9 adults) while 22 had a myeloid malignancy (18 CML-like myeloproliferative neoplasm (MPN), 4 AML). Besides routine diagnostic examinations, we analyzed the presence of fusion transcript variants, genomic profile using MLPA and SNP-array, gene expression profile on microarrays and the presence of BCR-ABL1-like expression signature using quantitative PCR-based low density expression arrays. Results Systematic screening of >3500 cases revealed that ETV6-ABL1 is rare in childhood ALL (0.17% cases) and slightly more prevalent in adult ALL (0.38%). The equal number of MPN and ALL cases and the relative incidence of ALL and MPN in adulthood suggests ETV6-ABL1 is more common in MPN. The type B variant (including ETV6 exon 5) is the dominant transcript and its detection by PCR screening is a more reliable diagnostic approach than FISH with commercial probes for ETV6-RUNX1 and BCR-ABL1. In BCP ALL, ETV6-ABL1 fusion always localized to the der(12) whereas in T-ALL and myeloid cases the fusion localized to the der(9), der(12) or a third chromosome. The genomic profile of ETV6-ABL1 ALL resembled BCR-ABL1 and BCR-ABL1-like ALL with 80% cases having concurrent CDKN2A/B and IKZF1 deletions. The gene expression signature of ETV6-ABL1 ALL cases was more similar to BCR-ABL1 than BCR-ABL1-like principally due to low CRLF2 expression. Nonetheless, 11/12 ETV6-ABL1 ALL cases were classified as BCR-ABL1-like by a standardized qPCR-based expression array. Survival of ETV6-ABL1-positive ALL is 46% in children (6/13 alive) and 13% in adults (1/8 alive). While prognosis of childhood ALL patients responding well to initial treatment seems to be favorable (3/3 with end-induction MRD < 5x10e-5 are in the 1st remission >4 years from diagnosis), children with inferior response have very poor prognosis. Survival of MPN is 50% (9/18 alive) and depends on the disease status at diagnosis (chronic vs. blastic phase). Conclusion ETV6-ABL1 fusion occurs in lymphoid and myeloid leukemia. Its genomic and expression profile, spectrum of malignancies and clinical behavior resemble BCR-ABL1, including the unfavorable prognosis, particularly in acute leukemias. Systematic screening confirmed low frequency of ETV6-ABL1 fusion in ALL. Due to high false-negative rate of FISH, PCR diagnostics are recommended for systematic screening of ALL and FISH-negative CML-like MPN. Despite the generally poor outcome, childhood ALL cases with favorable early treatment response can be treated with standard modern therapeutic protocols. To improve prognosis of the others, early diagnostics of ETV6-ABL1 and treatment with TKI should be considered. Supported by grants IGA MZ NT/13170-4 and GAUK 694414. Disclosures Mullighan: Amgen: Honoraria; Incyte: Consultancy.
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- 2016
9. No clear benefit of preventive cranial radiotherapy in childhood Philadelphia-positive acute lymphoblastic leukemia: a retrospective analysis of the EsPhALL2010 study.
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Conter V, Valsecchi MG, De Lorenzo P, Gandemer V, Heyman M, Saha V, Diaz P, Li CK, Attarbaschi A, Escherich G, Stary J, Schrappe M, Pieters R, Cario G, and Biondi A
- Abstract
Not available.
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- 2024
- Full Text
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10. Spontaneous remission and loss of monosomy 7: a window of opportunity for young children with SAMD9L syndrome.
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Erlacher M, Andresen F, Sukova M, Stary J, De Moerloose B, Bosch JVWT, Dworzak M, Seidel MG, Polychronopoulou S, Beier R, Kratz CP, Nathrath M, Frühwald MC, Göhring G, Bergmann AK, Mayerhofer C, Lebrecht D, Ramamoorthy S, Yoshimi A, Strahm B, Wlodarski MW, and Niemeyer CM
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- Humans, Child, Child, Preschool, Infant, Remission, Spontaneous, Disease Progression, Transcription Factors genetics, Monosomy, Chromosomes, Human, Pair 7 genetics, Intracellular Signaling Peptides and Proteins genetics, Chromosome Deletion, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes therapy
- Abstract
Monosomy 7 is the most common cytogenetic abnormality in pediatric myelodysplastic syndrome (MDS) and associated with a high risk of disease progression. However, in young children, spontaneous loss of monosomy 7 with concomitant hematologic recovery has been described, especially in the presence of germline mutations in SAMD9 and SAMD9L genes. Here, we report on our experience of close surveillance instead of upfront hematopoietic stem cell transplantation (HSCT) in seven patients diagnosed with SAMD9L syndrome and monosomy 7 at a median age of 0.6 years (range, 0.4-2.9). Within 14 months from diagnosis, three children experienced spontaneous hematological remission accompanied by a decrease in monosomy 7 clone size. Subclones with somatic SAMD9L mutations in cis were identified in five patients, three of whom attained hematological remission. Two patients acquired RUNX1 and EZH2 mutations during the observation period, of whom one progressed to myelodysplastic syndrome with excess of blasts (MDS-EB). Four patients underwent allogeneic HSCT at a median time of 26 months (range, 14-40) from diagnosis for MDSEB, necrotizing granulomatous lymphadenitis, persistent monosomy 7, and severe neutropenia. At last follow-up, six patients were alive, while one passed away due to transplant-related causes. These data confirm previous observations that monosomy 7 can be transient in young children with SAMD9L syndrome. However, they also indicate that delaying HSCT poses a substantial risk of severe infection and disease progression. Finally, surveillance of patients with SAMD9L syndrome and monosomy 7 is critical to define the evolving genetic landscape and to determine the appropriate timing of HSCT (clinicaltrials gov. Identifier: NCT00662090).
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- 2024
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11. Effect of two additional doses of intrathecal methotrexate during induction therapy on serious infectious toxicity in pediatric patients with acute lymphoblastic leukemia.
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Heilmann J, Vieth S, Möricke A, Attarbaschi A, Barbaric D, Bodmer N, Colombini A, Dalla-Pozza L, Elitzur S, Izraeli S, Mann G, Niggli F, Silvestri D, Stary J, Rizzari C, Valsecchi MG, Zapotocka E, Zimmermann M, Cario G, Schrappe M, and Conter V
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- Child, Humans, Induction Chemotherapy adverse effects, Combined Modality Therapy, Antineoplastic Combined Chemotherapy Protocols adverse effects, Methotrexate therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma complications, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Although initial central nervous system (CNS) involvement is rarely detected in childhood acute lymphoblastic leukemia (ALL), risk-adapted CNS-directed therapy is essential for all patients. Treatment intensity depends on the initial CNS status. In the AIEOP-BFM ALL 2009 trial, patients with cytomorphologic detection of leukemic blasts in initial cerebrospinal fluid were classified as CNS2 or CNS3 and received five intrathecal doses of methotrexate (MTX) in induction therapy compared to patients with CNS1 status (no blasts detected) who received three doses. The impact of additional intrathecal (IT) MTX on systemic toxicity in induction therapy is unknown. Between June 1st 2010 and February 28th 2017, a total of 6,136 ALL patients aged 1-17 years were enrolled onto the AIEOP-BFM ALL 2009 trial. The effect of three versus five doses of IT MTX during induction therapy on the incidence of severe infectious complications was analyzed. Among 4,706 patients treated with three IT MTX doses, 77 (1.6%) had a life-threatening infection during induction as compared to 59 of 1,350 (4.4%) patients treated with five doses (P<0.001; Odds Ratio 2.86 [95% Confidence Interval 1.99-4.13]). In a multivariate regression model, treatment with additional IT MTX proved to be the strongest risk factor for life-threatening infections (Odds Ratio 2.85 [1.96-4.14]). Fatal infections occurred in 16 (0.3%) and 38 (1.6%) patients treated with three or five IT MTX doses, respectively (P<0.001). As the relevance of additional intrathecal MTX in induction for relapse prevention in CNS2 patients is unclear, doses of intrathecal therapy have been reduced for these patients. (Clinicaltrials.gov identifiers: NCT01117441 and NCT00613457).
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- 2023
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12. DUX4r, ZNF384r and PAX5-P80R mutated B-cell precursor acute lymphoblastic leukemia frequently undergo monocytic switch.
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Novakova M, Zaliova M, Fiser K, Vakrmanova B, Slamova L, Musilova A, Brüggemann M, Ritgen M, Fronkova E, Kalina T, Stary J, Winkowska L, Svec P, Kolenova A, Stuchly J, Zuna J, Trka J, Hrusak O, and Mejstrikova E
- Subjects
- B-Lymphocytes, Humans, Immunophenotyping, Mutation, Neoplasm, Residual, PAX5 Transcription Factor genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Abstract
Recently, we described B-cell precursor acute lymphoblastic leukemia (BCP-ALL) subtype with early switch to the monocytic lineage and loss of the B-cell immunophenotype, including CD19 expression. Thus far, the genetic background has remained unknown. Among 726 children consecutively diagnosed with BCP-ALL, 8% patients experienced switch detectable by flow cytometry (FC). Using exome and RNA sequencing, switch was found to positively correlate with three different genetic subtypes: PAX5-P80R mutation (5 cases with switch out of 5), rearranged DUX4 (DUX4r; 30 cases of 41) and rearranged ZNF384 (ZNF384r; 4 cases of 10). Expression profiles or phenotypic patterns correlated with genotypes, but within each genotype they could not identify cases who subsequently switched. If switching was not taken into account, the B-cell-oriented FC assessment underestimated the minimal residual disease level. For patients with PAX5-P80R, a discordance between FC-determined and PCR-determined MRD was found on day 15, resulting from a rapid loss of the B-cell phenotype. Discordance on day 33 was observed in all the DUX4r, PAX5-P80R and ZNF384r subtypes. Importantly, despite the substantial phenotypic changes, possibly even challenging the appropriateness of BCP-ALL therapy, the monocytic switch was not associated with a higher incidence of relapse and poorer prognosis in patients undergoing standard ALL treatment.
- Published
- 2021
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13. Frequency and prognostic impact of ZEB2 H1038 and Q1072 mutations in childhood B-other acute lymphoblastic leukemia.
- Author
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Zaliova M, Potuckova E, Lukes J, Winkowska L, Starkova J, Janotova I, Sramkova L, Stary J, Zuna J, Stanulla M, Zimmermann M, Bornhauser B, Bourquin JP, Eckert C, Cario G, and Trka J
- Subjects
- Humans, Mutation, Prognosis, Zinc Finger E-box Binding Homeobox 2, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma epidemiology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma epidemiology, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Published
- 2021
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14. The clinical and biological characteristics of NUP98-KDM5A in pediatric acute myeloid leukemia.
- Author
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Noort S, Wander P, Alonzo TA, Smith J, Ries RE, Gerbing RB, Dolman MEM, Locatelli F, Reinhardt D, Baruchel A, Stary J, Molenaar JJ, Stam RW, van den Heuvel-Eibrink MM, Zwaan MC, and Meshinchi S
- Subjects
- Child, Homeodomain Proteins genetics, Humans, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, Retinoblastoma-Binding Protein 2, Translocation, Genetic, Leukemia, Myeloid, Acute genetics, Nuclear Pore Complex Proteins genetics
- Published
- 2021
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15. 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.
- Author
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Rizzari C, Lanvers-Kaminsky C, Valsecchi MG, Ballerini A, Matteo C, Gerss J, Wuerthwein G, Silvestri D, Colombini A, Conter V, Biondi A, Schrappe M, Moericke A, Zimmermann M, von Stackelberg A, Linderkamp C, Frühwald MC, Legien S, Attarbaschi A, Reismüller B, Kasper D, Smisek P, Stary J, Vinti L, Barisone E, Parasole R, Micalizzi C, Zucchetti M, and Boos J
- Subjects
- Adolescent, Austria, Child, Child, Preschool, Czech Republic, Drug Monitoring, Female, Germany, Humans, Infant, Italy, Male, Asparaginase therapeutic use, Asparagine cerebrospinal fluid, Polyethylene Glycols therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma cerebrospinal fluid, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
- Abstract
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
2 on days 12 and 26. Serum and cerebrospinal fluid samples obtained on days 33 and 45 were analyzed centrally. Since physiological levels of asparagine in the cerebrospinal fluid of children and adolescents are 4-10 μmol/L, in this study asparagine depletion was considered complete when the concentration of asparagine was ≤0.2 μmol/L, i.e. below the lower limit of quantification of the assay used. Over 24 months 736 patients (AIEOP n=245, BFM n=491) and 903 cerebrospinal fluid samples (n=686 on day 33 and n=217 on day 45) were available for analysis. Data were analyzed separately for the AIEOP and BFM cohorts and yielded superimposable results. Independently of serum asparaginase activity levels, cerebrospinal fluid asparagine levels were significantly reduced during the investigated study phase but only 28% of analyzed samples showed complete asparagine depletion while relevant levels, ≥1 μmol/L, were still detectable in around 23% of them. Complete cerebrospinal fluid asparagine depletion was found in around 5-6% and 33-37% of samples at serum asparaginase activity levels <100 and ≥ 1,500 IU/L, respectively. In this study cerebrospinal fluid asparagine levels were reduced during pegylated-asparaginase treatment, but complete depletion was only observed in a minority of patients. No clear threshold of serum pegylated-asparaginase activity level resulting in complete cerebrospinal fluid asparagine depletion was identified. The consistency of the results found in the two independent data sets strengthen the observations of this study. Details of the treatment are available in the European Clinical Trials Database at https://www.clin-icaltrialsregister.eu/ctr-search/trial/2007-004270-43/IT ., (Copyright© 2019 Ferrata Storti Foundation.)- Published
- 2019
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16. ERG deletions in childhood acute lymphoblastic leukemia with DUX4 rearrangements are mostly polyclonal, prognostically relevant and their detection rate strongly depends on screening method sensitivity.
- Author
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Zaliova M, Potuckova E, Hovorkova L, Musilova A, Winkowska L, Fiser K, Stuchly J, Mejstrikova E, Starkova J, Zuna J, Stary J, and Trka J
- Subjects
- Adolescent, Child, Child, Preschool, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Humans, Infant, Male, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma classification, Prognosis, Retrospective Studies, Survival Rate, Transcriptional Regulator ERG genetics, Biomarkers, Tumor genetics, Gene Deletion, Gene Rearrangement, Homeodomain Proteins genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
ERG -deletions occur recurrently in acute lymphoblastic leukemia, especially in the DUX4 -rearranged subtype. The ERG -deletion was shown to positively impact prognosis of patients with IKZF1 -deletion and its presence precludes assignment into IKZF1
plus group, a novel high-risk category on AIEOP-BFM ALL trials. We analyzed the impact of different methods on ERG -deletion detection rate, evaluated ERG -deletion as a potential marker for DUX4 -rearranged leukemia, studied its associations with molecular and clinical characteristics within this leukemia subtype, and analyzed its clonality. Using single-nucleotide-polymorphism array, genomic polymerase chain reaction (PCR) and amplicon-sequencing we found ERG -deletion in 34% (16 of 47), 66% (33 of 50) and 78% (39 of 50) of DUX4 -rearranged leukemia, respectively. False negativity of ERG -deletion by single-nucleotide-polymorphism array caused IKZF1plus misclassification in 5 patients. No ERG -deletion was found outside the DUX4 -rearranged cases. Within DUX4 -rearranged leukemia, the ERG -deletion was associated with higher total number of copy-number aberrations, and, importantly, the ERG -deletion positivity by PCR was associated with better outcome [5-year event-free survival (EFS), ERG -deletion-positive 93% vs. ERG -deletion-negative 68%, P =0.022; 5-year overall survival (OS), ERG -deletion-positive 97% vs. ERG -deletion-negative 75%, P =0.029]. Ultra-deep amplicon-sequencing revealed distinct co-existing ERG -deletions in 22 of 24 patients. In conclusion, our data demonstrate inadequate sensitivity of single-nucleotide-polymorphism array for ERG -deletion detection, unacceptable for proper IKZF1plus classification. Even using more sensitive methods (PCR/amplicon-sequencing) for its detection, ERG -deletion is absent in 22-34% of DUX4 -rearranged leukemia and does not represent an adequately sensitive marker of this leukemia subtype. Importantly, the ERG -deletion potentially stratifies the DUX4 -rearranged leukemia into biologically/clinically distinct subsets. Frequent polyclonal pattern of ERG -deletions shows that late origin of this lesion is more common than has been previously described., (Copyright© 2019 Ferrata Storti Foundation.)- Published
- 2019
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17. Genomic landscape of pediatric B-other acute lymphoblastic leukemia in a consecutive European cohort.
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Zaliova M, Stuchly J, Winkowska L, Musilova A, Fiser K, Slamova M, Starkova J, Vaskova M, Hrusak O, Sramkova L, Stary J, Zuna J, and Trka J
- Subjects
- Adolescent, Child, Child, Preschool, Cohort Studies, Europe, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Humans, Infant, Male, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma epidemiology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Prognosis, Biomarkers, Tumor genetics, Chromosome Aberrations, Genomics methods, Mutation, Oncogene Proteins, Fusion genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Transcriptome
- Abstract
Novel biological subtypes and clinically important genetic aberrations (druggable lesions, prognostic factors) have been described in B-other acute lymphoblastic leukemia (ALL) during the last decade; however, due to a lack of studies on unselected cohorts, their population frequency and mutual associations still have to be established. We studied 110 consecutively diagnosed and uniformly treated childhood B-other patients using single nucleotide polymorphism arrays and whole exome/transcriptome sequencing. The frequency of DUX4 -rearranged, BCR-ABL1 -like, ZNF384 -rearranged, ETV6-RUNX1 -like, iAMP21 and MEF2D -rearranged subtypes was 27%, 15%, 5%, 5%, 4%, and 2%, respectively; 43% of cases were not classified into any of these subtypes (B-rest). We found worse early response to treatment in DUX4 -rearranged leukemia and a strong association of ZNF384 -rearranged leukemia with B-myeloid immunophenotype. Of the druggable lesions, JAK/STAT-class and RAS/RAF/MAPK-class aberrations were found in 21% and 43% of patients, respectively; an ABL-class aberration was found in one patient. A recently described negative prognostic factor, IKZF1
plus , was found in 14% of patients and was enriched in (but not exclusive for) BCR-ABL1 -like subtype. PAX5 fusions (including 4 novel), intragenic amplifications and P80R mutations were mutually exclusive and only occurred in the B-rest subset, altogether accounting for 20% of the B-other group. PAX5 P80R was associated with a specific gene expression signature, potentially defining a novel leukemia subtype. Our study shows unbiased European population-based frequencies of novel ALL subtypes, recurrent (cyto)genetic aberrations and their mutual associations. This study also strengthens and widens the current knowledge of B-other ALL and provides an objective basis for optimization of current genetic diagnostics., (Copyright© 2019 Ferrata Storti Foundation.)- Published
- 2019
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18. Long-term follow up of pediatric Philadelphia positive acute lymphoblastic leukemia treated with the EsPhALL2004 study: high white blood cell count at diagnosis is the strongest prognostic factor.
- Author
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Biondi A, Cario G, De Lorenzo P, Castor A, Conter V, Leoni V, Gandemer V, Pieters R, Stary J, Escherich G, Campbell M, Attarbaschi A, Li CK, Vora A, Bradtke J, Saha V, Valsecchi MG, and Schrappe M
- Subjects
- Adolescent, Child, Child, Preschool, Disease-Free Survival, Female, Follow-Up Studies, Humans, Infant, Leukocyte Count, Male, Survival Rate, Imatinib Mesylate administration & dosage, Philadelphia Chromosome, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality
- Published
- 2019
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19. The long non-coding RNA landscape in juvenile myelomonocytic leukemia.
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Hofmans M, Lammens T, Helsmoortel HH, Bresolin S, Cavé H, Flotho C, Hasle H, van den Heuvel-Eibrink MM, Niemeyer C, Stary J, Van Roy N, Van Vlierberghe P, Philippé J, and De Moerloose B
- Subjects
- Child, Child, Preschool, Female, Humans, Leukemia, Myelomonocytic, Juvenile genetics, Leukemia, Myelomonocytic, Juvenile pathology, Male, RNA, Long Noncoding genetics, RNA, Neoplasm genetics, Gene Expression Regulation, Leukemic, Leukemia, Myelomonocytic, Juvenile metabolism, RNA, Long Noncoding biosynthesis, RNA, Neoplasm biosynthesis
- Published
- 2018
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20. Clofarabine, high-dose cytarabine and liposomal daunorubicin in pediatric relapsed/refractory acute myeloid leukemia: a phase IB study.
- Author
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van Eijkelenburg NKA, Rasche M, Ghazaly E, Dworzak MN, Klingebiel T, Rossig C, Leverger G, Stary J, De Bont ESJM, Chitu DA, Bertrand Y, Brethon B, Strahm B, van der Sluis IM, Kaspers GJL, Reinhardt D, and Zwaan CM
- Subjects
- Adolescent, Antineoplastic Combined Chemotherapy Protocols adverse effects, Child, Child, Preschool, Clofarabine administration & dosage, Clofarabine pharmacokinetics, Cytarabine administration & dosage, Cytarabine pharmacokinetics, Daunorubicin administration & dosage, Daunorubicin pharmacokinetics, Drug Administration Schedule, Drug Resistance, Neoplasm, Female, Humans, Infant, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute mortality, Liposomes, Male, Recurrence, Remission Induction, Retreatment, Survival Analysis, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Abstract
Survival in children with relapsed/refractory acute myeloid leukemia is unsatisfactory. Treatment consists of one course of fludarabine, cytarabine and liposomal daunorubicin, followed by fludarabine and cytarabine and stem-cell transplantation. Study ITCC 020/I-BFM 2009-02 aimed to identify the recommended phase II dose of clofarabine replacing fludarabine in the abovementioned combination regimen (3+3 design). Escalating dose levels of clofarabine (20-40 mg/m
2 /day × 5 days) and liposomal daunorubicin (40-80 mg/m2 /day) were administered with cytarabine (2 g/m2 /day × 5 days). Liposomal DNR was given on day 1, 3 and 5 only. The cohort at the recommended phase II dose was expanded to make a preliminary assessment of anti-leukemic activity. Thirty-four children were enrolled: refractory 1st (n=11), early 1st (n=15), ≥2nd relapse (n=8). Dose level 3 (30 mg/m2 clofarabine; 60 mg/m2 liposomal daunorubicin) appeared to be safe only in patients without subclinical fungal infections. Infectious complications were dose-limiting. The recommended phase II dose was 40 mg/m2 clofarabine with 60 mg/m2 liposomal daunorubicin. Side-effects mainly consisted of infections. The overall response rate was 68% in 31 response evaluable patients, and 80% at the recommended phase II dose (n=10); 22 patients proceeded to stem cell transplantation. The 2-year probability of event-free survival (pEFS) was 26.5±7.6 and probability of survival (pOS) 32.4±8.0%. In the 21 responding patients, the 2-year pEFS was 42.9±10.8 and pOS 47.6±10.9%. Clofarabine exposure in plasma was not significantly different from that in single-agent studies. In conclusion, clofarabine was well tolerated and showed high response rates in relapsed/refractory pediatric acute myeloid leukemia. Patients with (sub) clinical fungal infections should be treated with caution. Clofarabine has been taken forward in the Berlin-Frankfurt-Münster study for newly diagnosed acute myeloid leukemia. The Study ITCC-020 was registered as EUDRA-CT 2009-009457-13; Dutch Trial Registry number 1880., (Copyright© 2018 Ferrata Storti Foundation.)- Published
- 2018
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21. Predictive value of minimal residual disease in Philadelphia-chromosome-positive acute lymphoblastic leukemia treated with imatinib in the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia, based on immunoglobulin/T-cell receptor and BCR/ABL1 methodologies.
- Author
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Cazzaniga G, De Lorenzo P, Alten J, Röttgers S, Hancock J, Saha V, Castor A, Madsen HO, Gandemer V, Cavé H, Leoni V, Köhler R, Ferrari GM, Bleckmann K, Pieters R, van der Velden V, Stary J, Zuna J, Escherich G, Stadt UZ, Aricò M, Conter V, Schrappe M, Valsecchi MG, and Biondi A
- Subjects
- Biomarkers, Tumor, Combined Modality Therapy, Female, Humans, Imatinib Mesylate therapeutic use, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Prognosis, Recurrence, Survival Analysis, Treatment Outcome, Fusion Proteins, bcr-abl genetics, Immunoglobulins genetics, Neoplasm, Residual diagnosis, Neoplasm, Residual genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Receptors, Antigen, T-Cell genetics
- Abstract
The prognostic value of minimal residual disease (MRD) in Philadelphia-chromosome-positive (Ph+) childhood acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors is not fully established. We detected MRD by real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes (IG/TR) and/or BCR/ABL1 fusion transcript to investigate its predictive value in patients receiving Berlin-Frankfurt-Münster (BFM) high-risk (HR) therapy and post-induction intermittent imatinib (the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia (EsPhALL) study). MRD was monitored after induction (time point (TP)1), consolidation Phase IB (TP2), HR Blocks, reinductions, and at the end of therapy. MRD negativity progressively increased over time, both by IG/TR and BCR/ABL1. Of 90 patients with IG/TR MRD at TP1, nine were negative and none relapsed, while 11 with MRD<5×10
-4 and 70 with MRD≥5×10-4 had a comparable 5-year cumulative incidence of relapse of 36.4 (15.4) and 35.2 (5.9), respectively. Patients who achieved MRD negativity at TP2 had a low relapse risk (5-yr cumulative incidence of relapse (CIR)=14.3[9.8]), whereas those who attained MRD negativity at a later date showed higher CIR, comparable to patients with positive MRD at any level. BCR/ABL1 MRD negative patients at TP1 had a relapse risk similar to those who were IG/TR MRD negative (1/8 relapses). The overall concordance between the two methods is 69%, with significantly higher positivity by BCR/ABL1. In conclusion, MRD monitoring by both methods may be functional not only for measuring response but also for guiding biological studies aimed at investigating causes for discrepancies, although from our data IG/TR MRD monitoring appears to be more reliable. Early MRD negativity is highly predictive of favorable outcome. The earlier MRD negativity is achieved, the better the prognosis., (Copyright© 2018 Ferrata Storti Foundation.)- Published
- 2018
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22. Acute lymphoblastic leukemia with aleukemic prodrome: preleukemic dynamics and possible mechanisms of immunosurveillance.
- Author
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Zimmermannova O, Zaliova M, Moorman AV, Al-Shehhi H, Fronkova E, Zemanova Z, Kalina T, Vora A, Stary J, Trka J, Hrusak O, and Zuna J
- Subjects
- Adolescent, Biomarkers, Biopsy, Bone Marrow, Child, Child, Preschool, Clonal Evolution genetics, Clonal Evolution immunology, Female, Gene Rearrangement, Humans, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Translocation, Genetic, Immunologic Surveillance, Precancerous Conditions pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma etiology
- Published
- 2017
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23. Characterization of leukemias with ETV6-ABL1 fusion.
- Author
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Zaliova M, Moorman AV, Cazzaniga G, Stanulla M, Harvey RC, Roberts KG, Heatley SL, Loh ML, Konopleva M, Chen IM, Zimmermannova O, Schwab C, Smith O, Mozziconacci MJ, Chabannon C, Kim M, Frederik Falkenburg JH, Norton A, Marshall K, Haas OA, Starkova J, Stuchly J, Hunger SP, White D, Mullighan CG, Willman CL, Stary J, Trka J, and Zuna J
- Subjects
- Adolescent, Adult, Aged, Alternative Splicing, Child, Child, Preschool, Cluster Analysis, DNA Copy Number Variations, Female, Gene Expression Profiling, Humans, In Situ Hybridization, Fluorescence, Infant, Leukemia diagnosis, Leukemia mortality, Leukemia therapy, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Transcriptome, Translocation, Genetic, Young Adult, Leukemia genetics, Oncogene Proteins, Fusion genetics, Protein-Tyrosine Kinases genetics
- Abstract
To characterize the incidence, clinical features and genetics of ETV6-ABL1 leukemias, representing targetable kinase-activating lesions, we analyzed 44 new and published cases of ETV6-ABL1-positive hematologic malignancies [22 cases of acute lymphoblastic leukemia (13 children, 9 adults) and 22 myeloid malignancies (18 myeloproliferative neoplasms, 4 acute myeloid leukemias)]. The presence of the ETV6-ABL1 fusion was ascertained by cytogenetics, fluorescence in-situ hybridization, reverse transcriptase-polymerase chain reaction and RNA sequencing. Genomic and gene expression profiling was performed by single nucleotide polymorphism and expression arrays. Systematic screening of more than 4,500 cases revealed that in acute lymphoblastic leukemia ETV6-ABL1 is rare in childhood (0.17% cases) and slightly more common in adults (0.38%). There is no systematic screening of myeloproliferative neoplasms; however, the number of ETV6-ABL1-positive cases and the relative incidence of acute lymphoblastic leukemia and myeloproliferative neoplasms suggest that in adulthood ETV6-ABL1 is more common in BCR-ABL1-negative chronic myeloid leukemia-like myeloproliferations than in acute lymphoblastic leukemia. The genomic profile of ETV6-ABL1 acute lymphoblastic leukemia resembled that of BCR-ABL1 and BCR-ABL1-like cases with 80% of patients having concurrent CDKN2A/B and IKZF1 deletions. In the gene expression profiling all the ETV6-ABL1-positive samples clustered in close vicinity to BCR-ABL1 cases. All but one of the cases of ETV6-ABL1 acute lymphoblastic leukemia were classified as BCR-ABL1-like by a standardized assay. Over 60% of patients died, irrespectively of the disease or age subgroup examined. In conclusion, ETV6-ABL1 fusion occurs in both lymphoid and myeloid leukemias; the genomic profile and clinical behavior resemble BCR-ABL1-positive malignancies, including the unfavorable prognosis, particularly of acute leukemias. The poor outcome suggests that treatment with tyrosine kinase inhibitors should be considered for patients with this fusion., (Copyright© Ferrata Storti Foundation.)
- Published
- 2016
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24. LIN28B is over-expressed in specific subtypes of pediatric leukemia and regulates lncRNA H19.
- Author
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Helsmoortel HH, De Moerloose B, Pieters T, Ghazavi F, Bresolin S, Cavé H, de Vries A, de Haas V, Flotho C, Labarque V, Niemeyer C, De Paepe P, Van Roy N, Stary J, van den Heuvel-Eibrink MM, Benoit Y, Schulte J, Goossens S, Berx G, Haigh JJ, Speleman F, Van Vlierberghe P, and Lammens T
- Subjects
- Adolescent, Child, Child, Preschool, Female, Humans, Infant, Leukemia genetics, Leukemia pathology, Male, Neoplasm Proteins genetics, RNA, Long Noncoding genetics, RNA, Neoplasm genetics, RNA-Binding Proteins genetics, Gene Expression Regulation, Leukemic, Leukemia metabolism, Neoplasm Proteins biosynthesis, RNA, Long Noncoding metabolism, RNA, Neoplasm metabolism, RNA-Binding Proteins biosynthesis
- Published
- 2016
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25. BCOR and BCORL1 mutations in pediatric acute myeloid leukemia.
- Author
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de Rooij JD, van den Heuvel-Eibrink MM, Hermkens MC, Verboon LJ, Arentsen-Peters ST, Fornerod M, Baruchel A, Stary J, Reinhardt D, de Haas V, Pieters R, and Zwaan CM
- Subjects
- Age Factors, Child, Chromosome Aberrations, Exons, Gene Expression, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute mortality, Mutation Rate, Prognosis, Leukemia, Myeloid, Acute genetics, Mutation, Proto-Oncogene Proteins genetics, Repressor Proteins genetics
- Published
- 2015
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- View/download PDF
26. Mapping epigenetic regulator gene mutations in cytogenetically normal pediatric acute myeloid leukemia.
- Author
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Valerio DG, Katsman-Kuipers JE, Jansen JH, Verboon LJ, de Haas V, Stary J, Baruchel A, Zimmermann M, Pieters R, Reinhardt D, van den Heuvel-Eibrink MM, and Zwaan CM
- Subjects
- Adolescent, Child, Child, Preschool, Cohort Studies, Female, Humans, Male, Chromosome Mapping methods, Cytogenetic Analysis methods, Epigenesis, Genetic genetics, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Mutation genetics
- Published
- 2014
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27. Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood.
- Author
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Yoshimi A, van den Heuvel-Eibrink MM, Baumann I, Schwarz S, Simonitsch-Klupp I, de Paepe P, Campr V, Kerndrup GB, O'Sullivan M, Devito R, Leguit R, Hernandez M, Dworzak M, de Moerloose B, Stary J, Hasle H, Smith OP, Zecca M, Catala A, Schmugge M, Locatelli F, Führer M, Fischer A, Guderle A, Nöllke P, Strahm B, and Niemeyer CM
- Subjects
- Adolescent, Animals, Antilymphocyte Serum administration & dosage, Child, Child, Preschool, Female, Horses, Humans, Immunosuppressive Agents administration & dosage, Infant, Male, Pancytopenia diagnosis, Rabbits, Recurrence, Risk Factors, Treatment Outcome, Antilymphocyte Serum therapeutic use, Immunosuppression Therapy, Immunosuppressive Agents therapeutic use, Pancytopenia drug therapy
- Abstract
Refractory cytopenia of childhood is the most common subtype of myelodysplastic syndrome in children. In this study, we compared the outcome of immunosuppressive therapy using horse antithymocyte globulin (n=46) with that using rabbit antithymocyte globulin (n=49) in 95 patients with refractory cytopenia of childhood and hypocellular bone marrow. The response rate at 6 months was 74% for horse antithymocyte globulin and 53% for rabbit antithymocyte globulin (P=0.04). The inferior response in the rabbit antithymocyte globulin group resulted in lower 4-year transplantation-free (69% versus 46%; P=0.003) and failure-free (58% versus 48%; P=0.04) survival rates in this group compared with those in the horse antithymocyte globulin group. However, because of successful second-line hematopoietic stem cell transplantation, overall survival was comparable between groups (91% versus 85%; P=ns). The cumulative incidence of relapse (15% versus 9%; P=ns) and clonal evolution (12% versus 4%; P=ns) at 4 years was comparable between groups. Our results suggest that the outcome of immunosuppressive therapy with rabbit antithymocyte globulin is inferior to that of horse antithymocyte globulin. Although immunosuppressive therapy is an effective therapy in selected patients with refractory cytopenia of childhood, the long-term risk of relapse or clonal evolution remains. (ClinicalTrial.gov identifiers: NCT00662090).
- Published
- 2014
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28. Minimal residual disease in peripheral blood at day 15 identifies a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with superior prognosis.
- Author
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Volejnikova J, Mejstrikova E, Valova T, Reznickova L, Hodonska L, Mihal V, Sterba J, Jabali Y, Prochazkova D, Blazek B, Hak J, Cerna Z, Hrusak O, Stary J, Trka J, and Fronkova E
- Subjects
- Adolescent, Bone Marrow metabolism, Bone Marrow pathology, Child, Child, Preschool, Humans, Infant, Male, Neoplasm, Residual, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Prognosis, Real-Time Polymerase Chain Reaction, Time Factors, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma blood, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Background: Most minimal residual disease-directed treatment interventions in current treatment protocols for acute lymphoblastic leukemia are based on bone marrow testing, which is a consequence of previous studies showing the superiority of bone marrow over peripheral blood as an investigational material. Those studies typically did not explore the prognostic impact of peripheral blood involvement and lacked samples from very early time points of induction., Design and Methods: In this study, we employed real-time quantitative polymerase chain reaction analysis to examine minimal residual disease in 398 pairs of blood and bone marrow follow-up samples taken from 95 children with B-cell precursor acute lymphoblastic leukemia treated with the ALL IC-BFM 2002 protocol., Results: We confirmed the previously published poor correlation between minimal residual disease in blood and marrow at early treatment time points, with levels in bone marrow being higher than in blood in most samples (median 7.9-fold, range 0.04-8,293-fold). A greater involvement of peripheral blood at diagnosis was associated with a higher white blood cell count at diagnosis (P=0.003) and with enlargement of the spleen (P=0.0004) and liver (P=0.05). At day 15, a level of minimal residual disease in blood lower than 10(-4) was associated with an excellent 5-year relapse-free survival in 78 investigated patients (100% versus 69 ± 7%; P=0.0003). Subgroups defined by the level of minimal residual disease in blood at day 15 (high-risk: ≥ 10(-2), intermediate-risk: <10(-2) and ≥ 10(-4), standard-risk: <10(-4)) partially correlated with bone marrow-based stratification described previously, but the risk groups did not match completely. No other time point analyses were predictive of outcome in peripheral blood, except for a weak association at day 8., Conclusions: Minimal residual disease in peripheral blood at day 15 identified a large group of patients with an excellent prognosis and added prognostic information to the risk stratification based on minimal residual disease at day 33 and week 12.
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- 2011
- Full Text
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29. Integrative analysis of type-I and type-II aberrations underscores the genetic heterogeneity of pediatric acute myeloid leukemia.
- Author
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Balgobind BV, Hollink IH, Arentsen-Peters ST, Zimmermann M, Harbott J, Beverloo HB, von Bergh AR, Cloos J, Kaspers GJ, de Haas V, Zemanova Z, Stary J, Cayuela JM, Baruchel A, Creutzig U, Reinhardt D, Pieters R, Zwaan CM, and van den Heuvel-Eibrink MM
- Subjects
- Adolescent, Age Factors, Child, Child, Preschool, Cohort Studies, Female, Humans, Infant, Infant, Newborn, Karyotype, Leukemia, Myeloid, Acute mortality, Male, Mutation, Nucleophosmin, Prognosis, Sex Factors, Survival Analysis, Chromosome Aberrations, Genetic Heterogeneity, Leukemia, Myeloid, Acute genetics
- Abstract
Background: Several studies of pediatric acute myeloid leukemia have described the various type-I or type-II aberrations and their relationship with clinical outcome. However, there has been no recent comprehensive overview of these genetic aberrations in one large pediatric acute myeloid leukemia cohort., Design and Methods: We studied the different genetic aberrations, their associations and their impact on prognosis in a large pediatric acute myeloid leukemia series (n=506). Karyotypes were studied, and hotspot regions of NPM1, CEPBA, MLL, WT1, FLT3, N-RAS, K-RAS, PTPN11 and KIT were screened for mutations of available samples. The mutational status of all type-I and type-II aberrations was available in 330 and 263 cases, respectively. Survival analysis was performed in a subset (n=385) treated on consecutive acute myeloid leukemia Berlin-Frankfurt-Munster Study Group and Dutch Childhood Oncology Group treatment protocols., Results: Genetic aberrations were associated with specific clinical characteristics, e.g. significantly higher diagnostic white blood cell counts in MLL-rearranged, WT1-mutated and FLT3-ITD-positive acute myeloid leukemia. Furthermore, there was a significant difference in the distribution of these aberrations between children below and above the age of two years. Non-random associations, e.g. KIT mutations with core-binding factor acute myeloid leukemia, and FLT3-ITD with t(15;17)(q22;q21), NPM1- and WT1-mutated acute myeloid leukemia, respectively, were observed. Multivariate analysis revealed a 'favorable karyotype', i.e. t(15;17)(q22;q21), t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16)(p13;q22). NPM1 and CEBPA double mutations were independent factors for favorable event-free survival. WT1 mutations combined with FLT3-ITD showed the worst outcome for 5-year overall survival (22±14%) and 5-year event-free survival (20±13%), although it was not an independent factor in multivariate analysis., Conclusions: Integrative analysis of type-I and type-II aberrations provides an insight into the frequencies, non-random associations and prognostic impact of the various aberrations, reflecting the heterogeneity of pediatric acute myeloid leukemia. These aberrations are likely to guide the stratification of pediatric acute myeloid leukemia and may direct the development of targeted therapies.
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- 2011
- Full Text
- View/download PDF
30. Evaluation of gene expression signatures predictive of cytogenetic and molecular subtypes of pediatric acute myeloid leukemia.
- Author
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Balgobind BV, Van den Heuvel-Eibrink MM, De Menezes RX, Reinhardt D, Hollink IH, Arentsen-Peters ST, van Wering ER, Kaspers GJ, Cloos J, de Bont ES, Cayuela JM, Baruchel A, Meyer C, Marschalek R, Trka J, Stary J, Beverloo HB, Pieters R, Zwaan CM, and den Boer ML
- Subjects
- Adult, Biomarkers, Tumor metabolism, Child, Cytogenetic Analysis, Gene Rearrangement, Histone-Lysine N-Methyltransferase, Humans, Leukemia, Myeloid, Acute classification, Leukemia, Myeloid, Acute metabolism, Myeloid-Lymphoid Leukemia Protein, Nucleophosmin, Oligonucleotide Array Sequence Analysis, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction, Biomarkers, Tumor genetics, Gene Expression Profiling, Leukemia, Myeloid, Acute genetics
- Abstract
Background: Pediatric acute myeloid leukemia is a heterogeneous disease characterized by non-random genetic aberrations related to outcome. The genetic subtype is currently detected by different diagnostic procedures which differ in success rate and/or specificity., Design and Methods: We examined the potential of gene expression profiles to classify pediatric acute myeloid leukemia. Gene expression microarray data of 237 children with acute myeloid leukemia were collected and a double-loop cross validation approach was used to generate a subtype-predictive gene expression profile in the discovery cohort (n=157) which was then tested for its true predictive value in the independent validation cohort (n=80). The classifier consisted of 75 probe sets, representing the top 15 discriminating probe sets for MLL-rearranged, t(8;21)(q22;q22), inv(16)(p13q22), t(15;17)(q21;q22) and t(7;12)(q36;p13)-positive acute myeloid leukemia., Results: These cytogenetic subtypes represent approximately 40% of cases of pediatric acute myeloid leukemia and were predicted with 92% and 99% accuracy in the discovery and independent validation cohort, respectively. However, for NPM1, CEBPA, MLL(-PTD), FLT3(-ITD), KIT, PTPN11 and N/K-RAS gene expression signatures had limited predictive value. This may be caused by a limited frequency of these mutations and by underlying cytogenetics. This latter is exemplified by the fact that different gene expression signatures were discovered for FLT3-ITD in patients with normal cytogenetics and in those with t(15;17)(q21;q22)-positive acute myeloid leukemia, which pointed to HOXB-upregulation being specific for FLT3-ITD(+) cytogenetically normal acute myeloid leukemia., Conclusions: In conclusion, gene expression profiling correctly predicted the most prevalent cytogenetic subtypes of pediatric acute myeloid leukemia with high accuracy. In clinical practice, this gene expression signature may replace multiple diagnostic tests for approximately 40% of pediatric acute myeloid leukemia cases whereas only for the remaining cases (predicted as 'acute myeloid leukemia-other') are additional tests indicated. Moreover, the discriminative genes reveal new insights into the biology of acute myeloid leukemia subtypes that warrants follow-up as potential targets for new therapies.
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- 2011
- Full Text
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31. Prognosis of children with mixed phenotype acute leukemia treated on the basis of consistent immunophenotypic criteria.
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Mejstrikova E, Volejnikova J, Fronkova E, Zdrahalova K, Kalina T, Sterba J, Jabali Y, Mihal V, Blazek B, Cerna Z, Prochazkova D, Hak J, Zemanova Z, Jarosova M, Oltova A, Sedlacek P, Schwarz J, Zuna J, Trka J, Stary J, and Hrusak O
- Subjects
- Adolescent, Child, Child, Preschool, Diagnosis, Differential, Follow-Up Studies, Humans, Infant, Infant, Newborn, Leukemia immunology, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute immunology, Leukemia, Myeloid, Acute therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Prognosis, Receptors, Antigen, T-Cell immunology, Immunophenotyping methods, Leukemia diagnosis, Leukemia therapy, Phenotype
- Abstract
Background: Mixed phenotype acute leukemia (MPAL) represents a diagnostic and therapeutic dilemma. The European Group for the Immunological Classification of Leukemias (EGIL) scoring system unambiguously defines MPAL expressing aberrant lineage markers. Discussions surrounding it have focused on scoring details, and information is limited regarding its biological, clinical and prognostic significance. The recent World Health Organization classification is simpler and could replace the EGIL scoring system after transformation into unambiguous guidelines., Design and Methods: Simple immunophenotypic criteria were used to classify all cases of childhood acute leukemia in order to provide therapy directed against acute lymphoblastic leukemia or acute myeloid leukemia. Prognosis, genotype and immunoglobulin/T-cell receptor gene rearrangement status were analyzed., Results: The incidences of MPAL were 28/582 and 4/107 for children treated with acute lymphoblastic leukemia and acute myeloid leukemia regimens, respectively. In immunophenotypic principal component analysis, MPAL treated as T-cell acute lymphoblastic leukemia clustered between cases of non-mixed T-cell acute lymphoblastic leukemia and acute myeloid leukemia, while other MPAL cases were included in the respective non-mixed B-cell progenitor acute lymphoblastic leukemia or acute myeloid leukemia clusters. Analogously, immunoglobulin/T-cell receptor gene rearrangements followed the expected pattern in patients treated as having acute myeloid leukemia (non-rearranged, 4/4) or as having B-cell progenitor acute lymphoblastic leukemia (rearranged, 20/20), but were missing in 3/5 analyzed cases of MPAL treated as having T-cell acute lymphobastic leukemia. In patients who received acute lymphoblastic leukemia treatment, the 5-year event-free survival of the MPAL cases was worse than that of the non-mixed cases (53+/-10% and 76+/-2% at 5 years, respectively, P=0.0075), with a more pronounced difference among B lineage cases. The small numbers of MPAL cases treated as T-cell acute lymphoblastic leukemia or as acute myeloid leukemia hampered separate statistics. We compared prognosis of all subsets with the prognosis of previously published cohorts., Conclusions: Simple immunophenotypic criteria are useful for therapy decisions in MPAL. In B lineage leukemia, MPAL confers poorer prognosis. However, our data do not justify a preferential use of current acute myeloid leukemia-based therapy in MPAL.
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- 2010
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32. Mitotic recombination and compound-heterozygous mutations are predominant NF1-inactivating mechanisms in children with juvenile myelomonocytic leukemia and neurofibromatosis type 1.
- Author
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Steinemann D, Arning L, Praulich I, Stuhrmann M, Hasle H, Stary J, Schlegelberger B, Niemeyer CM, and Flotho C
- Subjects
- Child, Child, Preschool, Female, Humans, Infant, Loss of Heterozygosity, Male, Recombination, Genetic, Leukemia, Myelomonocytic, Juvenile genetics, Mutation, Neurofibromatosis 1 genetics, Neurofibromin 1 genetics
- Abstract
Children with neurofibromatosis type 1 (NF-1), being constitutionally deficient for one allele of the NF1 gene, are at greatly increased risk of juvenile myelomonocytic leukemia (JMML). NF1 is a negative regulator of RAS pathway activity, which has a central role in JMML. To further clarify the role of biallelic NF1 gene inactivation in the pathogenesis of JMML, we investigated the somatic NF1 lesion in 10 samples from children with JMML/NF-1. We report that two-thirds of somatic events involved loss of heterozygosity (LOH) at the NF1 locus, predominantly caused by segmental uniparental disomy of large parts of chromosome arm 17q. One-third of leukemias showed compound-heterozygous NF1-inactivating mutations. A minority of cases exhibited somatic interstitial deletions. The findings reinforce the emerging role of somatic mitotic recombination as a leukemogenic mechanism. In addition, they support the concept that biallelic NF1 inactivation in hematopoietic progenitor cells is required for transformation to JMML in children with NF-1.
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- 2010
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33. Eligibility for allogeneic transplantation in very high risk childhood acute lymphoblastic leukemia: the impact of the waiting time.
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Balduzzi A, De Lorenzo P, Schrauder A, Conter V, Uderzo C, Peters C, Klingebiel T, Stary J, Felice MS, Magyarosy E, Schrappe M, Dini G, Gadner H, and Valsecchi MG
- Subjects
- Antineoplastic Agents therapeutic use, Child, Cohort Studies, Disease-Free Survival, Humans, Immunophenotyping, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Prospective Studies, Remission Induction, Risk, Time Factors, Translocation, Genetic, Treatment Outcome, Bone Marrow Transplantation methods, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Transplantation, Homologous methods
- Abstract
The advantage of allogeneic transplant from compatible related donors versus chemotherapy in children with very-high-risk acute lymphoblastic leukemia in first complete remission was previously demonstrated in an international prospective trial. This study quantified the impact of time elapsed in first remission in the same cohort. Of 357 pediatric patients with very-high-risk acute lymphoblastic leukemia, 259 received chemotherapy, 55 transplantation from compatible related and 43 from unrelated donors. The 5-year disease-free survival was 44.2% overall and 42.5% for chemotherapy only patients. The chemotherapy conditional 5-year disease-free survival increased to 44.4%, 47.6%, 51.7%, and 60.4% in patients who maintained their first remission for at least 3, 6, 9, and 12 months respectively. The overall outcome was superior to that obtained with chemotherapy-only at any time-point. The relative advantage of transplant from compatible related donors in very-high-risk childhood acute lymphoblastic leukemia was consistent for any time elapsed in first remission.
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- 2008
- Full Text
- View/download PDF
34. Significance of real-time quantitative PCR detection of p16 gene deletions in childhood acute lymphoblastic leukemia.
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Zuna J, Muzikova K, Hrusak O, Stary J, and Trka J
- Subjects
- Base Sequence, Child, DNA Mutational Analysis, Humans, Polymerase Chain Reaction methods, Polymerase Chain Reaction standards, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Predictive Value of Tests, Genes, p16, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Sequence Deletion
- Published
- 2002
35. Monitoring of minimal residual disease and mixed chimerism in a case of high-risk TEL/AML1+ acute lymphoblastic leukemia pre- and post-bone marrow transplantation. Czech Pediatric Haematology Working Group.
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Sedlácek P, Trka J, Zuna J, Hrusák O, Honzátková-Krsková L, and Stary J
- Subjects
- Animals, Child, Preschool, Core Binding Factor Alpha 2 Subunit, Humans, Neoplasm, Residual genetics, Transplantation Chimera, Transplantation, Homologous, Bone Marrow Transplantation, Neoplasm, Residual diagnosis, Oncogene Proteins, Fusion genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
- Published
- 2000
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