697 results on '"Ulrich Germing"'
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2. Chronic myelomonocytic leukemia with ring sideroblasts/SF3B1 mutation presents with low monocyte count and resembles myelodysplastic syndromes with-RS/SF3B1 mutation in terms of phenotype and prognosis
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Blanca Xicoy, Helena Pomares, Mireia Morgades, Ulrich Germing, Montserrat Arnan, Mar Tormo, Laura Palomo, Elisa Orna, Matteo Della Porta, Felicitas Schulz, Marina Díaz-Beya, Ada Esteban, Antonieta Molero, Luca Lanino, Alejandro Avendaño, Francisca Hernández, Verónica Roldan, Marta Ubezio, Alberto Pineda, María Díez-Campelo, and Lurdes Zamora
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CMML-RS/SF3B1 ,CMML ,MDS-RS/SF3B1 ,phenotype ,mutational profile ,prognosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
IntroductionChronic myelomonocytic leukemia (CMML) and myelodysplastic syndromes (MDS) with ring sideroblasts (RS) or SF3B1 mutation (MDS-RS/SF3B1) differ in many clinical features, but share others, such as anemia. RS and SF3B1 mutation can also be found in CMML.MethodsWe compared CMML with and without RS/SF3B1 and MDS-RS/SF3B1 considering the criteria established by the 2022 World Health Organization classification.ResultsA total of 815 patients were included (CMML, n=319, CMML-RS/SF3B1, n=172 and MDS-RS/SF3B1, n=324). The percentage of RS was ≥15% in almost all CMML-RS/SF3B1 patients (169, 98.3%) and most (125, 72.7%) showed peripheral blood monocyte counts between 0.5 and 0.9 x109/L and low risk prognostic categories. CMML-RS/SF3B1 differed significantly from classical CMML in the main clinical characteristics, whereas it resembled MDS-RS/SF3B1. At a molecular level, CMML and CMML-RS/SF3B1 had a significantly higher frequency of mutations in TET2 (mostly multi-hit) and ASXL1 (p=0.013) and CMML had a significantly lower frequency of DNMT3A and SF3B1 mutations compared to CMML/MDS-RS/SF3B1. Differences in the median overall survival among the three groups were statistically significant: 6.75 years (95% confidence interval [CI] 5.41-8.09) for CMML-RS/SF3B1 vs. 3.17 years (95% CI 2.56-3.79) for CMML vs. 16.47 years (NA) for MDS-RS/SF3B1, p
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- 2024
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3. Comparison of cytomorphology and histomorphology in myelodysplastic syndromes
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Kathrin Nachtkamp, Corinna Strupp, Rosa Faoro, Norbert Gattermann, Sascha Dietrich, Ulrich Germing, and Stefan Baldus
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myelodysplastic syndromes ,cytomorphology ,histopathology ,prognosis ,WHO2022 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Gold standard for the establishment of the diagnosis of myelodysplastic syndromes (MDS) are cytomorphological features of hematopoietic cells in peripheral blood and bone marrow aspirates. There is increasing evidence that bone marrow histomorphology not only aids in the diagnosis of MDS but can provide additional prognostic information, particularly through assessment of fibrosis and cellularity. However, there is only sparse data on direct comparison between histological and cytomorphological findings within the same MDS patient cohort. Therefore, we performed such an analysis under exceptionally well-standardized conditions. We reexamined biopsy material of 128 patients from the Düsseldorf MDS registry who underwent bone marrow trephine biopsy (in addition to bone marrow aspiration) at the time of diagnosis, addressing the following items: a. Analysis of concordance of diagnoses made by histology and cytomorphology b. Analysis of additional information by histology with regard to the diagnosis and prognosis. The respective biomaterials were available at our institution and had been processed according to unchanged protocols between 1992 and 2010. Fresh histopathological sections were obtained from the tissue blocks, stained under identical conditions and re-assessed by a designated expert pathologist (C.B.) without knowledge of the previous histopathological report or the respective cytomorphological diagnosis. The latter, likewise, was uniformly made by the same expert cytomorphologist (U.G.). Histopathology of bone marrow trephine biopsies reliably captured the diagnosis of MDS. Assignment to the diagnostic WHO subgroup was not entirely concordant with cytomorphology, mainly due to incongruences between the proportion of CD34-positive cells on histopathology and the cytomorphological blast count. Histopathology provided additional diagnostic and prognostic information with high diagnostic and prognostic significance, such as fibrosis. Likewise, histopathology allowed more reliable estimation of bone marrow cellularity.
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- 2024
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4. Allogeneic hematopoietic stem cell transplantation and pre-transplant strategies in patients with NPM1-mutated acute myeloid leukemia: a single center experience
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Paul Jäger, Christina Rautenberg, Jennifer Kaivers, Annika Kasprzak, Stefanie Geyh, Ben-Niklas Baermann, Rainer Haas, Ulrich Germing, Thomas Schroeder, and Guido Kobbe
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Medicine ,Science - Abstract
Abstract Patients with acute myeloid leukemia (AML) and nucleophosmin 1 gene mutations (NPM1mut) show a favorable prognosis with chemotherapy (CT) in the absence of negative prognostic genetic abnormalities. Between 2008 and 2021 64 patients with NPM1mutAML received alloHSCT because of additional adverse prognostic factors (1st line), inadequate response to or relapse during or after CT (2nd line). To expand the evidence in alloTX in NPM1mut AML, clinical and molecular data were retrospectively analyzed with respect to pre-transplant strategies and outcome. Patients with minimal residual disease negative (MRD−) CR at transplant had better 2-y-PFS and 2-y-OS (77% and 88%) than patients with minimal residual disease positive (MRD+) CR (41% and 71%) or patients with active disease (AD) at transplant (20% and 52%). The 2nd line patients with relapse after completing CT responded well to high dose cytarabine based salvage chemotherapy (salvage CT) in contrast to patients relapsing while still on CT (90% vs 20%, P = 0.0170). 2-y-PFS and 2-y-OS was 86% in patients who achieved a 2nd MRD− CR pre alloHSCT. Outcome in NPM1mutAML depends on disease burden at alloHSCT. Time and type of relapse in relation to CT are predictive for response to salvage CT.
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- 2023
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5. Overlapping Stromal Alterations in Myeloid and Lymphoid Neoplasms
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Lucienne Bogun, Annemarie Koch, Bo Scherer, Ulrich Germing, Roland Fenk, Uwe Maus, Felix Bormann, Karl Köhrer, Patrick Petzsch, Thorsten Wachtmeister, Guido Kobbe, Sascha Dietrich, Rainer Haas, Thomas Schroeder, Stefanie Geyh, and Paul Jäger
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myeloid neoplasms ,lymphoid neoplasms ,MPN ,MDS ,AML ,ALL ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Myeloid and lymphoid neoplasms share the characteristics of potential bone marrow infiltration as a primary or secondary effect, which readily leads to hematopoietic insufficiency. The mechanisms by which clonal malignant cells inhibit normal hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) have not been unraveled so far. Given the pivotal role of mesenchymal stromal cells (MSCs) in the regulation of hematopoiesis in the BM niche it is assumed that MSCs also play a relevant role in the pathogenesis of hematological neoplasms. We aimed to identify overlapping mechanisms in MSCs derived from myeloid and lymphoid neoplasms contributing to disease progression and suppression of HSPCs to develop interventions that target these mechanisms. MSCs derived from healthy donors (n = 44) and patients diagnosed with myeloproliferative neoplasia (n = 11), myelodysplastic syndromes (n = 16), or acute myeloid leukemia (n = 25) and B-Non-Hodgkin lymphoma (n = 9) with BM infiltration and acute lymphoblastic leukemia (n = 9) were analyzed for their functionality and by RNA sequencing. A reduced growth and differentiation capacity of MSCs was found in all entities. RNA sequencing distinguished both groups but clearly showed overlapping differentially expressed genes, including major players in the BMP/TGF and WNT-signaling pathway which are crucial for growth, osteogenesis, and hematopoiesis. Functional alterations in healthy MSCs were inducible by exposure to supernatants from malignant cells, implicating the involvement of these factors in disease progression. Overall, we were able to identify overlapping factors that pose potential future therapeutic targets.
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- 2024
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6. Molecular and clinical aspects relevant for counseling individuals with clonal hematopoiesis of indeterminate potential
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Anna Maria Cacic, Felicitas Isabel Schulz, Ulrich Germing, Sascha Dietrich, and Norbert Gattermann
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clonal hematopoiesis of indeterminate potential (CHIP) ,preleukemia ,myelodysplastic syndromes ,germline mutations ,PARP inhibitors ,mutation analysis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) has fascinated the medical community for some time. Discovered about a decade ago, this phenomenon links age-related alterations in hematopoiesis not only to the later development of hematological malignancies but also to an increased risk of early-onset cardiovascular disease and some other disorders. CHIP is detected in the blood and is characterized by clonally expanded somatic mutations in cancer-associated genes, predisposing to the development of hematologic neoplasms such as MDS and AML. CHIP-associated mutations often involve DNA damage repair genes and are frequently observed following prior cytotoxic cancer therapy. Genetic predisposition seems to be a contributing factor. It came as a surprise that CHIP significantly elevates the risk of myocardial infarction and stroke, and also contributes to heart failure and pulmonary hypertension. Meanwhile, evidence of mutant clonal macrophages in vessel walls and organ parenchyma helps to explain the pathophysiology. Besides aging, there are some risk factors promoting the appearance of CHIP, such as smoking, chronic inflammation, chronic sleep deprivation, and high birth weight. This article describes fundamental aspects of CHIP and explains its association with hematologic malignancies, cardiovascular disorders, and other medical conditions, while also exploring potential progress in the clinical management of affected individuals. While it is important to diagnose conditions that can lead to adverse, but potentially preventable, effects, it is equally important not to stress patients by confronting them with disconcerting findings that cannot be remedied. Individuals with diagnosed or suspected CHIP should receive counseling in a specialized outpatient clinic, where professionals from relevant medical specialties may help them to avoid the development of CHIP-related health problems. Unfortunately, useful treatments and clinical guidelines for managing CHIP are still largely lacking. However, there are some promising approaches regarding the management of cardiovascular disease risk. In the future, strategies aimed at restoration of gene function or inhibition of inflammatory mediators may become an option.
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- 2023
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7. Infectious Complications in Patients with Myelodysplastic Syndromes: A Report from the Düsseldorf MDS Registry
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Annika Kasprzak, Julia Andresen, Kathrin Nachtkamp, Andrea Kündgen, Felicitas Schulz, Corinna Strupp, Guido Kobbe, Colin MacKenzie, Jörg Timm, Sascha Dietrich, Norbert Gattermann, and Ulrich Germing
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myelodysplastic syndromes ,infectious complications ,prognosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Despite notable advancements in infection prevention and treatment, individuals with hematologic malignancies still face the persistent threat of frequent and life-threatening complications. Those undergoing chemotherapy or other disease-modifying therapies are particularly vulnerable to developing infectious complications, increasing the risk of mortality. Myelodysplastic syndromes (MDS) predominantly affect the elderly, with the incidence rising with age and peaking at around 70 years. Patients with MDS commonly present with unexplained low blood-cell counts, primarily anemia, and often experience varying degrees of neutropenia as the disease progresses. In our subsequent retrospective study involving 1593 patients from the Düsseldorf MDS Registry, we aimed at outlining the incidence of infections in MDS patients and identifying factors contributing to heightened susceptibility to infectious complications in this population.
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- 2024
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8. Smart Conditioning with Venetoclax-Enhanced Sequential FLAMSA + RIC in Patients with High-Risk Myeloid Malignancies
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Felicitas Schulz, Paul Jäger, Johanna Tischer, Alessia Fraccaroli, Gesine Bug, Andreas Hausmann, Ben-Niklas Baermann, Patrick Tressin, Alexander Hoelscher, Annika Kasprzak, Kathrin Nachtkamp, Johannes Schetelig, Inken Hilgendorf, Ulrich Germing, Sascha Dietrich, and Guido Kobbe
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FLAMSA ,allogeneic transplant (aHSCT) ,sequential conditioning ,AML ,MDS ,myeloid malignancies ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Up to 50% of patients with high-risk myeloid malignancies die of relapse after allogeneic stem cell transplantation. Current sequential conditioning regimens like the FLAMSA protocol combine intensive induction therapy with TBI or alkylators. Venetoclax has synergistic effects to chemotherapy. In a retrospective survey among German transplant centers, we identified 61 patients with myeloid malignancies that had received FLAMSA-based sequential conditioning with venetoclax between 2018 and 2022 as an individualized treatment approach. Sixty patients (98%) had active disease at transplant and 74% had genetic high-risk features. Patients received allografts from matched unrelated, matched related, or mismatched donors. Tumor lysis syndrome occurred in two patients but no significant non-hematologic toxicity related to venetoclax was observed. On day +30, 55 patients (90%) were in complete remission. Acute GvHD II°–IV° occurred in 17 (28%) and moderate/severe chronic GvHD in 7 patients (12%). Event-free survival and overall survival were 64% and 80% at 1 year as well as 57% and 75% at 2 years, respectively. The off-label combination of sequential FLAMSA-RIC with venetoclax appears to be safe and highly effective. To further validate these insights and enhance the idea of smart conditioning, a controlled prospective clinical trial was initiated in July 2023.
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- 2024
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9. S173: RETROSPECTIVE STUDY OF LENALIDOMIDE DISCONTINUATION IN PATIENTS WITH MYELODYSPLASTIC SYNDROME HARBORING DEL(5Q). A HARMONY ALLIANCE STUDY
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Elena Crisà, María Díez Campelo, Ulrich Germing, Elvira Mora Castera, Francisca Hernandez Mohedo, Kündgen Andrea, Ebeling Freja, Mikko Myllymäki, Martin Jädersten, Eva Hellström Lindberg, Detlef Haase, Isabella Capodanno, Antonella Poloni, Carlo Finelli, Monica Crugnola, Claudio Fozza, Anna Calvisi, Chiara Frairia, Giuseppe Pietrantuono, Marco Cerrano, Rosanna Ciancia, Daniela Barraco, Wolf-Karsten Hofmann, Axel Ruefer, Cécile Bally, Pierre Fenaux, Guillermo Sanz Santillana, and Valeria Santini
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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10. P725: BATTLE OF THE GIANTS – COMPARISON OF IPSS-M AND IPSS-R IN PATIENTS WITH MISSING MOLECULAR DATA EXCEPT TP53 MUTATION STATUS FROM THE DÜSSELDORF MDS REGISTRY
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Felicitas Schulz, Carolin Kellersmann, Beate Betz, Barbara Hildebrandt, Christina Ganster, Johannes Heiders, Arndt Nusch, Jörg Lipke, Fabian Beier, Katja Sockel, Michael Pfeilstoecker, Detlef Haase, Katharina Götze, Kathrin Nachtkamp, Norbert Gattermann, and Ulrich Germing
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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11. PB2670: EQOL-MDS TRIAL: PATIENT-REPORTED OUTCOMES IN PATIENTS WITH LOWER RISK MYELODYSPLASTIC SYNDROMES WITH SEVERE THROMBOCYTOPENIA.
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Esther Oliva, Giuseppe Iannì, Marta Riva, Pasquale Niscola, Valeria Santini, Massimo Breccia, Valentina Gaidano, Antonella Poloni, Andrea Patriarca, Elena Crisà, Isabella Capodanno, Prassede Salutari, Gianluigi Reda, Grazia Sanpaolo, Dario Ferrero, Attilio Guarini, Giovanni Tripepi, Andrea Castelli, Bruno Fattizzo, Germana Beltrami, Monica Bocchia, Alfredo Molteni, Pierre Fenaux, Ulrich Germing, Alessandra Ricco, Giuseppe A. Palumbo, Stefana Impera, Nicola DI Renzo, Francesco Buccisano, Aspasia Stamatoullas, Anna Marina Liberati, Anna Candoni, Ilaria Maria Delfino, Patrizia Cufari, Lorenzo Rizzo, and Roberto Latagliata
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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12. The ABNL-MARRO 001 study: a phase 1–2 study of randomly allocated active myeloid target compound combinations in MDS/MPN overlap syndromes
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Tamara K. Moyo, Jason H. Mendler, Raphael Itzykson, Ashwin Kishtagari, Eric Solary, Adam C. Seegmiller, Aaron T. Gerds, Gregory D. Ayers, Amy E. Dezern, Aziz Nazha, Peter Valent, Arjan A. van de Loosdrecht, Francesco Onida, Lisa Pleyer, Blanca Xicoy Cirici, Raoul Tibes, Klaus Geissler, Rami S. Komrokji, Jing Zhang, Ulrich Germing, David P. Steensma, Daniel H. Wiseman, Michael Pfeilstöecker, Chiara Elena, Nicholas C. P. Cross, Jean-Jacques Kiladjian, Michael Luebbert, Ruben A. Mesa, Guillermo Montalban-Bravo, Guillermo F. Sanz, Uwe Platzbecker, Mrinal M. Patnaik, Eric Padron, Valeria Santini, Pierre Fenaux, Michael R. Savona, and On Behalf of the MDS/MPN International Working Group
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ABNL MARRO ,MDS/MPN ,ASTX727 ,Itacitinib ,Phase 1b/2 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response. Methods ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability. Discussion Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population. Trial registration This trial was registered with ClinicalTrials.gov on August 19, 2019 (Registration No. NCT04061421).
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- 2022
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13. Azacitidine, lenalidomide and donor lymphocyte infusions for relapse of myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia after allogeneic transplant: the Azalena-Trial
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Thomas Schroeder, Matthias Stelljes, Maximilian Christopeit, Eva Esseling, Christoph Scheid, Jan-Henrik Mikesch, Christina Rautenberg, Paul Jäger, Ron-Patrick Cadeddu, Nadja Drusenheimer, Udo Holtick, Stefan Klein, Rudolf Trenschel, Rainer Haas, Ulrich Germing, Nicolaus Kröger, and Guido Kobbe
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Azacitidine (Aza) combined with donor lymphocyte infusions (DLI) is an established treatment for relapse of myeloid malignancies after allogeneic transplantation. Based on its immunomodulatory and anti-leukemic properties we considered Lenalidomide (Lena) to act synergistically with Aza/DLI to improve outcome. We, therefore, prospectively investigated tolerability and efficacy of this combination as first salvage therapy for adults with post-transplant relapse of acute myeloid leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia. Patients were scheduled for eight cycles Aza (75 mg/m2 day 1-7), Lena (2.5 or 5 mg, days 1-21) and up to three DLI with increasing T-cell dosages (0.5×106-1.5×107 cells/kg). Primary endpoint was safety, while secondary endpoints included response, graft-versus-host disease (GvHD) and overall survival (OS). Fifty patients with molecular (52%) or hematological (48%) relapse of myelodysplastic syndromes (n=24), acute myeloid leukemia (n=23) or chronic myelomonocytic leukemia (n=3) received a median of seven (range, 1-8) cycles including 14 patients with 2.5 mg and 36 with 5 mg Lena daily dosage. Concomitantly, 34 patients (68%) received at least one DLI. Overall response rate was 56% and 25 patients (50%) achieved complete remission being durable in 80%. Median OS was 21 months and 1-year OS rate 65% with no impact of type of or time to relapse and Lena dosages. Treatment was well tolerated indicated by febrile neutropenia being the only grade ≥3 non-hematologic adverse event in >10% of patients and modest acute (grade 2-4 24%) and chronic (moderate/severe 28%) GvHD incidences. In summary, Lena can be safely added to Aza/DLI without excess of GvHD and toxicity. Its significant anti-leukemic activity suggests that this combination is a novel salvage option for post-transplant relapse (clinicaltrials gov. Identifier: NCT02472691).
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- 2023
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14. Iron Chelation in Patients with Myelodysplastic Syndromes and Myeloproliferative Neoplasms—Real-World Data from the German Noninterventional Study EXCALIBUR
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Felicitas Schulz, Ulrich Hauch, Sandra Ketzler-Henkel, Eyck von der Heyde, Michael Koenigsmann, Michael Lauseker, Nora Schulte, and Ulrich Germing
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iron chelation ,iron overload ,myelodysplastic syndromes ,MDS ,myeloproliferative neoplasms ,MPN ,Medicine - Abstract
Myelodysplastic syndromes and myeloproliferative neoplasms both represent hematologic diseases associated with bone marrow failure often resulting in anemia. For those patients, transfusion of red blood cell (RBC) units is essential but results in iron overload (IOL) that may affect various organ functions. Therefore, iron chelation therapy plays a major role in anemic patients, not only because it reduces IOL, but also because it may improve hematopoietic function by increasing hemoglobin or diminishing the requirement for RBC transfusions. To assess the utility, efficacy, and safety of the different iron chelation medications approved in Germany, as well as to examine the effect of chelation on hematopoietic insufficiency, a prospective, multicenter, noninterventional study named EXCALIBUR was designed. In total, 502 patients from 106 German hospitals and medical practices were enrolled. A large proportion of patients switched from a deferasirox dispersible tablet to a deferasirox-film-coated tablet, mainly because of more convenient application, which was reflected in the treatment satisfaction questionnaire for medication scores. Iron chelation was effective in lowering serum ferritin levels, with the observed adverse drug reactions being in line with the known safety profile. Hematologic response occurred in a few patients, comparable to other studies that examined hematologic improvement in patients with MDS.
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- 2023
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15. Volasertib as a monotherapy or in combination with azacitidine in patients with myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myeloid leukemia: summary of three phase I studies
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Uwe Platzbecker, Joerg Chromik, Jan Krönke, Hiroshi Handa, Stephen Strickland, Yasushi Miyazaki, Martin Wermke, Wataru Sakamoto, Yoshifumi Tachibana, Tillmann Taube, and Ulrich Germing
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Volasertib ,Phase I ,Myelodysplastic syndrome ,Chronic myelomonocytic leukemia ,Acute myeloid leukemia ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background This report summarizes three phase I studies evaluating volasertib, a polo-like kinase inhibitor, plus azacitidine in adults with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia, or acute myeloid leukemia. Methods Patients received intravenous volasertib in 28-day cycles (dose-escalation schedules). In Part 1 of 1230.33 (Study 1; NCT01957644), patients received 250–350 mg volasertib on day (D)1 and D15; in Part 2, patients received different schedules [A, D1: 170 mg/m2; B, D7: 170 mg/m2; C, D1 and D7: 110 mg/m2]. In 1230.35 (Study 2; NCT02201329), patients received 200–300 mg volasertib on D1 and D15. In 1230.43 (Study 3; NCT02721875), patients received 110 mg/m2 volasertib on D1 and D8. All patients in Studies 1 and 2, and approximately half of the patients in Study 3, were scheduled to receive subcutaneous azacitidine 75 mg/m2 on D1–7. Results Overall, 22 patients were treated (17 with MDS; 12 previously untreated). Across Studies 1 and 2 (n = 21), the most common drug-related adverse events were hematological (thrombocytopenia [n = 11]; neutropenia [n = 8]). All dose-limiting toxicities were grade 4 thrombocytopenia. The only treated patient in Study 3 experienced 18 adverse events following volasertib monotherapy. Studies 1 and 2 showed preliminary activity (objective response rates: 25 and 40%). Conclusions The safety of volasertib with azacitidine in patients with MDS was consistent with other volasertib studies. All studies were terminated prematurely following the discontinuation of volasertib for non-clinical reasons by Boehringer Ingelheim; however, safety information on volasertib plus azacitidine are of interest for future studies in other diseases.
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- 2022
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16. Editorial: Hybrid or mixed myelodyplastic/myeloproliferative disorders: Current trends in diagnosis and treatment
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Argiris Symeonidis and Ulrich Germing
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mixed MDS/MPN ,chronic myelomonocytic leukemia (CCML) ,atypical chronic myeloid leukemia (aCML) ,myelodyslastic/myeloproliferative neoplasms (MDS/MPN) ,WHO classification - myeloid neoplasms - diagnostic criteria ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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17. The Absolute Monocyte Count at Diagnosis Affects Prognosis in Myelodysplastic Syndromes Independently of the IPSS-R Risk Score
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Tobias Silzle, Sabine Blum, Annika Kasprzak, Kathrin Nachtkamp, Martina Rudelius, Barbara Hildebrandt, Katharina S. Götze, Norbert Gattermann, Michael Lauseker, and Ulrich Germing
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myelodysplastic syndrome ,prognostication ,absolute monocyte count ,revised international prognostic scoring system ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The absolute monocyte count (AMC) is associated with mortality in a variety of medical conditions. Its prognostic impact in myelodysplastic syndromes (MDSs) is less well studied. Therefore, we investigated its potential prognostic value in a cohort from the Düsseldorf MDS registry in relationship to the revised international prognostic scoring system (IPSS-R). An AMC below the population’s median (9/L) was associated with several adverse disease features such as lower haemoglobin levels, lower count of neutrophils and platelets, and a higher percentage of blasts in the bone marrow. MDS patients with an AMC < 0.2 × 109/L had a significantly higher risk of progression into acute myeloid leukemia (AML). In a univariate, proportional hazards model the effect of the AMC as a continuous variable was modelled via p-splines. We found a U-shaped effect with the lowest hazard around 0.3 × 109/L. Accordingly, an AMC within the last quartile of the population (0.4 × 109/L) was associated with a reduced overall survival independently of IPSS-R, but not with the risk of secondary AML. Considering monocytopenia as a risk factor for AML progression in MDS may provide an additional argument for allogeneic transplantation or the use of hypomethylating agents in patients who are not clear candidates for those treatments according to current prognostic scoring systems and/or recommendations. Further studies are needed to assess the prognostic impact of the AMC in the context of prognostic scoring systems, considering the molecular risk profile, and to identify the mechanisms responsible for the higher mortality in MDS patients with a subtle monocytosis.
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- 2023
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18. Real-world experience of CPX-351 as first-line treatment for patients with acute myeloid leukemia
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Christina Rautenberg, Friedrich Stölzel, Christoph Röllig, Matthias Stelljes, Verena Gaidzik, Michael Lauseker, Oliver Kriege, Mareike Verbeek, Julia Marie Unglaub, Felicitas Thol, Stefan W. Krause, Mathias Hänel, Charlotte Neuerburg, Vladan Vucinic, Christian-Friedrich Jehn, Julia Severmann, Maxi Wass, Lars Fransecky, Jens Chemnitz, Udo Holtick, Kerstin Schäfer-Eckart, Josephine Schröder, Sabrina Kraus, William Krüger, Ulrich Kaiser, Sebastian Scholl, Kathrin Koch, Lea Henning, Guido Kobbe, Rainer Haas, Nael Alakel, Maximilian-Alexander Röhnert, Katja Sockel, Maher Hanoun, Uwe Platzbecker, Tobias A. W. Holderried, Anke Morgner, Michael Heuser, Tim Sauer, Katharina S. Götze, Eva Wagner-Drouet, Konstanze Döhner, Hartmut Döhner, Christoph Schliemann, Johannes Schetelig, Martin Bornhäuser, Ulrich Germing, Thomas Schroeder, and Jan Moritz Middeke
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract To investigate the efficacy and toxicities of CPX-351 outside a clinical trial, we analyzed 188 patients (median age 65 years, range 26–80) treated for therapy-related acute myeloid leukemia (t-AML, 29%) or AML with myelodysplasia-related changes (AML-MRC, 70%). Eighty-six percent received one, 14% two induction cycles, and 10% received consolidation (representing 22% of patients with CR/CRi) with CPX-351. Following induction, CR/CRi rate was 47% including 64% of patients with available information achieving measurable residual disease (MRD) negativity (
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- 2021
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19. A phase I/II multicenter, open-label, dose escalation and randomized trial of BI 836858 in patients with low- or intermediate-1-risk myelodysplastic syndrome
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Rami S. Komrokji, Hetty E. Carraway, Ulrich Germing, Martin Wermke, Amer M. Zeidan, Eric Fu, Björn Rüter, Ute Burkard, Annika Osswald, and James M. Foran
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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20. Falciparum malaria-induced secondary hemophagocytic lymphohistiocytosis successfully treated with ruxolitinib
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André Fuchs, Hans-Martin Orth, Ulrich Germing, Mustafa Kondakci, Martha Holtfreter, Torsten Feldt, Björn Erik-Ole Jensen, and Dieter Häussinger
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Malaria tropica ,HLH ,Hemophagocytosis ,JAK1/2 inhibition ,JAK/STAT ,Infectious and parasitic diseases ,RC109-216 - Abstract
JAK/STAT signaling plays a major role in the pathogenesis of secondary hemophagocytic lymphohistiocytosis. This case report on a critically ill patient with secondary hemophagocytic lymphohistiocytosis due to falciparum malaria treated successfully with ruxolitinib, demonstrates that JAK1/2 inhibition might be a promising treatment option for severe cases.
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- 2020
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21. Hybrid or Mixed Myelodysplastic/Myeloproliferative Disorders – Epidemiological Features and Overview
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Andrea Kuendgen, Annika Kasprzak, and Ulrich Germing
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MDS/MPN ,overlap syndromes ,CMML ,MDS/MPN-RS-T ,aCML ,JMML ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The WHO-category Myelodysplastic/Myeloproliferative neoplasms (MDS/MPNs) recognizes a unique group of clonal myeloid malignancies exhibiting overlapping features of myelodysplastic as well as myeloproliferative neoplasms. The group consists of chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia, BCR-ABL1-negative (aCML), juvenile myelomonocytic leukemia (JMML), myelodysplastic/myeloproliferative neoplasm with ringed sideroblasts and thrombocytosis (MDS/MPN-RS-T), and myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U). The most frequent entity in this category is CMML, while all other diseases are extremely rare. Thus, only very limited data on the epidemiology of these subgroups exists. An appropriate diagnosis and classification can be challenging since the diagnosis is still largely based on morphologic criteria and myelodysplastic as well as myeloproliferative features can be found in various occurrences. The diseases in this category share several features that are common in this specific WHO-category, but also exhibit specific traits for each disease. This review summarizes published data on epidemiological features and offers a brief overview of the main diagnostic criteria and clinical characteristics of the five MDS/MPN subgroups.
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- 2021
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22. Clinical and Cytogenetic Characterization of Early and Late Relapses in Patients Allografted for Myeloid Neoplasms with a Myelodysplastic Component
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Victoria Platte, Anika Bergmann, Barbara Hildebrandt, Dagmar Wieczorek, Esther Schuler, Ulrich Germing, Jennifer Kaivers, Rainer Haas, Guido Kobbe, Thomas Schroeder, and Christina Rautenberg
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AML ,MDS ,relapse ,transplant ,cytogenetics ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
An improved understanding of relapse kinetics is required to optimize detection and treatment strategies for the post-transplant relapse of myeloid neoplasms. Therefore, we retrospectively analyzed data from 91 patients allografted for MDS (n = 54), AML-MRC (n = 29) and chronic myelomonocytic leukemia (CMML, n = 8), who relapsed after transplant. Patients with early (n = 56) and late relapse (>12 months, n = 35) were compared regarding patient-, disease- and transplant-related factors, including karyotype analyses at diagnosis and relapse. After a median follow-up of 17.4 months after relapse, late relapses showed improved outcomes compared with early relapses (2-yr OS 67% vs. 32%, p = 0.0048). Comparing frequency of distinct patient-, disease- and transplant-related factors among early and late relapses, complex karyotype (p = 0.0004) and unfavorable disease risk at diagnosis (p = 0.0008) as well as clonal evolution at relapse (p = 0.03) were more common in early than in late relapses. Furthermore, patients receiving transplant without prior cytoreduction or in complete remission were more frequently present in the group of late relapses. These data suggest that cytogenetics rather than disease burden at diagnosis and transplant-related factors determine the timepoint of post-transplant relapse and that upfront transplantation may be favored in order to delay relapse.
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- 2022
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23. The EHA Research Roadmap: Malignant Myeloid Diseases
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Hartmut Döhner, Luca Malcovati, Gert J. Ossenkoppele, Andreas Hochhaus, Alessandro Maria Vannucchi, Lars Bullinger, Francisco Cervantes, Charles Craddock, Theo de Witte, Konstanze Döhner, Hervé Dombret, Pierre Fenaux, Jan Geissler, Ulrich Germing, Francois Guilhot, Claire Harrison, Eva Hellström-Lindberg, Francesco Passamonti, Jorge Sierra, Radek Skoda, and Agnieszka Wierzbowska
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2021
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24. Assessing the Prognosis of Patients with Myelodysplastic Syndromes (MDS)
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Annika Kasprzak, Kathrin Nachtkamp, Norbert Gattermann, and Ulrich Germing
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myelodysplastic syndromes ,prognosis ,chronic myelomonocytic leukemia ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Prognostic stratification in patients with myelodysplastic syndrome (MDS) relies on a number of key factors. Combining such patient-related and disease-related prognostic parameters into useful assessment tools remains a challenge. The most widely used scoring systems include the international prognostic scoring system (IPSS), the revised IPSS (IPSS-R), the World Health Organization (WHO) Prognostic Scoring System (WPSS), and the new molecular IPSS (IPSS-M). Similar to the IPSS-R and the IPSS-M, the chronic myelomonocytic leukemia (CMML) prognostic scoring system (CPSS) and the CPSS molecular (CPSS-mol) are powerful and reliable prognostic tools that help to assess the individual prognosis of patients with CMML. The well-established prognostic assessment of MDS and CMML may be further augmented by additional disease-related parameters, such as somatic mutations, or patient-related factors, such as comorbidities. In this article, we briefly describe useful prognostic scoring systems for myelodysplastic syndromes and identify some open questions that require further investigation.
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- 2022
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25. Opportunities for Participation in Randomized Controlled Trials for Patients with Multiple Myeloma: Trial Access Depends on Restrictive Eligibility Criteria and Patient Expectations
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Amelie Boquoi, Veronika Rings, Annemarie Mohring, Ingrida Savickaite, Romans Zukovs, Judith Strapatsas, Kathrin Nachtkamp, Guido Kobbe, Ulrich Germing, and Roland Fenk
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multiple myeloma ,randomized clinical trials ,eligibility ,real-world ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Randomized controlled trials (RCT) are the driver of therapeutic innovations. However, it has been frequently shown that less than 5% of adult cancer patients enroll in clinical trials, although 70% of patients are considered as being willing to participate. Barriers to trial participation have been extensively studied. Although there is evidence that trial participation correlates with improved survival and reduced mortality, the rate of participation has not changed substantially. We provide retrospective data from a single-center analysis of 411 patients with multiple myeloma (MM) who were treated at the University Hospital Duesseldorf in Germany between January 2014 and December 2016. Each patient was analyzed for the real-world possibility of participating in a clinical study, based on the inclusion and exclusion (I/E) criteria and the recruiting period of open studies. The overall rate of study participation was 19%. A total of 53% of NDMM patients were eligible for first-line studies (GMMG-HD6, LenaMain). Of these, 80% consented to enrolment (42% of all). In contrast, only 38% of the RRMM population was eligible (GMMG-Relapse, Castor, Tourmaline, Admyre). Of these, only 22% (7% of all) consented. This was confirmed by virtual analysis, showing that only 29% of all RRMM patients would have been eligible for six internationally recruiting trials leading to later drug approval. The majority of cases were rendered ineligible by only one I/E criterion. The most common criteria were study-specific (prior therapies or refractory disease to a specific drug), kidney disease, and previous malignancy, followed by internal, neurologic, and infectious disease. In summary, this single-center analysis showed that I/E criteria permit study participation for most NNDM patients, with a dramatic decrease in the RRMM population. This is aggravated by the fact that the willingness for study participation also significantly declines in RRMM. Thus, addressing patient expectations and priorities seems to be the most promising approach to increasing patient enrollment in clinical trials.
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- 2022
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26. Novel dynamic outcome indicators and clinical endpoints in myelodysplastic syndrome; the European LeukemiaNet MDS Registry and MDS-RIGHT project perspective
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Theo de Witte, Luca Malcovati, Pierre Fenaux, David Bowen, Argiris Symeonidis, Moshe Mittelman, Reinhard Stauder, Guillermo Sanz, Jaroslav Čermák, Saskia Langemeijer, Eva Hellström-Lindberg, Ulrich Germing, Mette Skov Holm, Krzysztof Mądry, Aurelia Tatic, António Medina Almeida, Aleksandar Savic, Inga Mandac Rogulj, Raphael Itzykson, Marlijn Hoeks, Hege Gravdahl Garelius, Dominic Culligan, Ioannis Kotsianidis, Lionel Ades, Arjan A. Van de Loosdrecht, Corine van Marrewijk, Ge Yu, Simon Crouch, and Alex Smith
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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27. Impact of treatment with iron chelation therapy in patients with lower-risk myelodysplastic syndromes participating in the European MDS registry
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Marlijn Hoeks, Ge Yu, Saskia Langemeijer, Simon Crouch, Louise de Swart, Pierre Fenaux, Argiris Symeonidis, Jaroslav Čermák, Eva Hellström-Lindberg, Guillermo Sanz, Reinhard Stauder, Mette Skov Holm, Moshe Mittelman, Krzysztof Mądry, Luca Malcovati, Aurelia Tatic, Antonio Medina Almeida, Ulrich Germing, Aleksandar Savic, Njetočka Gredelj Šimec, Dominic Culligan, Raphael Itzykson, Agnes Guerci-Bresler, Borhane Slama, Jackie Droste, Corine van Marrewijk, Arjan van de Loosdrecht, Nicole Blijlevens, Marian van Kraaij, David Bowen, Theo de Witte, Alex Smith, and on behalf of the EUMDS Registry Participants
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Iron overload due to red blood cell (RBC) transfusions is associated with morbidity and mortality in lower-risk myelodysplastic syndrome (MDS) patients. Many studies have suggested improved survival after iron chelation therapy (ICT), but valid data are limited. The aim of this study was to assess the effect of ICT on overall survival and hematologic improvement in lower-risk MDS patients in the European MDS registry. We compared chelated patients with a contemporary, non-chelated control group within the European MDS registry, that met the eligibility criteria for starting iron chelation. A Cox proportional hazards model was used to assess overall survival (OS), treating receipt of chelation as a time-varying variable. Additionally, chelated and non-chelated patients were compared using a propensity-score matched model. Of 2,200 patients, 224 received iron chelation. The hazard ratio and 95% confidence interval for OS for chelated patients, adjusted for age, sex, comorbidity, performance status, cumulative RBC transfusions, Revised-International Prognostic Scoring System (IPSS-R), and presence of ringed sideroblasts was 0.50 (0.34-0.74). The propensity-score analysis, matched for age, sex, country, RBC transfusion intensity, ferritin level, comorbidity, performance status, and IPSS-R, and, in addition, corrected for cumulative RBC transfusions and presence of ringed sideroblasts, demonstrated a significantly improved OS for chelated patients with a hazard ratio of 0.42 (0.27-0.63) compared to non-chelated patients. Up to 39% of chelated patients reached an erythroid response. In conclusion, our results suggest that iron chelation may improve OS and hematopoiesis in transfused lower-risk MDS patients. This trial was registered at clinicaltrials.gov identifier: 00600860.
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- 2020
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28. Impact of red blood cell transfusion dose density on progression-free survival in patients with lower-risk myelodysplastic syndromes
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Louise de Swart, Simon Crouch, Marlijn Hoeks, Alex Smith, Saskia Langemeijer, Pierre Fenaux, Argiris Symeonidis, Jaroslav Cermâk, Eva Hellström-Lindberg, Reinhard Stauder, Guillermo Sanz, Moshe Mittelman, Mette Skov Holm, Luca Malcovati, Krzysztof Mądry, Ulrich Germing, Aurelia Tatic, Aleksandar Savic, Antonio Medina Almeida, Njetocka Gredelj-Simec, Agnes Guerci-Bresler, Odile Beyne-Rauzy, Dominic Culligan, Ioannis Kotsianidis, Raphael Itzykson, Corine van Marrewijk, Nicole Blijlevens, David Bowen, Theo de Witte, and on behalf of the EUMDS Registry Participants
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Progression-free survival (PFS) of patients with lower-risk myelodysplastic syndromes (MDS) treated with red blood cell transfusions is usually reduced, but it is unclear whether transfusion dose density is an independent prognostic factor. The European MDS Registry collects prospective data at 6-monthly intervals from newly diagnosed lower-risk myelodysplastic syndromes patients in 16 European countries and Israel. Data on the transfusion dose density - the cumulative dose received at the end of each interval divided by the time since the beginning of the interval in which the first transfusion was received - were analyzed using proportional hazards regression with time-varying co-variates, with death and progression to higher-risk MDS/acute myeloid leukemia as events. Of the 1,267 patients included in the analyses, 317 died without progression; in 162 patients the disease had progressed. PFS was significantly associated with age, EQ-5D index, baseline World Health Organization classification, bone marrow blast count, cytogenetic risk category, number of cytopenias, and country. Transfusion dose density was inversely associated with PFS (P
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- 2020
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29. Treatment of Anemia in Transfusion-Dependent and Non-Transfusion-Dependent Lower-Risk MDS: Current and Emerging Strategies
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Ulrich Germing, Ester N. Oliva, Devendra Hiwase, and Antonio Almeida
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract. Myelodysplastic syndromes (MDS) are a heterogeneous group of bone marrow disorders with a highly diverse clinical course. For lower-risk MDS patients, therapeutic objectives aim to correct chronic anemia and improve/maintain health-related quality of life (HRQoL). However, disease burden is often insufficiently recognized, and although some patients do not respond/lose response to standard treatment, many are treated late. This is the case for non-transfusion-dependent patients with symptomatic anemia, in whom delayed treatment initiation may lead to unnecessary morbidity. Current active treatment options for lower-risk MDS are limited. Standard care for lower-risk 5q deletion [del(5q)] MDS patients with anemia remains supportive, consisting of red blood cell (RBC) transfusions, iron chelation therapy, and treatment with erythropoiesis-stimulating agents (ESAs) in the case of low serum erythropoietin levels. Response rates to ESAs range from 15% to 63%, whereas 56% to 67% of patients with del(5q) MDS achieve RBC transfusion independence with lenalidomide. Treatment options for patients’ refractory to ESAs and/or lenalidomide, however, are limited. Frequent transfusions are associated with profound clinical, HRQoL, and economic consequences for transfusion-dependent patients. This review focuses on the multiple unmet clinical needs that exist in the treatment of anemia associated with lower-risk MDS and the current and future treatment options that may improve disease management and patient outcomes.
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- 2019
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30. Evaluation of induction chemotherapies after hypomethylating agent failure in myelodysplastic syndromes and acute myeloid leukemia
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Brian Ball, Rami S. Komrokji, Lionel Adès, Mikkael A. Sekeres, Amy E. DeZern, Lisa Pleyer, Norbert Vey, Antonio Almeida, Ulrich Germing, Thomas Cluzeau, Uwe Platzbecker, Steven D. Gore, Pierre Fenaux, and Thomas Prebet
- Subjects
Specialties of internal medicine ,RC581-951 - Abstract
Abstract: Hypomethylating agent (HMA) failure in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) carries a poor prognosis with limited treatment options. Although intensive, remission induction chemotherapy is often used subsequently, in particular to bridge to allogeneic transplantation, it is not clear whether an advantage exists for any particular regimen. Based on an international collaboration, we retrospectively analyzed induction response rate and survival in 366 patients after HMA failure. Patients received 7+3, intermediate- to high-dose cytarabine (IDAC), or purine nucleoside analog–based regimens. For the MDS cohort (n = 307), the overall response rate (ORR) was 41%; median overall survival (OS) was 10.8 months, and 40% of responding patients bridged to allogeneic stem cell transplant (allo-SCT). For the AML cohort (n = 59), the ORR was 32%, OS 6 months, and 42% of responding patients bridged to allo-SCT. Prognostic factors for response in MDS included adverse cytogenetics (odds ratio [OR], 0.46, P = .01), age ≥65 years (OR, 0.47; P < .01), and use of IDAC (OR, 2.91, P = .01). Shorter survival was associated with adverse cytogenetics (hazard ratio [HR], 1.43; P = .06). In the AML cohort, OS was decreased by disease progression at time of HMA failure (HR, 2.66; P = .02) and prolonged with use of an anthracycline-containing regimen (HR, 0.37; P = .01). In conclusion, intensive chemotherapy after HMA failure may be a reasonable treatment option for selected patients as a bridge to allogeneic transplantation and should be considered a potential platform for future investigations.
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- 2018
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31. Early platelet count kinetics has prognostic value in lower-risk myelodysplastic syndromes
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Raphael Itzykson, Simon Crouch, Erica Travaglino, Alex Smith, Argiris Symeonidis, Eva Hellström-Lindberg, Guillermo Sanz, Jaroslav Čermák, Reinhard Stauder, Chiara Elena, Ulrich Germing, Moshe Mittelman, Saskia Langemeijer, Krzysztof Mądry, Aurelia Tatic, Mette Skov Holm, Antonio Medina Almeida, Aleksandar Savic, Njetočka Gredelj Šimec, Elisa Luño, Dominic Culligan, Agnes Guerci-Bresler, Luca Malcovati, Corine van Marrewijk, David Bowen, Theo de Witte, and Pierre Fenaux
- Subjects
Specialties of internal medicine ,RC581-951 - Abstract
Abstract: Prognosis of lower-risk (International Prognostic Scoring System [IPSS] low/intermediate-1) myelodysplastic syndrome (MDS) is heterogeneous and relies on steady-state assessment of cytopenias. We analyzed relative drops in neutrophil and platelet counts during the first 6 months of follow-up of lower-risk MDS patients. We performed a landmark analysis of overall survival (OS) of lower-risk MDS patients prospectively included in the European LeukaemiaNet MDS registry having a visit at 6 ± 1 month from inclusion to assess the prognostic relevance of relative drops in neutrophils and platelets, defined as (count at landmark − count at inclusion)/count at inclusion. Of 2102 patients, 807 were eligible for the stringent 6-month landmark analysis. Median age was 73 years. Revised IPSS was very low, low, and intermediate/higher in 26%, 43%, and 31% of patients, respectively. A relative drop in platelets >25% at landmark predicted shorter OS (5-year OS, 21.9% vs 48.6% with platelet drop ≤25%, P < 10−4), regardless of baseline IPSS-revised or absolute platelet counts. Relative neutrophil drop >25% had no significant impact on OS. We built a classifier based on red blood cell transfusion dependence (RBC-TD) and relative platelet drop >25% at landmark. Patients with none (62%), either (27%), or both criteria (11%) had 5-year OS of 53.3%, 32.7%, and 9.0%, respectively (P < 10−4). This classifier was validated in an independent cohort of 335 patients. Combining relative platelet drop >25% and RBC-TD at 6 months from diagnosis provides an inexpensive and noninvasive way to predict outcome in lower-risk MDS. This study was registered at www.clinicaltrials.gov as #NCT00600860.
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- 2018
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32. The use of immunosuppressive therapy in MDS: clinical outcomes and their predictors in a large international patient cohort
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Maximilian Stahl, Michelle DeVeaux, Theo de Witte, Judith Neukirchen, Mikkael A. Sekeres, Andrew M. Brunner, Gail J. Roboz, David P. Steensma, Vijaya R. Bhatt, Uwe Platzbecker, Thomas Cluzeau, Pedro H. Prata, Raphaël Itzykson, Pierre Fenaux, Amir T. Fathi, Alexandra Smith, Ulrich Germing, Ellen K. Ritchie, Vivek Verma, Aziz Nazha, Jaroslaw P. Maciejewski, Nikolai A. Podoltsev, Thomas Prebet, Valeria Santini, Steven D. Gore, Rami S. Komrokji, and Amer M. Zeidan
- Subjects
Specialties of internal medicine ,RC581-951 - Abstract
Abstract: Most studies of immunosuppressive therapy (IST) in myelodysplastic syndromes (MDS) are limited by small numbers and their single-center nature, and report conflicting data regarding predictors for response to IST. We examined outcomes associated with IST and predictors of benefit in a large international cohort of patients with MDS. Data were collected from 15 centers in the United States and Europe. Responses, including red blood cell (RBC) transfusion independence (TI), were assessed based on the 2006 MDS International Working Group criteria, and overall survival (OS) was estimated by Kaplan-Meier methods. Logistic regression models estimated odds for response and TI, and Cox Proportional Hazard models estimated hazards ratios for OS. We identified 207 patients with MDS receiving IST, excluding steroid monotherapy. The most common IST regimen was anti-thymocyte globulin (ATG) plus prednisone (43%). Overall response rate (ORR) was 48.8%, including 11.2% (95% confidence interval [CI], 6.5%-18.4%) who achieved a complete remission and 30% (95% CI, 22.3%-39.5%) who achieved RBC TI. Median OS was 47.4 months (95% CI, 37-72.3 months) and was longer for patients who achieved a response or TI. Achievement of RBC TI was associated with a hypocellular bone marrow (cellularity < 20%); horse ATG plus cyclosporine was more effective than rabbit ATG or ATG without cyclosporine. Age, transfusion dependence, presence of paroxysmal nocturnal hemoglobinuria or large granular lymphocyte clones, and HLA DR15 positivity did not predict response to IST. IST leads to objective responses in nearly half the selected patients with the highest rate of RBC TI achieved in patients with hypocellular bone marrows.
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- 2018
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33. Mastering the multitude of monocytoses
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Ulrich Germing and Norbert Gattermann
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2019
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34. Hypomethylating agents in relapsed and refractory AML: outcomes and their predictors in a large international patient cohort
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Maximilian Stahl, Michelle DeVeaux, Pau Montesinos, Raphael Itzykson, Ellen K. Ritchie, Mikkael A. Sekeres, John D. Barnard, Nikolai A. Podoltsev, Andrew M. Brunner, Rami S. Komrokji, Vijaya R. Bhatt, Aref Al-Kali, Thomas Cluzeau, Valeria Santini, Amir T. Fathi, Gail J. Roboz, Pierre Fenaux, Mark R. Litzow, Sarah Perreault, Tae Kon Kim, Thomas Prebet, Norbert Vey, Vivek Verma, Ulrich Germing, Juan Miguel Bergua, Josefina Serrano, Steven D. Gore, and Amer M. Zeidan
- Subjects
Specialties of internal medicine ,RC581-951 - Abstract
Abstract: Although hypomethylating agents (HMAs) are frequently used in the frontline treatment of older acute myeloid leukemia (AML) patients, little is known about their effectiveness in relapsed or primary treatment–refractory (RR)-AML. Using an international multicenter retrospective database, we studied the effectiveness of HMAs in RR-AML and evaluated for predictors of response and overall survival (OS). A total of 655 patients from 12 centers received azacitidine (57%) or decitabine (43%), including 290 refractory (44%) and 365 relapsed (56%) patients. Median age at diagnosis was 65 years. Best response to HMAs was complete remission (CR; 11%) or CR with incomplete count recovery (CRi; 5.3%). Additionally, 8.5% experienced hematologic improvement. Median OS was 6.7 months (95% confidence interval, 6.1-7.3). As expected, OS differed significantly by best response, with patients achieving CR and CRi having a median OS of 25.3 and 14.6 months, respectively. In multivariate analysis, the presence of ≤5% circulating blasts and a 10-day schedule of decitabine were associated with improved response rates, whereas the presence of >5% circulating blasts and >20% bone marrow blasts were associated with decreased OS. A significant subset of RR-AML patients (16%) achieved CR/CRi with HMAs and experienced a median OS of 21 months. Outside of a clinical trial, HMAs represent a reasonable therapeutic option for some patients with RR-AML.
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- 2018
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35. Deep sequencing of bone marrow microenvironments of patients with del(5q) myelodysplastic syndrome reveals imprints of antigenic selection as well as generation of novel T-cell clusters as a response pattern to lenalidomide
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Thorben Mährle, Nuray Akyüz, Pim Fuchs, Nicola Bonzanni, Donjete Simnica, Ulrich Germing, Anne Marie Asemissen, Johann Christoph Jann, Florian Nolte, Wolf-Karsten Hofmann, Daniel Nowak, and Mascha Binder
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
In myelodysplastic syndromes with a partial deletion of the long arm of chromosome 5, del(5q), lenalidomide is believed to reverse anergic T-cell immunity in the bone marrow resulting in suppression of the del(5q) clone. In this study we used next-generation sequencing of immunoglobulin heavy chain (IGH) and T-cell receptor beta (TRB) rearrangements in bone marrow-residing and peripheral blood-circulating lymphocytes of patients with del(5q) myelodysplastic syndromes to assess the immune architecture and track adaptive immune responses during treatment with lenalidomide. The baseline bone marrow B-cell space in patients was comparable to that of age-matched healthy controls in terms of gene usage and IGH clonality, but showed a higher percentage of hypermutated IGH sequences, indicating an expanded number of antigen-experienced B lineage cells. Bone marrow B lineage clonality decreased significantly and hypermutated IGH clones normalized upon lenalidomide treatment, well in line with the proliferative effect on healthy antigen-inexperienced B-cell precursors previously described for this drug. The T-cell space in bone marrow of patients with del(5q) myelodysplastic syndromes showed higher TRB clonality compared to that of healthy controls. Upon lenalidomide treatment, myelodysplastic syndrome-specific T-cell clusters with low to medium spontaneous generation probabilities emerged; these clusters were shared across patients, indicating a common antigen-driven T-cell response pattern. Hence, we observed B lineage diversification and generation of new, antigen-dependent T-cell clusters, compatible with a model of adaptive immunity induced against the del(5q) clone by lenalidomide. Overall, this supports the concept that lenalidomide not only alters the functional T-cell state, but also the composition of the T- and B-cell repertoires in del(5q) myelodysplastic syndromes.
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- 2019
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36. Diagnosis and Treatment of Chronic Myelomonocytic Leukemias in Adults
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Raphael Itzykson, Pierre Fenaux, David Bowen, Nicholas C.P. Cross, Jorge Cortes, Theo De Witte, Ulrich Germing, Francesco Onida, Eric Padron, Uwe Platzbecker, Valeria Santini, Guillermo F. Sanz, Eric Solary, Arjan Van de Loosdrecht, Luca Malcovati, and on behalf of the European Hematology Association, the European LeukemiaNet
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract. Chronic myelomonocytic leukemia (CMML) is a disease of the elderly, and by far the most frequent overlap myelodysplastic/myeloproliferative neoplasm in adults. Aside from the chronic monocytosis that remains the cornerstone of its diagnosis, the clinical presentation of CMML includes dysplastic features, cytopenias, excess of blasts, or myeloproliferative features including high white blood cell count or splenomegaly. Prognosis is variable, with several prognostic scoring systems reported in recent years, and treatment is poorly defined, with options ranging from watchful waiting to allogeneic stem cell transplantation, which remains the only curative therapy for CMML. Here, we present on behalf of the European Hematology Association and the European LeukemiaNet, evidence- and consensus-based guidelines, established by an international group of experts, from Europe and the United States, for standardized diagnostic and prognostic procedures and for an appropriate choice of therapeutic interventions in adult patients with CMML.
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- 2018
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37. Normal and pathological erythropoiesis in adults: from gene regulation to targeted treatment concepts
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Peter Valent, Guntram Büsche, Igor Theurl, Iris Z. Uras, Ulrich Germing, Reinhard Stauder, Karl Sotlar, Wolfgang Füreder, Peter Bettelheim, Michael Pfeilstöcker, Rainer Oberbauer, Wolfgang R. Sperr, Klaus Geissler, Jürg Schwaller, Richard Moriggl, Marie C. Béné, Ulrich Jäger, Hans-Peter Horny, and Olivier Hermine
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Pathological erythropoiesis with consequent anemia is a leading cause of symptomatic morbidity in internal medicine. The etiologies of anemia are complex and include reactive as well as neoplastic conditions. Clonal expansion of erythroid cells in the bone marrow may result in peripheral erythrocytosis and polycythemia but can also result in anemia when clonal cells are dysplastic and have a maturation arrest that leads to apoptosis and hinders migration, a constellation typically seen in the myelodysplastic syndromes. Rarely, clonal expansion of immature erythroid blasts results in a clinical picture resembling erythroid leukemia. Although several mechanisms underlying normal and abnormal erythropoiesis and the pathogenesis of related disorders have been deciphered in recent years, little is known about specific markers and targets through which prognosis and therapy could be improved in anemic or polycythemic patients. In order to discuss new markers, targets and novel therapeutic approaches in erythroid disorders and the related pathologies, a workshop was organized in Vienna in April 2017. The outcomes of this workshop are summarized in this review, which includes a discussion of new diagnostic and prognostic markers, the updated WHO classification, and an overview of new drugs used to stimulate or to interfere with erythropoiesis in various neoplastic and reactive conditions. The use and usefulness of established and novel erythropoiesis-stimulating agents for various indications, including myelodysplastic syndromes and other neoplasms, are also discussed.
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- 2018
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38. Prediction of Response and Survival Following Treatment with Azacitidine for Relapse of Acute Myeloid Leukemia and Myelodysplastic Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation
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Christina Rautenberg, Anika Bergmann, Ulrich Germing, Caroline Fischermanns, Sabrina Pechtel, Jennifer Kaivers, Paul Jäger, Esther Schuler, Rainer Haas, Guido Kobbe, and Thomas Schroeder
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AML ,MDS ,allogeneic stem cell transplantation ,relapse ,azacitidine ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
To provide long-term outcome data and predictors for response and survival, we retrospectively analyzed all 151 patients with relapse of myeloid neoplasms after allogeneic hematopoietic stem cell transplantation (allo-HSCT) who were uniformly treated with first-line azacitidine (Aza) salvage therapy at our center. Patients were treated for molecular (39%) or hematologic relapse (61%), with a median of 5 cycles of Aza and at least one donor lymphocyte infusion in 70% of patients. Overall response was 46%, with 41% achieving complete (CR) and 5% achieving partial remission. CR was achieved after a median of 4 cycles and lasted for a median of 11 months (range 0.9 to 120 months). With a median follow-up of 22 months (range: 1 to 122 months), the 2-year survival rate was 38% ± 9%, including 17 patients with ongoing remission for >5 years. Based on results from multivariate analyses, molecular relapse and time to relapse were integrated into a score, clearly dividing patients into 3 subgroups with CR rates of 71%, 39%, and 29%; and 2-year survival rates of 64%, 38%, and 27%, respectively. In the subgroup of MDS and secondary AML, receiving upfront transplantation was associated with superior response and survival, and therefore pretransplant strategy was integrated together with relapse type into a MDS–sAML-specific score. Overall, Aza enables meaningful responses and long-term survival, which is a predictable with a simple-to-use scoring system.
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- 2020
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39. Correlation of RAS-Pathway Mutations and Spontaneous Myeloid Colony Growth with Progression and Transformation in Chronic Myelomonocytic Leukemia—A Retrospective Analysis in 337 Patients
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Klaus Geissler, Eva Jäger, Agnes Barna, Michael Gurbisz, Temeida Graf, Elmir Graf, Thomas Nösslinger, Michael Pfeilstöcker, Heinz Tüchler, Thamer Sliwa, Felix Keil, Christoph Geissler, Sonja Heibl, Josef Thaler, Sigrid Machherndl-Spandl, Otto Zach, Ansgar Weltermann, Peter Bettelheim, Reinhard Stauder, Armin Zebisch, Heinz Sill, Ilse Schwarzinger, Bruno Schneeweiss, Leopold Öhler, Ernst Ulsperger, Rajko Kusec, Ulrich Germing, Wolfgang R. Sperr, Paul Knöbl, Ulrich Jäger, Gregor Hörmann, and Peter Valent
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CMML ,AML ,RAS-pathway mutations ,CFU-GM ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Although the RAS-pathway has been implicated as an important driver in the pathogenesis of chronic myelomonocytic leukemia (CMML) a comprehensive study including molecular and functional analyses in patients with progression and transformation has not been performed. A close correlation between RASopathy gene mutations and spontaneous in vitro myeloid colony (CFU-GM) growth in CMML has been described. Molecular and/or functional analyses were performed in three cohorts of 337 CMML patients: in patients without (A, n = 236) and with (B, n = 61) progression/transformation during follow-up, and in patients already transformed at the time of sampling (C, n = 40 + 26 who were before in B). The frequencies of RAS-pathway mutations (variant allele frequency ≥ 20%) in cohorts A, B, and C were 30%, 47%, and 71% (p < 0.0001), and of high colony growth (≥20/105 peripheral blood mononuclear cells) 31%, 44%, and 80% (p < 0.0001), respectively. Increases in allele burden of RAS-pathway mutations and in numbers of spontaneously formed CFU-GM before and after transformation could be shown in individual patients. Finally, the presence of mutations in RASopathy genes as well as the presence of high colony growth prior to transformation was significantly associated with an increased risk of acute myeloid leukemia (AML) development. Together, RAS-pathway mutations in CMML correlate with an augmented autonomous expansion of neoplastic precursor cells and indicate an increased risk of AML development which may be relevant for targeted treatment strategies.
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- 2020
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40. Transforming growth factor β1-mediated functional inhibition of mesenchymal stromal cells in myelodysplastic syndromes and acute myeloid leukemia
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Stefanie Geyh, Manuel Rodríguez-Paredes, Paul Jäger, Annemarie Koch, Felix Bormann, Julian Gutekunst, Christoph Zilkens, Ulrich Germing, Guido Kobbe, Frank Lyko, Rainer Haas, and Thomas Schroeder
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Mesenchymal stromal cells are involved in the pathogenesis of myelodysplastic syndromes and acute myeloid leukemia, but the underlying mechanisms are incompletely understood. To further characterize the pathological phenotype we performed RNA sequencing of mesenchymal stromal cells from patients with myelodysplastic syndromes and acute myeloid leukemia and found a specific molecular signature of genes commonly deregulated in these disorders. Pathway analysis showed a strong enrichment of genes related to osteogenesis, senescence, inflammation and inhibitory cytokines, thereby reflecting the structural and functional deficits of mesenchymal stromal cells in myelodysplastic syndromes and acute myeloid leukemia on a molecular level. Further analysis identified transforming growth factor β1 as the most probable extrinsic trigger factor for this altered gene expression. Following exposure to transforming growth factor β1, healthy mesenchymal stromal cells developed functional deficits and adopted a phenotype reminiscent of that observed in patient-derived stromal cells. These suppressive effects of transforming growth factor β1 on stromal cell functionality were abrogated by SD-208, an established inhibitor of transforming growth factor β receptor signaling. Blockade of transforming growth factor β signaling by SD-208 also restored the osteogenic differentiation capacity of patient-derived stromal cells, thus confirming the role of transforming growth factor β1 in the bone marrow microenvironment of patients with myelodysplastic syndromes and acute myeloid leukemia. Our findings establish transforming growth factor β1 as a relevant trigger causing functional inhibition of mesenchymal stromal cells in myelodysplastic syndromes and acute myeloid leukemia and identify SD-208 as a candidate to revert these effects.
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- 2018
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41. First Results from a Screening of 300 Naturally Occurring Compounds: 4,6-dibromo-2-(2′,4′-dibromophenoxy)phenol, 4,5,6-tribromo-2-(2′,4′-dibromophenoxy)phenol, and 5-epi-nakijinone Q as Substances with the Potential for Anticancer Therapy
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Saskia Mayer, Marie Prechtl, Pia Liebfried, Ron-Patrick Cadeddu, Fabian Stuhldreier, Matthias Kohl, Folker Wenzel, Björn Stork, Sebastian Wesselborg, Peter Proksch, Ulrich Germing, Rainer Haas, and Paul Jäger
- Subjects
marine sponge derived natural products ,polybrominated diphenyl ethers ,sesquiterpene aminoquinone ,bioactive natural products ,cytotoxic activity ,apoptosis ,peripheral blood mononuclear cells ,primary leukemic cells ,acute myeloid leukemia ,drug leads ,Biology (General) ,QH301-705.5 - Abstract
There is a variety of antineoplastic drugs that are based on natural compounds from ecological niches with high evolutionary pressure. We used two cell lines (Jurkat J16 and Ramos) in a screening to assess 300 different naturally occurring compounds with regard to their antineoplastic activity. The results of the compounds 4,6-dibromo-2-(2′,4′-dibromophenoxy)phenol (P01F03), 4,5,6-tribromo-2-(2′,4′-dibromophenoxy)phenol (P01F08), and 5-epi-nakijinone Q (P03F03) prompted us to perform further research. Using viability and apoptosis assays on the cell lines of primary human leukemic and normal hematopoietic cells, we found that P01F08 induced apoptosis in the cell lines at IC50 values between 1.61 and 2.95 μM after 72 h. IC50 values of peripheral blood mononuclear cells (PBMNCs) from healthy donors were higher, demonstrating that the cytotoxicity in the cell lines reached 50%, while normal PBMNCs were hardly affected. The colony-forming unit assay showed that the hematopoietic progenitor cells were not significantly affected in their growth by P01F08 at a concentration of 3 μM. P01F08 showed a 3.2-fold lower IC50 value in primary leukemic cells [acute myeloid leukemia (AML)] compared to the PBMNC of healthy donors. We could confirm the antineoplastic effect of 5-epi-nakijinone Q (P03F03) on the cell lines via the induction of apoptosis but noted a similarly strong cytotoxic effect on normal PBMNCs.
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- 2019
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42. Clonal Hematopoiesis with Oncogenic Potential (CHOP): Separation from CHIP and Roads to AML
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Peter Valent, Wolfgang Kern, Gregor Hoermann, Jelena D. Milosevic Feenstra, Karl Sotlar, Michael Pfeilstöcker, Ulrich Germing, Wolfgang R. Sperr, Andreas Reiter, Dominik Wolf, Michel Arock, Torsten Haferlach, and Hans-Peter Horny
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premalignant states ,neoplastic stem cells ,clonal evolution ,cancer ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The development of leukemia is a step-wise process that is associated with molecular diversification and clonal selection of neoplastic stem cells. Depending on the number and combinations of lesions, one or more sub-clones expand/s after a variable latency period. Initial stages may develop early in life or later in adulthood and include premalignant (indolent) stages and the malignant phase, defined by an acute leukemia. We recently proposed a cancer model in which the earliest somatic lesions are often age-related early mutations detectable in apparently healthy individuals and where additional oncogenic mutations will lead to the development of an overt neoplasm that is usually a preleukemic condition such as a myelodysplastic syndrome. These neoplasms may or may not transform to overt acute leukemia over time. Thus, depending on the type and number of somatic mutations, clonal hematopoiesis (CH) can be divided into CH with indeterminate potential (CHIP) and CH with oncogenic potential (CHOP). Whereas CHIP mutations per se usually create the molecular background of a neoplastic process, CHOP mutations are disease-related or even disease-specific lesions that trigger differentiation and/or proliferation of neoplastic cells. Over time, the acquisition of additional oncogenic events converts preleukemic neoplasms into secondary acute myeloid leukemia (sAML). In the present article, recent developments in the field are discussed with a focus on CHOP mutations that lead to distinct myeloid neoplasms, their role in disease evolution, and the impact of additional lesions that can drive a preleukemic neoplasm into sAML.
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- 2019
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43. Relapse of Acute Myeloid Leukemia after Allogeneic Stem Cell Transplantation: Prevention, Detection, and Treatment
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Christina Rautenberg, Ulrich Germing, Rainer Haas, Guido Kobbe, and Thomas Schroeder
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acute myeloid leukemia ,allogeneic transplantation ,relapse ,maintenance ,minimal residual disease ,salvage therapy ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Acute myeloid leukemia (AML) is a phenotypically and prognostically heterogeneous hematopoietic stem cell disease that may be cured in eligible patients with intensive chemotherapy and/or allogeneic stem cell transplantation (allo-SCT). Tremendous advances in sequencing technologies have revealed a large amount of molecular information which has markedly improved our understanding of the underlying pathophysiology and enables a better classification and risk estimation. Furthermore, with the approval of the FMS-like tyrosine kinase 3 (FLT3) inhibitor Midostaurin a first targeted therapy has been introduced into the first-line therapy of younger patients with FLT3-mutated AML and several other small molecules targeting molecular alterations such as isocitrate dehydrogenase (IDH) mutations or the anti-apoptotic b-cell lymphoma 2 (BCL-2) protein are currently under investigation. Despite these advances, many patients will have to undergo allo-SCT during the course of disease and depending on disease and risk status up to half of them will finally relapse after transplant. Here we review the current knowledge about the molecular landscape of AML and how this can be employed to prevent, detect and treat relapse of AML after allo-SCT.
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- 2019
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44. Impaired cytotoxicity associated with defective natural killer cell differentiation in myelodysplastic syndromes
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Maryam Hejazi, Angela R. Manser, Julia Fröbel, Andrea Kündgen, Xiaoyi Zhao, Kathrin Schönberg, Ulrich Germing, Rainer Haas, Norbert Gattermann, and Markus Uhrberg
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Natural killer cells are well known to mediate anti-leukemic responses in myeloid leukemia but their role in myelodysplastic syndromes is not well understood. Here, in a cohort of newly diagnosed patients (n=75), widespread structural and functional natural killer cell defects were identified. One subgroup of patients (13%) had a selective deficiency of peripheral natural killer cells (count
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- 2015
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45. Validation of cytogenetic risk groups according to International Prognostic Scoring Systems by peripheral blood CD34+FISH: results from a German diagnostic study in comparison with an international control group
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Friederike Braulke, Uwe Platzbecker, Catharina Müller-Thomas, Katharina Götze, Ulrich Germing, Tim H. Brümmendorf, Florian Nolte, Wolf-Karsten Hofmann, Aristoteles A. N. Giagounidis, Michael Lübbert, Peter L. Greenberg, John M. Bennett, Francesc Solé, Mar Mallo, Marilyn L. Slovak, Kazuma Ohyashiki, Michelle M. Le Beau, Heinz Tüchler, Michael Pfeilstöcker, Thomas Nösslinger, Barbara Hildebrandt, Katayoon Shirneshan, Carlo Aul, Reinhard Stauder, Wolfgang R. Sperr, Peter Valent, Christa Fonatsch, Lorenz Trümper, Detlef Haase, and Julie Schanz
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
International Prognostic Scoring Systems are used to determine the individual risk profile of myelodysplastic syndrome patients. For the assessment of International Prognostic Scoring Systems, an adequate chromosome banding analysis of the bone marrow is essential. Cytogenetic information is not available for a substantial number of patients (5%–20%) with dry marrow or an insufficient number of metaphase cells. For these patients, a valid risk classification is impossible. In the study presented here, the International Prognostic Scoring Systems were validated based on fluorescence in situ hybridization analyses using extended probe panels applied to cluster of differentiation 34 positive (CD34+) peripheral blood cells of 328 MDS patients of our prospective multicenter German diagnostic study and compared to chromosome banding results of 2902 previously published patients with myelodysplastic syndromes. For cytogenetic risk classification by fluorescence in situ hybridization analyses of CD34+ peripheral blood cells, the groups differed significantly for overall and leukemia-free survival by uni- and multivariate analyses without discrepancies between treated and untreated patients. Including cytogenetic data of fluorescence in situ hybridization analyses of peripheral CD34+ blood cells (instead of bone marrow banding analysis) into the complete International Prognostic Scoring System assessment, the prognostic risk groups separated significantly for overall and leukemia-free survival. Our data show that a reliable stratification to the risk groups of the International Prognostic Scoring Systems is possible from peripheral blood in patients with missing chromosome banding analysis by using a comprehensive probe panel (clinicaltrials.gov identifier:01355913).
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- 2015
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46. Criteria for evaluating response and outcome in clinical trials for children with juvenile myelomonocytic leukemia
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Charlotte M. Niemeyer, Mignon L. Loh, Annamaria Cseh, Todd Cooper, Christopher C. Dvorak, Rebecca Chan, Blanca Xicoy, Ulrich Germing, Seiji Kojima, Atsushi Manabe, Michael Dworzak, Barbara De Moerloose, Jan Starý, Owen P. Smith, Riccardo Masetti, Albert Catala, Eva Bergstraesser, Marek Ussowicz, Oskana Fabri, André Baruchel, Hélène Cavé, Michel Zwaan, Franco Locatelli, Henrik Hasle, Marry M. van den Heuvel-Eibrink, Christian Flotho, and Ayami Yoshimi
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Juvenile myelomonocytic leukemia is a rare myeloproliferative disease in young children. While hematopoietic stem cell transplantation remains the only curative therapeutic option for most patients, children with juvenile myelomonocytic leukemia increasingly receive novel agents in phase I–II clinical trials as pre-transplant therapy or therapy for relapse after transplantation. However, response criteria or definitions of outcome for standardized evaluation of treatment effect in patients with juvenile myelomonocytic leukemia are currently lacking. Here we propose criteria to evaluate the response to the non-transplant therapy and definitions of remission status after hematopoietic stem cell transplantation. For the evaluation of non-transplant therapy, we defined 6 clinical variables (white blood cell count, platelet count, hematopoietic precursors and blasts in peripheral blood, bone marrow blast percentage, spleen size and extramedullary disease) and 3 genetic variables (cytogenetic, molecular and chimerism response) which serve to describe the heterogeneous picture of response to therapy in each individual case. It is hoped that these criteria will facilitate the comparison of results between clinical trials in juvenile myelomonocytic leukemia.
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- 2015
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47. Response to azacitidine is independent of p53 expression in higher-risk myelodysplastic syndromes and secondary acute myeloid leukemia
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Catharina Müller-Thomas, Martina Rudelius, Ina-Christine Rondak, Torsten Haferlach, Julie Schanz, Christina Huberle, Burkhard Schmidt, Rainer Blaser, Marcus Kremer, Christian Peschel, Ulrich Germing, Uwe Platzbecker, and Katharina Götze
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2014
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48. Feedback signals in myelodysplastic syndromes: increased self-renewal of the malignant clone suppresses normal hematopoiesis.
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Thomas Walenda, Thomas Stiehl, Hanna Braun, Julia Fröbel, Anthony D Ho, Thomas Schroeder, Tamme W Goecke, Björn Rath, Ulrich Germing, Anna Marciniak-Czochra, and Wolfgang Wagner
- Subjects
Biology (General) ,QH301-705.5 - Abstract
Myelodysplastic syndromes (MDS) are triggered by an aberrant hematopoietic stem cell (HSC). It is, however, unclear how this clone interferes with physiologic blood formation. In this study, we followed the hypothesis that the MDS clone impinges on feedback signals for self-renewal and differentiation and thereby suppresses normal hematopoiesis. Based on the theory that the MDS clone affects feedback signals for self-renewal and differentiation and hence suppresses normal hematopoiesis, we have developed a mathematical model to simulate different modifications in MDS-initiating cells and systemic feedback signals during disease development. These simulations revealed that the disease initiating cells must have higher self-renewal rates than normal HSCs to outcompete normal hematopoiesis. We assumed that self-renewal is the default pathway of stem and progenitor cells which is down-regulated by an increasing number of primitive cells in the bone marrow niche--including the premature MDS cells. Furthermore, the proliferative signal is up-regulated by cytopenia. Overall, our model is compatible with clinically observed MDS development, even though a single mutation scenario is unlikely for real disease progression which is usually associated with complex clonal hierarchy. For experimental validation of systemic feedback signals, we analyzed the impact of MDS patient derived serum on hematopoietic progenitor cells in vitro: in fact, MDS serum slightly increased proliferation, whereas maintenance of primitive phenotype was reduced. However, MDS serum did not significantly affect colony forming unit (CFU) frequencies indicating that regulation of self-renewal may involve local signals from the niche. Taken together, we suggest that initial mutations in MDS particularly favor aberrant high self-renewal rates. Accumulation of primitive MDS cells in the bone marrow then interferes with feedback signals for normal hematopoiesis--which then results in cytopenia.
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- 2014
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49. The myelodysplastic syndrome-comorbidity index provides additional prognostic information on patients stratified according to the revised international prognostic scoring system
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Esther Zipperer, Nina Tanha, Corinna Strupp, Andrea Kündgen, Kathrin Nachtkamp, Judith Neukirchen, Barbara Hildebrandt, Rainer Haas, Norbert Gattermann, and Ulrich Germing
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2014
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50. Targeted re-sequencing analysis of 25 genes commonly mutated in myeloid disorders in del(5q) myelodysplastic syndromes
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Marta Fernandez-Mercado, Adam Burns, Andrea Pellagatti, Aristoteles Giagounidis, Ulrich Germing, Xabier Agirre, Felipe Prosper, Carlo Aul, Sally Killick, James S. Wainscoat, Anna Schuh, and Jacqueline Boultwood
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Interstitial deletion of chromosome 5q is the most common chromosomal abnormality in myelodysplastic syndromes. The catalogue of genes involved in the molecular pathogenesis of myelodysplastic syndromes is rapidly expanding and next-generation sequencing technology allows detection of these mutations at great depth. Here we describe the design, validation and application of a targeted next-generation sequencing approach to simultaneously screen 25 genes mutated in myeloid malignancies. We used this method alongside single nucleotide polymorphism-array technology to characterize the mutational and cytogenetic profile of 43 cases of early or advanced del(5q) myelodysplastic syndromes. A total of 29 mutations were detected in our cohort. Overall, 45% of early and 66.7% of advanced cases had at least one mutation. Genes with the highest mutation frequency among advanced cases were TP53 and ASXL1 (25% of patients each). These showed a lower mutation frequency in cases of 5q- syndrome (4.5% and 13.6%, respectively), suggesting a role in disease progression in del(5q) myelodysplastic syndromes. Fifty-two percent of mutations identified were in genes involved in epigenetic regulation (ASXL1, TET2, DNMT3A and JAK2). Six mutations had allele frequencies
- Published
- 2013
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