69 results on '"Metzler, Markus"'
Search Results
2. Finding a balance in reduced toxicity hematopoietic stem cell transplantation for thalassemia: role of infused CD3+ cell count and immunosuppression
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Meissner, Barbara, Lang, Peter, Bader, Peter, Hoenig, Manfred, Müller, Ingo, Meisel, Roland, Greil, Johann, Sauer, Martin G., Metzler, Markus, Corbacioglu, Selim, Burkhardt, Birgit, Wölfl, Matthias, Strahm, Brigitte, Kafa, Kinan, Basu, Oliver, Lode, Holger N., Gruhn, Bernd, Cario, Holger, Ozga, Ann-Kathrin, Zimmermann, Martin, Jarisch, Andrea, and Beier, Rita
- Abstract
We performed a retrospective analysis on 124 patients with transfusion-dependent thalassemia who were registered in the German pediatric registry for stem cell transplantation. All patients underwent first allogeneic hematopoietic stem cell transplantation (HSCT) between 2011 and 2020 and belonged mainly to Pesaro risk class 1–2. Four-year overall (OS) and thalassemia-free survival (TFS) were 94.5% ± 2.9% and 88.0% ± 3.4% after treosulfan-fludarabine-thiotepa- and 96.9% ± 3.1% (P= 0.763) and 96.9% ± 3.1% (P= 0.155) after busulfan-fludarabine-based conditioning. Mixed chimerism below 75% occurred predominantly in treosulfan-based regimens (27.5% versus 6.2%). OS and TFS did not differ significantly between matched sibling, other matched family and matched unrelated donor (UD) HSCTs (OS: 100.0%, 100.0%, 96.3% ± 3.6%; TFS: 96.5% ± 2.4%, 90.0% ± 9.5%, 88.9% ± 6.0%). However, mismatched UD-HSCTs performed less favorable (OS: 84.7% ± 7.3% (P= 0.029); TFS: 79.9% ± 7.4% (P= 0.082)). We generated a scoring system reflecting the risk to develop mixed chimerism in our cohort. The main risk-reducing factors were a high CD3+ cell count (≥6 × 107/kg) in the graft, busulfan-conditioning, pre-conditioning therapy and low-targeted ciclosporin A trough levels. Acute GvHD grade III-IV in treosulfan-based concepts predominantly occurred in patients with UD and reduced GvHD prophylaxis but not in the context of high CD3+ cell doses. Taken together, this information might be used to develop more risk-adapted HSCT regimens for thalassemia patients.
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- 2024
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3. Management of children and adolescents with chronic myeloid leukemia in blast phase: International pediatric CML expert panel recommendations
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Sembill, Stephanie, Ampatzidou, Maria, Chaudhury, Sonali, Dworzak, Michael, Kalwak, Krzysztof, Karow, Axel, Kiani, Alexander, Krumbholz, Manuela, Luesink, Maaike, Naumann-Bartsch, Nora, De Moerloose, Barbara, Osborn, Michael, Schultz, Kirk R., Sedlacek, Petr, Giona, Fiorina, Zwaan, Christian Michel, Shimada, Hiroyuki, Versluijs, Birgitta, Millot, Frederic, Hijiya, Nobuko, Suttorp, Meinolf, and Metzler, Markus
- Abstract
Treatment of chronic myeloid leukemia has improved significantly with the introduction of tyrosine kinase inhibitors (TKIs), and treatment guidelines based on numerous clinical trials are available for chronic phase disease. However for CML in the blast phase (CML-BP), prognosis remains poor and treatment options are much more limited. The spectrum of treatment strategies for children and adolescents with CML-BP has largely evolved empirically and includes treatment principles derived from adult CML-BP and pediatric acute leukemia. Given this heterogeneity of treatment approaches, we formed an international panel of pediatric CML experts to develop recommendations for consistent therapy in children and adolescents with this high-risk disease based on the current literature and national standards. Recommendations include detailed information on initial diagnosis and treatment monitoring, differentiation from Philadelphia-positive acute leukemia, subtype-specific selection of induction therapy, and combination with tyrosine kinase inhibitors. Given that allogeneic hematopoietic stem cell transplantation currently remains the primary curative intervention for CML-BP, we also provide recommendations for the timing of transplantation, donor and graft selection, selection of a conditioning regimen and prophylaxis for graft-versus-host disease, post-transplant TKI therapy, and management of molecular relapse. Management according to the treatment recommendations presented here is intended to provide the basis for the design of future prospective clinical trials to improve outcomes for this challenging disease.
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- 2023
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4. Data mining of pediatric reference intervals
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Zierk, Jakob, Metzler, Markus, and Rauh, Manfred
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Laboratory tests are essential to assess the health status and to guide patient care in individuals of all ages. The interpretation of quantitative test results requires availability of appropriate reference intervals, and reference intervals in children have to account for the extensive physiological dynamics with age in many biomarkers. Creation of reference intervals using conventional approaches requires the sampling of healthy individuals, which is opposed by ethical and practical considerations in children, due to the need for a large number of blood samples from healthy children of all ages, including neonates and young infants. This limits the availability and quality of pediatric reference intervals, and ultimately negatively impacts pediatric clinical decision-making. Data mining approaches use laboratory test results and clinical information from hospital information systems to create reference intervals. The extensive number of available test results from laboratory information systems and advanced statistical methods enable the creation of pediatric reference intervals with an unprecedented age-related accuracy for children of all ages. Ongoing developments regarding the availability and standardization of electronic medical records and of indirect statistical methods will further improve the benefit of data mining for pediatric reference intervals.
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- 2021
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5. The age of the bone marrow microenvironment influences B-cell acute lymphoblastic leukemia progression via CXCR5-CXCL13
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Zanetti, Costanza, Kumar, Rahul, Ender, Joscha, Godavarthy, Parimala S., Hartmann, Mark, Hey, Joschka, Breuer, Kersten, Weissenberger, Eva S., Minciacchi, Valentina R., Karantanou, Christina, Gu, Zhaohui, Roberts, Kathryn G., Metzler, Markus, Stock, Wendy, Mullighan, Charles G., Bloomfield, Clara D., Filmann, Natalie, Bankov, Katrin, Hartmann, Sylvia, Hasserjian, Robert P., Cousins, Antony F., Halsey, Christina, Plass, Christoph, Lipka, Daniel B., and Krause, Daniela S.
- Abstract
B-cell acute lymphoblastic leukemia (B-ALL) occurs most commonly in children, whereas chronic myeloid leukemia is more frequent in adults. The myeloid bias of hematopoiesis in elderly individuals has been considered causative, but the age of the bone marrow microenvironment (BMM) may be contributory. Using various murine models of B-ALL in young vs old mice, we recapitulated B-ALL preponderance in children vs adults. We showed differential effects of young vs old BM macrophages on B-ALL cell function. Molecular profiling using RNA- and ATAC-sequencing revealed pronounced differences in young vs old BMM-derived macrophages and enrichment for gene sets associated with inflammation. In concordance with the role of C-X-C motif chemokine (CXCL) 13 for disease-associated B-cell chemoattraction, we found CXCL13 to be highly expressed in young macrophages on a translational compared with a transcriptional level. Inhibition of CXCL13 in BM macrophages impaired leukemia cell migration and decreased the proliferation of cocultured B-ALL cells, whereas recombinant CXCL13 increased pAKT and B-ALL cell expansion. Pretreatment of B-ALL–initiating cells with CXCL13 accelerated B-ALL progression. Deficiency of Cxcr5, the receptor for CXCL13, on B-ALL–initiating cells prolonged murine survival, whereas high expression of CXCR5 in pediatric B-ALL may predict central nervous system relapse. CXCL13 staining was increased in bone sections from pediatric compared with adult patients with B-ALL. Taken together, our study shows that the age of the BMM and, in particular, BM macrophages influence the leukemia phenotype. The CXCR5-CXCL13 axis may act as prognostic marker and an attractive novel target for the treatment of B-ALL.
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- 2021
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6. The age of the bone marrow microenvironment influences B-cell acute lymphoblastic leukemia progression via CXCR5-CXCL13
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Zanetti, Costanza, Kumar, Rahul, Ender, Joscha, Godavarthy, Parimala S., Hartmann, Mark, Hey, Joschka, Breuer, Kersten, Weissenberger, Eva S., Minciacchi, Valentina R., Karantanou, Christina, Gu, Zhaohui, Roberts, Kathryn G., Metzler, Markus, Stock, Wendy, Mullighan, Charles G., Bloomfield, Clara D., Filmann, Natalie, Bankov, Katrin, Hartmann, Sylvia, Hasserjian, Robert P., Cousins, Antony F., Halsey, Christina, Plass, Christoph, Lipka, Daniel B., and Krause, Daniela S.
- Abstract
B-cell acute lymphoblastic leukemia (B-ALL) occurs most commonly in children, whereas chronic myeloid leukemia is more frequent in adults. The myeloid bias of hematopoiesis in elderly individuals has been considered causative, but the age of the bone marrow microenvironment (BMM) may be contributory. Using various murine models of B-ALL in young vs old mice, we recapitulated B-ALL preponderance in children vs adults. We showed differential effects of young vs old BM macrophages on B-ALL cell function. Molecular profiling using RNA- and ATAC-sequencing revealed pronounced differences in young vs old BMM-derived macrophages and enrichment for gene sets associated with inflammation. In concordance with the role of C-X-C motif chemokine (CXCL) 13 for disease-associated B-cell chemoattraction, we found CXCL13 to be highly expressed in young macrophages on a translational compared with a transcriptional level. Inhibition of CXCL13 in BM macrophages impaired leukemia cell migration and decreased the proliferation of cocultured B-ALL cells, whereas recombinant CXCL13 increased pAKT and B-ALL cell expansion. Pretreatment of B-ALL–initiating cells with CXCL13 accelerated B-ALL progression. Deficiency of Cxcr5, the receptor for CXCL13, on B-ALL–initiating cells prolonged murine survival, whereas high expression of CXCR5in pediatric B-ALL may predict central nervous system relapse. CXCL13 staining was increased in bone sections from pediatric compared with adult patients with B-ALL. Taken together, our study shows that the age of the BMM and, in particular, BM macrophages influence the leukemia phenotype. The CXCR5-CXCL13 axis may act as prognostic marker and an attractive novel target for the treatment of B-ALL.
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- 2021
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7. Präzisionsonkologie und Phase-I/II-Netzwerke in der Kinderkrebsmedizin
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Nesper-Brock, Martina, Metzler, Markus, Reinhardt, Dirk, Rutkowski, Stefan, Thorwarth, Anne, van Tilburg, Cornelis M., Pfister, Stefan M., Schrappe, Martin, and Witt, Olaf
- Abstract
Für die Therapie pädiatrischer Rezidiv- oder Hochrisikopatienten in frühen klinischen Studien der Phase I und II wurden unter dem Dach der Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) seit 2016 fünf regionale Phase-I/II-Studiennetzwerke etabliert. Durch die Verbundstruktur werden die Kompetenzen und Ressourcen gebündelt, um so die rasche und effiziente Durchführung früher klinischer Studien mit pädiatrischen Patienten zu unterstützen. Mit der INFORM-Studie steht in der pädiatrischen Onkologie eine populationsbasierte molekulare Diagnostikstudie für Kinder- und Jugendliche mit rezidivierten Tumorerkrankungen in Deutschland und 12 anderen Ländern zur Verfügung. Erste Daten zeigen, dass Präzisionsmedizin in der pädiatrischen Onkologie im internationalen, multizentrischen Setting möglich ist, einen klinischen Nutzen erbringt und dazu beiträgt, hereditäre Krebsprädispositionssyndrome zu identifizieren, Diagnosen zu präzisieren und Patienten passenden Phase-I/II-Studien zuzuordnen. Das Angebot an innovativen molekularen Therapiestudien der Phase I/II für Kinder und Jugendliche in Deutschland ist aktuell limitiert. Die pädiatriespezifische Entwicklung zielgerichteter Therapiekonzepte und Kombinationstherapien, eine breite molekulargenetische Charakterisierung und eine darauf basierende, effiziente Zuordnung der Patienten zu Studien sind daher wichtige Aufgaben in den kommenden Jahren.
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- 2021
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8. Exploitable metabolic dependencies in MLL-ENL–induced leukemia
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Garcia-Cuellar, Maria-Paz, Lawlor, Jennifer, Böttcher, Martin, Mougiakakos, Dimitrios, Metzler, Markus, and Slany, Robert K.
- Abstract
Mixed-lineage leukemia (MLL) fusions are transcriptional activators that induce leukemia, with a dismal prognosis that mandates further elucidation of their transformation mechanism. In this study, knockdown of the direct MLL-ENL target gene polypyrimidine tract binding protein-1 (PTBP1) was rate limiting for cell proliferation and caused a metabolic phenotype associated with reduced glucose consumption and lactate production. This effect was accompanied by a reduction of splice isoform-2 of pyruvate kinase M (PKM2). Because PKM2 restricts glycolytic outflow to provide anabolic intermediates, we tested the consequences of glucose, energy, and Ser/Gly starvation for cell physiology. Administration of deoxyglucose, energetic decoupling with rotenone, and inhibition of Ser biosynthesis by CBR5884 had a significantly stronger influence on self-renewal and survival of transformed cells than on normal controls. In particular, inhibition of Ser synthesis, which branches off glycolysis caused accumulation of reactive oxygen species, DNA damage, and apoptosis, predominantly in leukemic cells. Depletion of exogenous Ser/Gly affected proliferation and self-renewal of murine and human leukemia samples, even though they are classified as nonessential amino acids. Response to Ser/Gly starvation correlated with glucose transport, but did not involve activation of the AMPK energy homeostasis system. Finally, survival times in transplantation experiments were significantly extended by feeding recipients a Ser/Gly-free diet. These results suggest selective starvation as an option for supportive leukemia treatment.
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- 2020
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9. Bone marrow niche-derived extracellular matrix-degrading enzymes influence the progression of B-cell acute lymphoblastic leukemia
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Verma, Divij, Zanetti, Costanza, Godavarthy, Parimala Sonika, Kumar, Rahul, Minciacchi, Valentina R., Pfeiffer, Jakob, Metzler, Markus, Lefort, Sylvain, Maguer-Satta, Véronique, Nicolini, Franck E., Burroni, Barbara, Fontenay, Michaela, and Krause, Daniela S.
- Abstract
Specific and reciprocal interactions with the bone marrow microenvironment (BMM) govern the course of hematological malignancies. Matrix metalloproteinase-9 (MMP-9), secreted by leukemia cells, facilitates tumor progression via remodeling of the extracellular matrix (ECM) of the BMM. Hypothesizing that leukemias may instruct the BMM to degrade the ECM, we show, that MMP-9-deficiency in the BMM prolongs survival of mice with BCR-ABL1-induced B-cell acute lymphoblastic leukemia (B-ALL) compared with controls and reduces leukemia-initiating cells. MMP-9-deficiency in the BMM leads to reduced degradation of proteins of the ECM and reduced invasion of B-ALL. Using various in vivo and in vitro assays, as well as recipient mice deficient for the receptor for tumor necrosis factor (TNF) α (TNFR1) we demonstrate that B-ALL cells induce MMP-9-expression in mesenchymal stem cells (MSC) and possibly other cells of the BMM via a release of TNFα. MMP-9-expression in MSC is mediated by activation of nuclear factor kappa B (NF-κB) downstream of TNFR1. Consistently, knockdown of TNF-α in B-ALL-initiating cells or pharmacological inhibition of MMP-9 led to significant prolongation of survival in mice with B-ALL. In summary, leukemia cell-derived Tnfα induced MMP-9-expression by the BMM promoting B-ALL progression. Inhibition of MMP-9 may act as an adjunct to existing therapies.
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- 2020
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10. Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma
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Desch, Ann-Kathrin, Hartung, Kristin, Botzen, Ante, Brobeil, Alexander, Rummel, Mathias, Kurch, Lars, Georgi, Thomas, Jox, Theresa, Bielack, Stefan, Burdach, Stefan, Classen, Carl Friedrich, Claviez, Alexander, Debatin, Klaus-Michael, Ebinger, Martin, Eggert, Angelika, Faber, Jörg, Flotho, Christian, Frühwald, Michael, Graf, Norbert, Jorch, Norbert, Kontny, Udo, Kramm, Christof, Kulozik, Andreas, Kühr, Joachim, Sykora, Karl-Walter, Metzler, Markus, Müller, Hermann L., Nathrath, Michaela, Nüßlein, Thomas, Paulussen, Michael, Pekrun, Arnulf, Reinhardt, Dirk, Reinhard, Harald, Rössig, Claudia, Sauerbrey, Axel, Schlegel, Paul-Gerhardt, Schneider, Dominik T., Scheurlen, Wolfram, Schweigerer, Lothar, Simon, Thorsten, Suttorp, Meinolf, Vorwerk, Peter, Schmitz, Roland, Kluge, Regine, Mauz-Körholz, Christine, Körholz, Dieter, Gattenlöhner, Stefan, and Bräuninger, Andreas
- Abstract
We used hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA) of pediatric Hodgkin lymphoma (PHL) patients to determine pathogenic mechanisms and assess the clinical utility of this method. Hodgkin-Reed/Sternberg (HRS) cell-derived single nucleotide variants, insertions/deletions, translocations and VH-DH-JHrearrangements were detected in pretherapy ccfDNA of 72 of 96 patients. Number of variants per patient ranged from 1 to 21 with allele frequencies from 0.6 to 42%. Nine translocation breakpoints were detected. Genes involved in JAK/STAT, NFkB and PI3K signaling and antigen presentation were most frequently affected. SOCS1variants, mainly deletions, were found in most circulating tumor (ct) DNAs, and seven of the nine translocation breakpoints involved SOCS1. Analysis of VH-DH-JHrearrangements revealed an origin of PHL HRS cells from partially selected germinal center B cells. Amounts of pretherapy ctDNA were correlated with metabolic tumor volumes. Furthermore, in all ccfDNA samples of 43 patients with early response assessment quantitative qPET < 3, indicative of a favorable clinical course, ctDNA was not detectable. In contrast, in five of six patients with qPET > 3, indicative of an unfavorable clinical course, ctDNA remained detectable. ccfDNA analysis of PHL is thus a suitable approach to determine pathogenic mechanisms and monitor therapy response.
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- 2020
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11. Machine Learning–Supported Diagnosis of Small Blue Round Cell Sarcomas Using Targeted RNA Sequencing
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Schlieben, Lea Dewi, Carta, Maria Giulia, Moskalev, Evgeny A., Stöhr, Robert, Metzler, Markus, Besendörfer, Manuel, Meidenbauer, Norbert, Semrau, Sabine, Janka, Rolf, Grützmann, Robert, Wiemann, Stefan, Hartmann, Arndt, Agaimy, Abbas, Haller, Florian, and Ferrazzi, Fulvia
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Small blue round cell sarcomas (SBRCSs) are a heterogeneous group of tumors with overlapping morphologic features but markedly varying prognosis. They are characterized by distinct chromosomal alterations, particularly rearrangements leading to gene fusions, whose detection currently represents the most reliable diagnostic marker. Ewing sarcomas are the most common SBRCSs, defined by gene fusions involving EWSR1and transcription factors of the ETS gene family, and the most frequent non–EWSR1-rearranged SBRCSs harbor a CICrearrangement. Unfortunately, the identification of CIC::DUX4translocation events, the most common CICrearrangement, is challenging with current methods. Here, a machine-learning approach to support SBRCS diagnosis relying on gene expression profiles measured via targeted sequencing is presented. The analyses on a curated cohort of 69 soft-tissue tumors showed markedly distinct expression patterns for SBRCS subgroups. A random forest classifier trained on Ewing sarcoma and CIC-rearranged cases predicted probabilities of being CIC-rearranged >0.9 for CIC-rearranged–like sarcomas and <0.6 for other SBRCS. Testing on a retrospective cohort of 1335 routine diagnostic cases identified 15 candidate CIC-rearranged tumors with a probability >0.75, all of which was supported by expert histopathologic reassessment. Furthermore, the multigene random forest classifier appeared advantageous over using high ETV4expression alone, previously proposed as a surrogate to identify CICrearrangement. Taken together, the expression-based classifier can offer valuable support for SBRCS pathologic diagnosis.
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- 2024
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12. Multinational Retrospective Analysis of Bridging Therapy Prior to Chimeric Antigen Receptor T Cells for Relapsed/Refractory Acute Lymphoblastic Leukemia in Children and Young Adults
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Breidenbach, Maike, Bader, Peter, Attarbaschi, Andishe, Rossig, Claudia, Meisel, Roland, Metzler, Markus, Subklewe, Marion, Mueller, Fabian, Schlegel, Paul-Gerhardt, Teichert von Lüttichau, Irene, Bourquin, Jean-Pierre, Escherich, Gabriele, Cario, Gunnar, Lang, Peter, Krauss, Ramona, von Stackelberg, Arend, Willier, Semjon, Peters, Christina, and Feuchtinger, Tobias
- Abstract
Background:Chimeric antigen receptor (CAR) T cells targeting CD19 are a well-established treatment option for children and young adults suffering from relapsed and/or refractory B-lineage acute lymphoblastic leukemia. Nonetheless, there is still insufficient data about the proper management of bridging therapy between eligibility for therapy and administration of CAR T cells taking into consideration that most of the patients are heavily pretreated. Bridging therapy has been designed to achieve a low leukemia burden prior to CAR T cell infusion. However, systematic data of bridging therapy are still limited and the effect of bridging therapy on outcome, side effects and response to CAR T cell therapy is still poorly understood. With this retrospective, multinational, large-scale study, we strive to understand the impact of low- and high-intensity bridging regimens on a variety of outcome parameters in order to improve the basis for clinical decision making in bridging therapy prior to CAR T cell administration.
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- 2023
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13. Distinct Pattern of ABL1 Genomic Breakpoints in Chronic Myeloid Leukemia and BCR::ABL1-Positive Acute Lymphoblastic Leukemia: Analysis of 884 Patients with Minor and Major BCR::ABL1 Fusion
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Hovorkova, Lenka, Winkowska, Lucie, Krotka, Justina, Krumbholz, Manuela, Meyer, Claus, Sutton, Rosemary, Henderson, Michelle, Clappier, Emmanuelle, Chiaretti, Sabina, Sramkova, Lucie, Stary, Jan, Benesova, Adela, Machova Polakova, Katerina, Marschalek, Rolf, Metzler, Markus, Cazzaniga, Giovanni, Cario, Gunnar, Trka, Jan, Zaliova, Marketa, and Zuna, Jan
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The BCR::ABL1fusion gene is a hallmark of chronic myeloid leukemia (CML) but is also found in patients with acute lymphoblastic leukemia (ALL). There are two main breakpoint clusters in BCR- “minor” (between exons 1-2, resulting in p190 fusion protein, prevalent in ALL and scarce in CML) and “Major” (between exons 13-15, resulting in p210 protein). On the ABL1side, the breakpoints are mostly localized between exons 1-3. Due to large intronic areas where the breakpoints occur, only a few papers have been published focusing on the structure of BCR::ABL1fusions. Moreover, with a single exception, these studies included only the Major- BCR::ABL1patients. Here, we focused on the analysis of BCR::ABL1breakpoints involving CML and ALL, children and adults, and Major and minor forms of fusion. To our knowledge, we present data on the largest cohort of patients with BCR::ABL1fusion identified at the DNA level described to date.
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- 2023
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14. Is the Eutos Long Term Survival (ELTS) Score a Useful Marker to Predict Outcome in Children with Newly Diagnosed Chronic Myeloid Leukemia (CML) in Chronic Phase (CP)? the Experience of the International Registry of Childhood CML
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Millot, Frederic, De Keizer, Joe, Metzler, Markus, Suttorp, Meinolf, Sedlacek, Petr, Luesink, Maaike, Cheng, Frankie WT, Kalwak, Krzysztof, Lausen, Birgitte, Jakovljevic, Gordana, De Moerloose, Barbara, Dworzak, Michael, Borisevich, Marina, Yajima, Julia, Ampatzidou, Mirella, Farah, Roula, Kaiserova, Emilia, Meral Günes, Adalet, and Baruchel, Andre
- Abstract
Aims.CML is a very rare disease in children. The present work aims to describe the characteristics of children with CML in chronic phase (CP) and to determine the outcome of this pediatric population.
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- 2023
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15. The preleukemic TCF3-PBX1 gene fusion can be generated in utero and is present in ˜0.6% of healthy newborns
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Hein, Daniel, Dreisig, Karin, Metzler, Markus, Izraeli, Shai, Schmiegelow, Kjeld, Borkhardt, Arndt, and Fischer, Ute
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- 2019
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16. The preleukemic TCF3-PBX1gene fusion can be generated in utero and is present in ≈0.6% of healthy newborns
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Hein, Daniel, Dreisig, Karin, Metzler, Markus, Izraeli, Shai, Schmiegelow, Kjeld, Borkhardt, Arndt, and Fischer, Ute
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- 2019
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17. Front-line imatinib treatment in children and adolescents with chronic myeloid leukemia: results from a phase III trial
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Suttorp, Meinolf, Schulze, Philipp, Glauche, Ingmar, Göhring, Gudrun, Neuhoff, Nils, Metzler, Markus, Sedlacek, Petr, Bont, Eveline, Balduzzi, Adriana, Lausen, Birgitte, Aleinikova, Olga, Sufliarska, Sabina, Henze, Günter, Strauss, Gabriele, Eggert, Angelika, Kremens, Bernhard, Groll, Andreas, Berthold, Frank, Klein, Christoph, Groß-Wieltsch, Ute, Sykora, Karl, Borkhardt, Arndt, Kulozik, Andreas, Schrappe, Martin, Nowasz, Christina, Krumbholz, Manuela, Tauer, Josephine, Claviez, Alexander, Harbott, Jochen, Kreipe, Hans, Schlegelberger, Brigitte, and Thiede, Christian
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A total of 156 patients (age range 1.3–18.0 years, median 13.2 years; 91 (58.3%) male) with newly diagnosed CML (N= 146 chronic phase (CML-CP), N= 3 accelerated phase (CML-AP), N= 7 blastic phase (CML-BP)) received imatinib up-front (300, 400, 500 mg/m2, respectively) within a prospective phase III trial. Therapy response, progression-free survival, causes of treatment failure, and side effects were analyzed in 148 children and adolescents with complete data. Event-free survival rate by 18 months for patients in CML-CP (median follow-up time 25 months, range: 1−120) was 97% (95% CI, 94.2−99.9%). According to the 2006 ELN-criteria complete hematologic response by month 3, complete cytogenetic response (CCyR) by month 12, and major molecular response (MMR) by month 18 were achieved in 98, 63, and 59% of the patients, respectively. By month 36, 86% of the patients achieved CCyR and 74% achieved MMR. Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response or intolerance (N= 9). In all, 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N= 3) or SCT-related complications (N = 2). This large pediatric trial extends and confirms data from smaller series that first-line imatinib in children is highly effective.
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- 2018
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18. MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia
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Germeshausen, Manuela, Ancliff, Phil, Estrada, Jaime, Metzler, Markus, Ponstingl, Eva, Rütschle, Horst, Schwabe, Dirk, Scott, Richard H., Unal, Sule, Wawer, Angela, Zeller, Bernward, and Ballmaier, Matthias
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Heterozygous mutations in MECOM (MDS1 and EVI1 complex locus) have been reported to be causative of a rare association of congenital amegakaryocytic thrombocytopenia and radioulnar synostosis. Here we report on 12 patients with congenital hypomegakaryocytic thrombocytopenia caused by MECOM mutations (including 10 novel mutations). The mutations affected different functional domains of the EVI1 protein. The spectrum of phenotypes was much broader than initially reported for the first 3 patients; we found familial as well as sporadic cases, and the clinical spectrum ranged from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormality. The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss. No single clinical manifestation was detected in all patients affected by MECOM mutations. Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1. We propose the term MECOM-associated syndrome for this heterogeneous hereditary disease and inclusion of MECOM sequencing in the diagnostic workup of congenital bone marrow failure.
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- 2018
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19. Recurrent Somatic PDGFRBMutations in Sporadic Infantile/Solitary Adult Myofibromas But Not in Angioleiomyomas and Myopericytomas
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Agaimy, Abbas, Bieg, Matthias, Michal, Michael, Geddert, Helene, Märkl, Bruno, Seitz, Jan, Moskalev, Evgeny A., Schlesner, Matthias, Metzler, Markus, Hartmann, Arndt, Wiemann, Stefan, Michal, Michal, Mentzel, Thomas, and Haller, Florian
- Abstract
Infantile myofibroma (MF) is an uncommon benign myofibroblastic tumor of infancy and childhood. Solitary adult MF shares similar features with infantile MF. The lesions occur in 3 clinicopathologic settings: solitary, multicentric, and generalized and can be either sporadic or familial. Traditionally, infantile MF has been included in the spectrum of infantile hemangiopericytoma. The recent World Health Organization classification listed MF, angioleiomyoma, and myopericytoma under the general heading of perivascular tumorsin the sense of a morphologic spectrum of perivascular myoid cell neoplasms. Although activating germline PDGFRBmutations have recently been linked to familial infantile MF, the molecular pathogenesis of sporadic infantile and adult solitary MF remained unclear. In this study, we analyzed 25 solitary MFs without evidence of familial disease (9 infantile and 16 adult MFs) to address the question whether somatic PDGFRBmutations might be responsible for the sporadic form of the disease. Given the presumed histogenetic link of MF to myopericytoma and angioleiomyoma, we additionally analyzed a control group of 6 myopericytomas and 9 angioleiomyomas for PDGFRBmutations. We detected PDGFRBmutations in 6/8 (75%) analyzable infantile and in 11/16 (69%) adult MFs but in none of the angioleiomyomas or myopericytomas. In 2 infantile MFs, additional sequencing of the germline confirmed the somatic nature of PDGFRBmutations. To our knowledge, this is the first study reporting apparently somatic recurrent PDGFRBmutations as molecular driver events in the majority of sporadic infantile and adult solitary MFs. Our results suggest molecular distinctness of MF as compared with angioleiomyoma/myopericytoma. Investigation of more cases including those with atypical and worrisome features, as well as other mimickers in the heterogenous morphologic spectrum of MF, is mandatory for validating the potential diagnostic value of PDGFRBmutation testing as a possible surrogate in difficult-to-classify lesions.
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- 2017
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20. Genotype, Clinical Course, and Therapeutic Decision Making in 76 Infants with Severe Generalized Junctional Epidermolysis Bullosa
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Hammersen, Johanna, Has, Cristina, Naumann-Bartsch, Nora, Stachel, Daniel, Kiritsi, Dimitra, Söder, Stephan, Tardieu, Mathilde, Metzler, Markus, Bruckner-Tuderman, Leena, and Schneider, Holm
- Abstract
Severe generalized junctional epidermolysis bullosa, a lethal hereditary blistering disorder, is usually treated by palliative care. Allogeneic stem cell transplantation (SCT) has been proposed as a therapeutic approach, yet without clinical evidence. Decision making was evaluated retrospectively in 76 patients with severe generalized junctional epidermolysis bullosa born in the years 2000–2015. The diagnosis was based on the absence of laminin-332 in skin biopsies. With an incidence of 1 of 150,000, severe generalized junctional epidermolysis bullosa occurred more often than published previously. Eleven as yet unreported mutations in the laminin-332 genes were detected. Although patients homozygous for the LAMB3mutation c.1903C>T lived longer than the others, life expectancy was greatly diminished (10.8 vs. 4.6 months). Most patients failed to thrive. In two patients with initially normal weight gain, the decision for SCT from haploidentical bone marrow or peripheral blood was made. Despite transiently increasing skin erosions, the clinical status of both subjects stabilized for several weeks after SCT, but finally deteriorated. Graft cells, but no laminin-332, were detected in skin biopsies. The patients died 96 and 129 days after SCT, respectively, one of them after receiving additional skin grafts. Treatment of severe generalized junctional epidermolysis bullosa by SCT is a last-ditch attempt still lacking proof of efficacy.
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- 2016
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21. Sclerosing epithelioid fibrosarcoma of the kidney: clinicopathologic and molecular study of a rare neoplasm at a novel location.
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Ohlmann, Carsten-Henning, Brecht, Ines B., Junker, Kerstin, van der Zee, Jill A., Nistor, Adriana, Bohle, Rainer M., Stöckle, Michael, Metzler, Markus, Hartmann, Arndt, and Agaimy, Abbas
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Sclerosing epithelioid fibrosarcoma (SEF) is a rare fibrosarcoma variant with specific histomorphology and consistent translocation (EWSR1-CREB3L1/2). To date, 110 cases have been reported; only 15 originated within the abdomen. With only 2 cases reported parallel to our study and one case briefly mentioned in a previous series, primary renal SEF is exceptionally rare but might be underrecognized. We herein describe 2 cases affecting a 23-year-old woman and a 43-year-old man. Tumor size was 22 and 4.2 cm, respectively. Patient 1 developed skeletal and multiple pulmonary metastases. She died of disease 82 months later, despite aggressive multimodality therapy. Patient 2 has no evidence of recurrence or metastasis (8 months after surgery). Histologic examination showed similar appearance with monotonous bland medium-sized epithelioid cells with rounded slightly vesicular nuclei and clear cytoplasm imparting a carcinoma-like appearance set within a highly sclerotic hyaline fibrous stroma. The tumor cells were arranged in nests, single cell cords, trabeculae, or solid sheets with frequent entrapment of renal tubules and glomeruli. Immunohistochemistry showed strong expression of vimentin, bcl2, CD99, and MUC4, whereas cytokeratin and other markers were negative. Fluorescence in situ hybridization showed a translocation involving the EWSR1 gene locus in case 2. Molecular analysis in case 1 was not successful due to poor signal quality. To our knowledge, this is the second report documenting primary renal SEF. Awareness of this entity would help avoid misinterpretation as clear cell carcinoma, sclerosing perivascular epithelioid cell tumor, Xp.11 translocation carcinoma, and other more frequent neoplasms at this site. [ABSTRACT FROM AUTHOR]
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- 2015
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22. Block of Counter-Regulation By Inhibition of Protein Synthesis Sensitizes Cancer Cells to IRE1α-Mediated Apoptosis Following Unfolded Protein Response
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Gsottberger, Franziska, Meier, Christina, Ammon, Anna, Parker, Scott, Wendland, Kerstin, George, Rebekka, Petkovic, Srdjan, Mellenthin, Lisa, Emmerich, Charlotte, Lutzny-Geier, Gloria, Metzler, Markus, Mackensen, Andreas, Chandramohan, Vidyalakshmi, and Mueller, Fabian
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- 2022
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23. Detection of Signature Double-Negative T Cells Is a Reliable Marker for ALPS Associated with FAS Mutation
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Eisenhauer, Nina, Miano, Maurizio, Naumann-Bartsch, Nora, Leyh, Joerg, Terranova, Paola, Hinze, Claas, Aigner, Michael, Wittkowski, Helmut, Bruns, Heiko, Ehl, Stephan, Metzler, Markus, Arkwright, Peter, Mackensen, Andreas, Rensing-Ehl, Anne, and Voelkl, Simon
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- 2022
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24. Block of Counter-Regulation By Inhibition of Protein Synthesis Sensitizes Cancer Cells to IRE1α-Mediated Apoptosis Following Unfolded Protein Response
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Gsottberger, Franziska, Meier, Christina, Ammon, Anna, Parker, Scott, Wendland, Kerstin, George, Rebekka, Petkovic, Srdjan, Mellenthin, Lisa, Emmerich, Charlotte, Lutzny-Geier, Gloria, Metzler, Markus, Mackensen, Andreas, Chandramohan, Vidyalakshmi, and Mueller, Fabian
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- 2022
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25. Detection of Signature Double-Negative T Cells Is a Reliable Marker for ALPS Associated with FAS Mutation
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Eisenhauer, Nina, Miano, Maurizio, Naumann-Bartsch, Nora, Leyh, Joerg, Terranova, Paola, Hinze, Claas, Aigner, Michael, Wittkowski, Helmut, Bruns, Heiko, Ehl, Stephan, Metzler, Markus, Arkwright, Peter, Mackensen, Andreas, Rensing-Ehl, Anne, and Voelkl, Simon
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- 2022
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26. Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome
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Völkl, Simon, Rensing-Ehl, Anne, Allgäuer, Andrea, Schreiner, Elisabeth, Lorenz, Myriam Ricarda, Rohr, Jan, Klemann, Christian, Fuchs, Ilka, Schuster, Volker, von Bueren, André O., Naumann-Bartsch, Nora, Gambineri, Eleonora, Siepermann, Kathrin, Kobbe, Robin, Nathrath, Michaela, Arkwright, Peter D., Miano, Maurizio, Stachel, Klaus-Daniel, Metzler, Markus, Schwarz, Klaus, Kremer, Anita N., Speckmann, Carsten, Ehl, Stephan, and Mackensen, Andreas
- Abstract
Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCRαβ+ CD4− CD8− double-negative T (DNT) cells. Although their phenotype resembles that of terminally differentiated or exhausted T cells, lack of KLRG1, high eomesodermin, and marginal T-bet expression point instead to a long-lived memory state with potent proliferative capacity. Here we show that despite their terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in vivo. Notably, hyperproliferation of ALPS DNT cells is associated with increased basal and activation-induced phosphorylation of serine-threonine kinases Akt and mechanistic target of rapamycin (mTOR). The mTOR inhibitor rapamycin abrogated survival and proliferation of ALPS DNT cells, but not of CD4+ or CD8+ T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation by DNT cells. Importantly, increased mitotic activity and hyperactive mTOR signaling was also observed in recently defined CD4+ or CD8+ precursor DNT cells, and mTOR inhibition specifically reduced these cells in vivo, indicating abnormal programming of Fas-deficient T cells before the DNT stage. Thus, our results identify the mTOR pathway as a major regulator of lymphoproliferation and aberrant differentiation in ALPS.
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- 2016
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27. Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome
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Völkl, Simon, Rensing-Ehl, Anne, Allgäuer, Andrea, Schreiner, Elisabeth, Lorenz, Myriam Ricarda, Rohr, Jan, Klemann, Christian, Fuchs, Ilka, Schuster, Volker, von Bueren, André O., Naumann-Bartsch, Nora, Gambineri, Eleonora, Siepermann, Kathrin, Kobbe, Robin, Nathrath, Michaela, Arkwright, Peter D., Miano, Maurizio, Stachel, Klaus-Daniel, Metzler, Markus, Schwarz, Klaus, Kremer, Anita N., Speckmann, Carsten, Ehl, Stephan, and Mackensen, Andreas
- Abstract
Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCRαβ+CD4−CD8−double-negative T (DNT) cells. Although their phenotype resembles that of terminally differentiated or exhausted T cells, lack of KLRG1, high eomesodermin, and marginal T-bet expression point instead to a long-lived memory state with potent proliferative capacity. Here we show that despite their terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in vivo. Notably, hyperproliferation of ALPS DNT cells is associated with increased basal and activation-induced phosphorylation of serine-threonine kinases Akt and mechanistic target of rapamycin (mTOR). The mTOR inhibitor rapamycin abrogated survival and proliferation of ALPS DNT cells, but not of CD4+or CD8+T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation by DNT cells. Importantly, increased mitotic activity and hyperactive mTOR signaling was also observed in recently defined CD4+or CD8+precursor DNT cells, and mTOR inhibition specifically reduced these cells in vivo, indicating abnormal programming of Fas-deficient T cells before the DNT stage. Thus, our results identify the mTOR pathway as a major regulator of lymphoproliferation and aberrant differentiation in ALPS.
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- 2016
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28. Pediatric chronic myeloid leukemia is a unique disease that requires a different approach
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Hijiya, Nobuko, Schultz, Kirk R., Metzler, Markus, Millot, Frederic, and Suttorp, Meinolf
- Abstract
Chronic myelogenous leukemia (CML) in children is relatively rare. Because of a lack of robust clinical study evidence, management of CML in children is not standardized and often follows guidelines developed for adults. Children and young adults tend to have a more aggressive clinical presentation than older adults, and prognostic scores for adult CML do not apply to children. CML in children has been considered to have the same biology as in adults, but recent data indicate that some genetic differences exist in pediatric and adult CML. Because children with CML may receive tyrosine kinase inhibitor (TKI) therapy for many decades, and are exposed to TKIs during a period of active growth, morbidities in children with CML may be distinct from those in adults and require careful monitoring. Aggressive strategies, such as eradication of CML stem cells with limited duration and intensive regimens of chemotherapy and TKIs, may be more advantageous in children as a way to avoid lifelong exposure to TKIs and their associated adverse effects. Blood and marrow transplantation in pediatric CML is currently indicated only for recurrent progressive disease, and the acute and long-term toxicities of this option should be carefully evaluated against the complications associated with lifelong use of TKIs.
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- 2016
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29. Pediatric chronic myeloid leukemia is a unique disease that requires a different approach
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Hijiya, Nobuko, Schultz, Kirk R., Metzler, Markus, Millot, Frederic, and Suttorp, Meinolf
- Abstract
Chronic myelogenous leukemia (CML) in children is relatively rare. Because of a lack of robust clinical study evidence, management of CML in children is not standardized and often follows guidelines developed for adults. Children and young adults tend to have a more aggressive clinical presentation than older adults, and prognostic scores for adult CML do not apply to children. CML in children has been considered to have the same biology as in adults, but recent data indicate that some genetic differences exist in pediatric and adult CML. Because children with CML may receive tyrosine kinase inhibitor (TKI) therapy for many decades, and are exposed to TKIs during a period of active growth, morbidities in children with CML may be distinct from those in adults and require careful monitoring. Aggressive strategies, such as eradication of CML stem cells with limited duration and intensive regimens of chemotherapy and TKIs, may be more advantageous in children as a way to avoid lifelong exposure to TKIs and their associated adverse effects. Blood and marrow transplantation in pediatric CML is currently indicated only for recurrent progressive disease, and the acute and long-term toxicities of this option should be carefully evaluated against the complications associated with lifelong use of TKIs.
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- 2016
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30. Pulmonary Dysfunction after Pediatric COVID-19
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Heiss, Rafael, Tan, Lina, Schmidt, Sandy, Regensburger, Adrian P., Ewert, Franziska, Mammadova, Dilbar, Buehler, Adrian, Vogel-Claussen, Jens, Voskrebenzev, Andreas, Rauh, Manfred, Rompel, Oliver, Nagel, Armin M., Lévy, Simon, Bickelhaupt, Sebastian, May, Matthias S., Uder, Michael, Metzler, Markus, Trollmann, Regina, Woelfle, Joachim, Wagner, Alexandra L., and Knieling, Ferdinand
- Abstract
Low-field-strength MRI showed persistent pulmonary dysfunction in children and adolescents who recovered from COVID-19 and those with long COVID.
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- 2022
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31. Malignant Epithelioid Peripheral Nerve Sheath Tumor With Prominent ReticularMicrocystic Pattern in a Child
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Agaimy, Abbas, Stachel, Klaus-Daniel, Jüngert, Jörg, Radkow, Tanja, Carbon, Roman, Metzler, Markus, and Holter, Wolfgang
- Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) constitute <2 of soft tissue neoplasms in children and display a wide histologic spectrum including low-grade and epithelioid variants, although most are high-grade spindle cell sarcomas. Here, we describe an unusual case of a large retroperitoneal epithelioid MPNST diagnosed in a 7-year-old girl without family history or clinical features of neurofibromatosis type 1. The patient was treated by repeated surgical interventions, polychemotherapy, autologous stem cell transplantation, and irradiation therapy. Over the years, she developed multiple disseminated abdominal recurrences but is currently alive with very slowly progressing disseminated intra-abdominal disease 18 years from initial diagnosis. Histologically, the tumor was composed of medium-sized polygonal and ovoid-to-spindled cells set within a copious myxoid matrix with a prominent reticular and microcystic pattern reminiscent of the recently described reticularmicrocystic schwannoma. Immunohistochemistry revealed strong and diffuse expression of S100, CD56, CD57, collagen IV, and neuron-specific enolase, with negativity for perineurial cell markers (claudin-1, epithelial membrane antigen, and glucose transporter-1) and other lineage-specific mesenchymal and epithelial antigens. This unusual variant of low-grade MPNST must be differentiated from a variety of other entities, in particular benign perineurioma, myxoid neurofibroma, and benign reticularmicrocystic schwannoma. Confinement of the recurrent disease to the abdominal cavity emphasizes the necessity of primary curative wide excision of this highly recurring but nonmetastasizing low-grade neoplasm.
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- 2014
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32. ETV6/RUNX1-positive relapses evolve from an ancestral clone and frequently acquire deletions of genes implicated in glucocorticoid signaling
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Kuster, Lilian, Grausenburger, Reinhard, Fuka, Gerhard, Kaindl, Ulrike, Krapf, Gerd, Inthal, Andrea, Mann, Georg, Kauer, Maximilian, Rainer, Johannes, Kofler, Reinhard, Hall, Andrew, Metzler, Markus, Meyer, Lüder Hinrich, Meyer, Claus, Harbott, Jochen, Marschalek, Rolf, Strehl, Sabine, Haas, Oskar A., and Panzer-Grümayer, Renate
- Abstract
Approximately 25% of childhood acute lymphoblastic leukemias carry the ETV6/RUNX1 fusion gene. Despite their excellent initial treatment response, up to 20% of patients relapse. To gain insight into the relapse mechanisms, we analyzed single nucleotide polymorphism arrays for DNA copy number aberrations (CNAs) in 18 matched diagnosis and relapse leukemias. CNAs were more abundant at relapse than at diagnosis (mean 12.5 vs 7.5 per case; P = .01) with 5.3 shared on average. Their patterns revealed a direct clonal relationship with exclusively new aberrations at relapse in only 21.4%, whereas 78.6% shared a common ancestor and subsequently acquired distinct CNA. Moreover, we identified recurrent, mainly nonoverlapping deletions associated with glucocorticoid-mediated apoptosis targeting the Bcl2 modifying factor (BMF) (n = 3), glucocorticoid receptor NR3C1 (n = 4), and components of the mismatch repair pathways (n = 3). Fluorescence in situ hybridization screening of additional 24 relapsed and 72 nonrelapsed ETV6/RUNX1-positive cases demonstrated that BMF deletions were significantly more common in relapse cases (16.6% vs 2.8%; P = .02). Unlike BMF deletions, which were always already present at diagnosis, NR3C1 and mismatch repair aberrations prevailed at relapse. They were all associated with leukemias, which poorly responded to treatment. These findings implicate glucocorticoid-associated drug resistance in ETV6/RUNX1-positive relapse pathogenesis and therefore might help to guide future therapies.
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- 2011
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33. ETV6/RUNX1-positive relapses evolve from an ancestral clone and frequently acquire deletions of genes implicated in glucocorticoid signaling
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Kuster, Lilian, Grausenburger, Reinhard, Fuka, Gerhard, Kaindl, Ulrike, Krapf, Gerd, Inthal, Andrea, Mann, Georg, Kauer, Maximilian, Rainer, Johannes, Kofler, Reinhard, Hall, Andrew, Metzler, Markus, Meyer, Lüder Hinrich, Meyer, Claus, Harbott, Jochen, Marschalek, Rolf, Strehl, Sabine, Haas, Oskar A., and Panzer-Grümayer, Renate
- Abstract
Approximately 25% of childhood acute lymphoblastic leukemias carry the ETV6/RUNX1fusion gene. Despite their excellent initial treatment response, up to 20% of patients relapse. To gain insight into the relapse mechanisms, we analyzed single nucleotide polymorphism arrays for DNA copy number aberrations (CNAs) in 18 matched diagnosis and relapse leukemias. CNAs were more abundant at relapse than at diagnosis (mean 12.5 vs 7.5 per case; P= .01) with 5.3 shared on average. Their patterns revealed a direct clonal relationship with exclusively new aberrations at relapse in only 21.4%, whereas 78.6% shared a common ancestor and subsequently acquired distinct CNA. Moreover, we identified recurrent, mainly nonoverlapping deletions associated with glucocorticoid-mediated apoptosis targeting the Bcl2 modifying factor (BMF) (n = 3), glucocorticoid receptor NR3C1(n = 4), and components of the mismatch repair pathways (n = 3). Fluorescence in situ hybridization screening of additional 24 relapsed and 72 nonrelapsed ETV6/RUNX1-positive cases demonstrated that BMFdeletions were significantly more common in relapse cases (16.6% vs 2.8%; P= .02). Unlike BMFdeletions, which were always already present at diagnosis, NR3C1and mismatch repair aberrations prevailed at relapse. They were all associated with leukemias, which poorly responded to treatment. These findings implicate glucocorticoid-associated drug resistance in ETV6/RUNX1-positive relapse pathogenesis and therefore might help to guide future therapies.
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- 2011
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34. A Phase I/II Study of Bosutinib in Pediatric Patients with Resistant/Intolerant or Newly Diagnosed Philadelphia Chromosome-Positive Chronic Myeloid Leukemia, Study ITCC (Innovative Therapies for Children with Cancer European Consortium) 054 and COG (Children's Oncology Group Consortium) AAML1921: Results from the Phase I Trial in Resistant/Intolerant Patients
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Pennesi, Edoardo, Brivio, Erica, Willemse, Marieke E., Huitema, Alwin D.R., Chandra, Saurabh, Vijayakumar, Ashwini, Van Der Velden, Vincent H.J., Beverloo, H. Berna, Durairaj, Chandra, Viqueira, Andrea, Ingrosso, Antonella, Locatelli, Franco, Motwani, Jayashree, Bourquin, Jean-Pierre, Bautista Sirvent, Francisco J., Rizzari, Carmelo, Petit, Arnaud, Lancaster, Donna, Metzler, Markus, Bertrand, Yves, Murillo-Sanjuán, Laura, Bukowkinski, Andrew J., Krystal, Julie, Van Der Sluis, Inge M., Roth, Michael E., Van Tinteren, Harm, Hijiya, Nobuko, and Zwaan, Christian M.
- Abstract
Bosutinib is a tyrosine kinase inhibitor (TKI), approved for adults with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML); 400 mg in newly diagnosed (ND) patients (pts), and 500 mg in resistant/intolerant (R/I) pts, administered once daily (QD) with food. Its toxicity profile differs from other TKIs approved in children (imatinib, dasatinib and nilotinib), showing a higher incidence of gastrointestinal (GI) adverse events (AEs) but fewer toxicities such as musculoskeletal AEs (Cortes JE et al, 2016). Furthermore, in mice, bosutinib showed less growth impairment compared to other TKIs (Tauer JT et al, 2015).
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- 2021
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35. A Phase I/II Study of Bosutinib in Pediatric Patients with Resistant/Intolerant or Newly Diagnosed Philadelphia Chromosome-Positive Chronic Myeloid Leukemia, Study ITCC (Innovative Therapies for Children with Cancer European Consortium) 054 and COG (Children's Oncology Group Consortium) AAML1921: Results from the Phase I Trial in Resistant/Intolerant Patients
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Pennesi, Edoardo, Brivio, Erica, Willemse, Marieke E., Huitema, Alwin D. R., Chandra, Saurabh, Vijayakumar, Ashwini, Van Der Velden, Vincent H.J., Beverloo, H. Berna, Durairaj, Chandra, Viqueira, Andrea, Ingrosso, Antonella, Locatelli, Franco, Motwani, Jayashree, Bourquin, Jean-Pierre, Bautista Sirvent, Francisco J., Rizzari, Carmelo, Petit, Arnaud, Lancaster, Donna, Metzler, Markus, Bertrand, Yves, Murillo-Sanjuán, Laura, Bukowkinski, Andrew J., Krystal, Julie, Van Der Sluis, Inge M., Roth, Michael E., Van Tinteren, Harm, Hijiya, Nobuko, and Zwaan, Christian M.
- Abstract
Durairaj: Pfizer Inc: Current Employment, Current equity holder in publicly-traded company. Viqueira: Pfizer: Current Employment, Current equity holder in publicly-traded company. Ingrosso: Pfizer: Current Employment, Current equity holder in publicly-traded company. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Hijiya: Novartis: Consultancy; Stemline Therapeutics: Consultancy. Zwaan: SANOFI: Consultancy; NOVARTIS: Consultancy; ROCHE: Consultancy; INCYTE: Consultancy; PFIZER: Consultancy, Research Funding; JAZZ: Other: travel funding, Research Funding; BMS: Research Funding; Abbvie: Research Funding.
- Published
- 2021
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36. Hematologic Features and Clinical Course of an Infant With Pearson Syndrome Caused by a Novel Deletion of Mitochondrial DNA
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Knerr, Ina, Metzler, Markus, Niemeyer, Charlotte Marie, Holter, Wolfgang, Gerecke, Anja, Baumann, Irith, Trollmann, Regina, and Repp, Reinald
- Abstract
Pearson bone marrow-pancreas syndrome (PS) is a rare, usually fatal mitochondrial disorder involving the hematopoietic system in early infancy. Due to the diversity of clinical symptoms, the diagnosis can be difficult. The authors describe a boy with severe hypoplastic anemia in whom extensive clinical, biochemical, and morphologic findings led to the diagnosis of PS, and molecular analysis revealed a novel deletion of mitochondrial DNA from nucleotide position 10.371 to 14.607.
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- 2003
37. Late relapses evolve from slow-responding subclones in t(12;21)-positive acute lymphoblastic leukemia: evidence for the persistence of a preleukemic clone
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Konrad, Marianne, Metzler, Markus, Panzer, Simon, Östreicher, Iris, Peham, Martina, Repp, Reinald, Haas, Oskar A., Gadner, Helmut, and Panzer-Grümayer, E. Renate
- Abstract
TEL/AML1-positive childhood acute lymphoblastic leukemias (ALLs) generally have low-risk features, but still about 20% of patients relapse. Our initial molecular genetic analyses in 2 off-treatment relapses suggested that the initial and relapse clones represent different subclones that evolved from a common TEL/AML1-positive, treatment-resistant precursor. In order to further elaborate on this hypothesis, we studied 2 patients with late systemic relapses of their TEL/AML1-positive ALL (41 months and 49 months after initial diagnosis, respectively) who had distinct clonal antigen receptor gene rearrangements at diagnosis and relapse. These clone-specific markers enabled us to determine the responsiveness of the individual clones to treatment. The matching genomic TEL/AML1 breakpoints of the initial and the relapse clones in these patients confirmed their origin from a common progenitor cell. This proof was especially important in one of these 2 leukemias without a common antigen receptor gene rearrangement. Our retrospective analysis revealed that in both cases the relapse clone was already present at diagnosis. Despite their small sizes (5 × 10−3 and 1 × 10−4, respectively), we were able to detect their much slower responses to therapy compared with the dominant leukemic clone. Moreover, in all instances, these initially slow-responding clones, after they had developed into the relapse leukemia, were rapidly eradicated by the relapse treatment, underlining their different biology at the 2 time points of leukemia manifestation. We thus hypothesize that the minor clone was not fully malignant at initial diagnosis but acquired further mutations that may be necessary for the manifestation of relapse.
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- 2003
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38. Late relapses evolve from slow-responding subclones in t(12;21)-positive acute lymphoblastic leukemia: evidence for the persistence of a preleukemic clone
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Konrad, Marianne, Metzler, Markus, Panzer, Simon, Östreicher, Iris, Peham, Martina, Repp, Reinald, Haas, Oskar A., Gadner, Helmut, and Panzer-Grümayer, E. Renate
- Abstract
TEL/AML1-positive childhood acute lymphoblastic leukemias (ALLs) generally have low-risk features, but still about 20% of patients relapse. Our initial molecular genetic analyses in 2 off-treatment relapses suggested that the initial and relapse clones represent different subclones that evolved from a common TEL/AML1-positive, treatment-resistant precursor. In order to further elaborate on this hypothesis, we studied 2 patients with late systemic relapses of their TEL/AML1-positive ALL (41 months and 49 months after initial diagnosis, respectively) who had distinct clonal antigen receptor gene rearrangements at diagnosis and relapse. These clone-specific markers enabled us to determine the responsiveness of the individual clones to treatment. The matching genomic TEL/AML1 breakpoints of the initial and the relapse clones in these patients confirmed their origin from a common progenitor cell. This proof was especially important in one of these 2 leukemias without a common antigen receptor gene rearrangement. Our retrospective analysis revealed that in both cases the relapse clone was already present at diagnosis. Despite their small sizes (5 × 10−3and 1 × 10−4, respectively), we were able to detect their much slower responses to therapy compared with the dominant leukemic clone. Moreover, in all instances, these initially slow-responding clones, after they had developed into the relapse leukemia, were rapidly eradicated by the relapse treatment, underlining their different biology at the 2 time points of leukemia manifestation. We thus hypothesize that the minor clone was not fully malignant at initial diagnosis but acquired further mutations that may be necessary for the manifestation of relapse.
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- 2003
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39. Novel MLL2Mutation in Kabuki Syndrome With Hypogammaglobulinemia and Severe Chronic Thrombopenia
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Brackmann, Florian, Krumbholz, Manuela, Langer, Thorsten, Rascher, Wolfgang, Holter, Wolfgang, and Metzler, Markus
- Abstract
Kabuki syndrome is a rare condition characterized by distinct dysmorphic features and a broad spectrum of organ anomalies. Differentiating it from other syndromes can be difficult, particularly in patients with incomplete phenotypic manifestation. Recently, MLL2gene mutations were identified as the underlying genetic cause of Kabuki syndrome in the majority of cases.
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- 2013
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40. Screening for leukemia- and clone-specific markers at birth in children with T-cell precursor ALL suggests a predominantly postnatal origin
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Fischer, Susanna, Mann, Georg, Konrad, Marianne, Metzler, Markus, Ebetsberger, Georg, Jones, Neil, Nadel, Bertrand, Bodamer, Olaf, Haas, Oskar A., Schmitt, Klaus, and Panzer-Grümayer, E. Renate
- Abstract
Childhood T-cell precursor acute lymphoblastic leukemia (TCP ALL) is an aggressive disease with a presumably short latency that differs in many biologic respects from B-cell precursor (BCP) ALL. We therefore addressed the issue of in utero origin of this particular type of leukemia by tracing oncogenic mutations and clone-specific molecular markers back to birth. These markers included various first- and second-hit genetic alterations (TCRD-LMO2 breakpoint regions, n = 2; TAL1 deletions, n = 3; Notch1 mutations, n = 1) and nononcogenic T-cell receptor rearrangements (n = 13) that were derived from leukemias of 16 children who were 1.5 to 11.2 years old at diagnosis of leukemia. Despite highly sensitive polymerase chain reaction (PCR) approaches (1 cell with a specific marker among 100 000 normal cells), we identified the leukemic clone in the neonatal blood spots in only 1 young child. These data suggest that in contrast to BCP ALL most TCP ALL cases are initiated after birth.
- Published
- 2007
- Full Text
- View/download PDF
41. Screening for leukemia- and clone-specific markers at birth in children with T-cell precursor ALL suggests a predominantly postnatal origin
- Author
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Fischer, Susanna, Mann, Georg, Konrad, Marianne, Metzler, Markus, Ebetsberger, Georg, Jones, Neil, Nadel, Bertrand, Bodamer, Olaf, Haas, Oskar A., Schmitt, Klaus, and Panzer-Grümayer, E. Renate
- Abstract
Childhood T-cell precursor acute lymphoblastic leukemia (TCP ALL) is an aggressive disease with a presumably short latency that differs in many biologic respects from B-cell precursor (BCP) ALL. We therefore addressed the issue of in utero origin of this particular type of leukemia by tracing oncogenic mutations and clone-specific molecular markers back to birth. These markers included various first- and second-hit genetic alterations (TCRD-LMO2breakpoint regions, n = 2; TAL1deletions, n = 3; Notch1mutations, n = 1) and nononcogenic T-cell receptor rearrangements (n = 13) that were derived from leukemias of 16 children who were 1.5 to 11.2 years old at diagnosis of leukemia. Despite highly sensitive polymerase chain reaction (PCR) approaches (1 cell with a specific marker among 100 000 normal cells), we identified the leukemic clone in the neonatal blood spots in only 1 young child. These data suggest that in contrast to BCP ALL most TCP ALL cases are initiated after birth.
- Published
- 2007
- Full Text
- View/download PDF
42. Vaccination with Live Attenuated Virus Vaccines in Four Pediatric Patients with CML While on Imatinib Treatment
- Author
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Bettoni Da Cunha-Riehm, Claudia, Hildebrand, Verena, Nathrath, Michaela, Metzler, Markus, and Suttorp, Meinolf
- Abstract
No relevant conflicts of interest to declare.
- Published
- 2019
- Full Text
- View/download PDF
43. The Influence of the Age of the Bone Marrow Microenvironment on Leukaemia Progression
- Author
-
Zanetti, Costanza, Ender, Joscha, Hartmann, Mark, Hey, Joschka, Godavarthy, Parimala Sonika, Weissenberger, Eva, Kumar, Rahul, Metzler, Markus, Gu, Zhaohui, Roberts, Kathryn G., Filmann, Natalie, Bloomfield, Clara D., Stock, Wendy, Mullighan, Charles G., Lipka, Daniel B., and Krause, Daniela S.
- Abstract
Kumar: Merck: Research Funding; European Patent No. 16187926.7: Other: USE OF FIBRONECTIN OR ILK INHIBITORS FOR USE IN THE TREATMENT OF LEUKEMIA. Stock:Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria. Mullighan:Amgen: Honoraria, Other: speaker, sponsored travel; Loxo Oncology: Research Funding; AbbVie: Research Funding; Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding. Lipka:InfectoPharm GmbH: Employment. Krause:Merck KGaA: Research Funding; Patent: Patents & Royalties: European Patents No. 16187926.7-1401, EP18184430.9-.
- Published
- 2019
- Full Text
- View/download PDF
44. The Influence of the Age of the Bone Marrow Microenvironment on Leukaemia Progression
- Author
-
Zanetti, Costanza, Ender, Joscha, Hartmann, Mark, Hey, Joschka, Godavarthy, Parimala Sonika, Weissenberger, Eva, Kumar, Rahul, Metzler, Markus, Gu, Zhaohui, Roberts, Kathryn G., Filmann, Natalie, Bloomfield, Clara D., Stock, Wendy, Mullighan, Charles G., Lipka, Daniel B., and Krause, Daniela S.
- Abstract
B-cell acute lymphoblastic leukaemia (B-ALL) occurs most commonly in children, while chronic myeloid leukaemia (CML) is more frequent in adults. So far, the myeloid bias of haematopoiesis in elderly people has been considered the main reason for these differences in leukaemia phenotype in different age groups. However, differential contribution of a young versus an old bone marrow (BM) microenvironment (BMM) to leukaemia development may have been underrecognized given the fact that the BMM undergoes constant remodelling during a lifetime.
- Published
- 2019
- Full Text
- View/download PDF
45. High Platelet Counts, Thrombosis, Bleeding Signs, and Acquired Von Willebrand Syndrome at Diagnosis of Pediatric Chronic Myeloid Leukemia
- Author
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Suttorp, Meinolf, Knoefler, Ralf, Deutsch, Hélène, Paul, Franziska, Tiebel, Oliver, Metzler, Markus, and Millot, Frederic
- Abstract
Background:At diagnosis of chronic myeloid leukemia (CML) patients (pats) may present with elevated platelets (PLT) counts. Generally, high PLT counts may result in thrombosis and/or bleeding complications, the latter being due to binding of von Willebrand factor (VWF) multimers to platelets. Pediatric CML is very rare (Hijiya N, Suttorp M 2019; Blood 33:2374-2384) and no systematic investigation on clinical complications of elevated PLT counts has so far been reported.
- Published
- 2019
- Full Text
- View/download PDF
46. High Platelet Counts, Thrombosis, Bleeding Signs, and Acquired Von Willebrand Syndrome at Diagnosis of Pediatric Chronic Myeloid Leukemia
- Author
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Suttorp, Meinolf, Knoefler, Ralf, Deutsch, Hélène, Paul, Franziska, Tiebel, Oliver, Metzler, Markus, and Millot, Frederic
- Abstract
No relevant conflicts of interest to declare.
- Published
- 2019
- Full Text
- View/download PDF
47. Vaccination with Live Attenuated Virus Vaccines in Four Pediatric Patients with CML While on Imatinib Treatment
- Author
-
Bettoni Da Cunha-Riehm, Claudia, Hildebrand, Verena, Nathrath, Michaela, Metzler, Markus, and Suttorp, Meinolf
- Abstract
Background:Documented experience on vaccination while on imatinib treatment is missing in children. According to current recommendations for all age groups of immunocompromised individuals inactive vaccines can safely be administered. However, depending on the grade of immunosuppression the immune response may be reduced or missing. Live attenuated vaccines must not be administered to immunosuppressed individuals according to general recommendations.
- Published
- 2019
- Full Text
- View/download PDF
48. Response to Front-Line Imatinib Treatment in Children and Adolescents with CML - Data from a Large Pediatric Cohort
- Author
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Suttorp, Meinolf, Schulze, Philipp, Glauche, Ingmar, Göhring, Gudrun, Von Neuhoff, Nils, Metzler, Markus, Sedlacek, Petr, de Bont, Eveline S., Balduzzi, Adriana, Lausen, Birgitte, Aleinikova, Olga, Sufliarska, Sabina, Henze, Guenter, Strauss, Gabriele, Eggert, Angelika, Kremens, Bernhard, Groll, Andreas H, Berthold, Frank, Klein, Christoph, Gross-Wieltsch, Ute, Sykora, Karl-Walter, Borkhardt, Arndt, Kulozik, Andreas E., Schrappe, Martin, Nowasz, Christina, Krumbholz, Manuela, Tauer, Josephine Tabea, Claviez, Alexander, Harbott, Jochen, Kreipe, Hans H, Schlegelberger, Brigitte, and Thiede, Christian
- Abstract
Suttorp: Novartis: Research Funding. Schrappe: JAZZ Pharma: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; SigmaTau: Consultancy, Research Funding; Medac: Consultancy, Research Funding. Thiede: Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Roche: Consultancy; Agendix: Employment.
- Published
- 2017
- Full Text
- View/download PDF
49. Response to Front-Line Imatinib Treatment in Children and Adolescents with CML - Data from a Large Pediatric Cohort
- Author
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Suttorp, Meinolf, Schulze, Philipp, Glauche, Ingmar, Göhring, Gudrun, Von Neuhoff, Nils, Metzler, Markus, Sedlacek, Petr, de Bont, Eveline S., Balduzzi, Adriana, Lausen, Birgitte, Aleinikova, Olga, Sufliarska, Sabina, Henze, Guenter, Strauss, Gabriele, Eggert, Angelika, Kremens, Bernhard, Groll, Andreas H, Berthold, Frank, Klein, Christoph, Gross-Wieltsch, Ute, Sykora, Karl-Walter, Borkhardt, Arndt, Kulozik, Andreas E., Schrappe, Martin, Nowasz, Christina, Krumbholz, Manuela, Tauer, Josephine Tabea, Claviez, Alexander, Harbott, Jochen, Kreipe, Hans H, Schlegelberger, Brigitte, and Thiede, Christian
- Abstract
Purpose
- Published
- 2017
- Full Text
- View/download PDF
50. Nivolumab As Salvage Therapy in Pediatric Patients with Relapsed and Refractory Lymphomas
- Author
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Naumann-Bartsch, Nora, Stachel, Daniel, Chada, Martin, Fritscher, Torsten, Rompel, Oliver, Haller, Florian, Hartmann, Arndt, Wößmann, Wilhelm, and Metzler, Markus
- Abstract
No relevant conflicts of interest to declare.
- Published
- 2016
- Full Text
- View/download PDF
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