13 results on '"Koschmieder, Steffen"'
Search Results
2. Myelofibrosis: Current unmet needs, emerging treatments, and future perspectives.
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Harrison, Claire N., Kiladjian, Jean‐Jacques, Koschmieder, Steffen, and Passamonti, Francesco
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MYELOFIBROSIS ,STEM cell transplantation ,POLYCYTHEMIA vera ,CYTOPENIA ,DRUG approval - Abstract
The current standard‐of‐care for treatment of myelofibrosis (MF) comprises inhibitors of the Janus kinase (JAK)/signal transducers and activators (STAT) pathway; however, despite their ability to alleviate symptoms, they do not appear to modify underlying disease and have not demonstrated substantial survival benefit. Allogeneic‐hematopoietic stem cell transplantation remains the only curative option for patients with MF but is limited to a subset of high‐risk and fit patients. Early disease modification could positively affect disease trajectory for lower risk patients with MF as well as those with conditions that can precede MF, such as polycythemia vera and essential thrombocythemia. Here, the authors discuss critical unmet needs in the MF treatment paradigm, including: the need for safe, impactful therapies for lower risk patients, thus allowing intervention when success is most likely; better development of first‐line therapies (likely highly novel or combination strategies) for intermediate‐risk/higher risk patients; and approved drugs to manage cytopenia. Finally, a consensus definition of disease modification is needed that informs trial design, allowing the development of clinical end points that enable understanding of therapies and responses and that facilitate the development of therapies that work according to this definition. Through close collaboration between clinicians, patients, and the pharmaceutical industry, better efforts to define benefit and identify patients most likely to benefit from a particular combination or treatment strategy should enable the development of more effective and safe treatments to extend and improve quality of life for patients with MF. Early disease modification could positively affect the disease trajectory for patients with myelofibrosis. Herein, the authors discuss critical unmet needs in the myelofibrosis treatment paradigm, including safe therapies for lower risk patients, better development of first‐line therapies for intermediate‐risk/higher risk patients, approved drugs to manage cytopenia, and a consensus definition of disease modification. [ABSTRACT FROM AUTHOR]
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- 2024
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3. The telomerase inhibitor imetelstat differentially targets JAK2V617F versus CALR mutant myeloproliferative neoplasm cells and inhibits JAK-STAT signaling.
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Olschok, Kathrin, Altenburg, Bianca, de Toledo, Marcelo A. S., Maurer, Angela, Abels, Anne, Beier, Fabian, Gezer, Deniz, Isfort, Susanne, Paeschke, Katrin, Brümmendorf, Tim H., Zenke, Martin, Chatain, Nicolas, and Koschmieder, Steffen
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MYELOPROLIFERATIVE neoplasms ,INDUCED pluripotent stem cells ,MYELOFIBROSIS ,TELOMERASE ,HEMATOPOIETIC stem cells ,GENE expression - Abstract
Imetelstat shows activity in patients with myeloproliferative neoplasms, including primary myelofibrosis (PMF) and essential thrombocythemia. Here, we describe a case of prolonged disease stabilization by imetelstat treatment of a high-risk PMF patient enrolled into the clinical study MYF2001. We confirmed continuous shortening of telomere length (TL) by imetelstat treatment but observed emergence and expansion of a KRAST58I mutated clone during the patient’s clinical course. In order to investigate the molecular mechanisms involved in the imetelstat treatment response, we generated induced pluripotent stem cells (iPSC) from this patient. TL of iPSC-derived hematopoietic stem and progenitor cells, which was increased after reprogramming, was reduced upon imetelstat treatment for 14 days. However, while imetelstat reduced clonogenic growth of the patient’s primary CD34+ cells, clonogenic growth of iPSC-derived CD34+ cells was not affected, suggesting that TL was not critically short in these cells. Also, the propensity of iPSC differentiation toward megakaryocytes and granulocytes was not altered. Using human TF-1
MPL and murine 32DMPL cell lines stably expressing JAK2V617F or CALRdel52, imetelstat-induced reduction of viability was significantly more pronounced in CALRdel52 than in JAK2V617F cells. This was associated with an immediate downregulation of JAK2 phosphorylation and downstream signaling as well as a reduction of hTERT and STAT3 mRNA expression. Hence, our data demonstrate that imetelstat reduces TL and targets JAK/STAT signaling, particularly in CALR-mutated cells. Although the exact patient subpopulation who will benefit most from imetelstat needs to be defined, our data propose that CALR-mutated clones are highly vulnerable. [ABSTRACT FROM AUTHOR]- Published
- 2023
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4. A phase Ib study to assess the efficacy and safety of vismodegib in combination with ruxolitinib in patients with intermediate- or high-risk myelofibrosis
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Couban, Stephen, Benevolo, Giulia, Donnellan, William, Cultrera, Jennifer, Koschmieder, Steffen, Verstovsek, Srdan, Hooper, Gregory, Hertig, Christian, Tandon, Maneesh, Dimier, Natalie, Malhi, Vikram, and Passamonti, Francesco
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- 2018
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5. BOREAS: a global, phase III study of the MDM2 inhibitor navtemadlin (KRT-232) in relapsed/refractory myelofibrosis.
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Verstovsek, Srdan, Al-Ali, Haifa Kathrin, Mascarenhas, John, Perkins, Andrew, Vannucchi, Alessandro Maria, Mohan, Sanjay R, Scott, Bart L, Woszczyk, Dariusz, Koschmieder, Steffen, García-Delgado, Regina, László, Rejtő, McGreivy, Jesse S, Rothbaum, Wayne P, and Kiladjian, Jean-Jacques
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Patients with myelofibrosis (MF) who discontinue ruxolitinib due to progression/resistance have poor prognoses. JAK inhibitors control symptoms and reduce spleen volumes with limited impact on underlying disease pathophysiology. Murine double minute 2 (MDM2), a negative regulator of p53, is overexpressed in circulating malignant CD34+ MF cells. The oral MDM2 inhibitor navtemadlin (KRT-232) restores p53 activity to drive apoptosis of wild-type TP53 tumor cells by inducing expression of pro-apoptotic Bcl-2 family proteins. Navtemadlin demonstrated promising clinical and disease-modifying activity and acceptable safety in a phase II study in patients with relapsed/refractory MF. The randomized phase III BOREAS study compares the efficacy and safety of navtemadlin to best available therapy in patients with MF that is relapsed/refractory to JAK inhibitor treatment. [ABSTRACT FROM AUTHOR]
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- 2022
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6. Among classic myeloproliferative neoplasms, essential thrombocythemia is associated with the greatest risk of venous thromboembolism during COVID-19
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Barbui, Tiziano, De Stefano, Valerio, Alvarez-Larran, Alberto, Iurlo, Alessandra, Masciulli, Arianna, Carobbio, Alessandra, Ghirardi, Arianna, Ferrari, Alberto, Cancelli, Valeria, Elli, Elena Maria, Andrade-Campos, Marcio Miguel, Kabat, Mercedes Gasior, Kiladjian, Jean-Jaques, Palandri, Francesca, Benevolo, Giulia, Garcia-Gutierrez, Valentin, Fox, Maria Laura, Foncillas, Maria Angeles, Morcillo, Carmen Montoya, Rumi, Elisa, Osorio, Santiago, Papadopoulos, Petros, Bonifacio, Massimiliano, Quiroz Cervantes, Keina, Serrano, Miguel Sagues, Carreño-Tarragona, Gonzalo, Sobas, Marta Anna, Lunghi, Francesca, Patriarca, Andrea, Elorza, Begoña Navas, Angona, Anna, Mazo, Elena Magro, Koschmieder, Steffen, Carli, Giuseppe, Cuevas, Beatriz, Hernandez-Boluda, Juan Carlos, Abadia, Emma Lopez, Xicoy, Blanca, Guglielmelli, Paola, Garrote, Marta, Cattaneo, Daniele, Daffini, Rosa, Cavalca, Fabrizio, Bellosillo Paricio, Beatriz, Benajiba, Lina, Curto-Garcia, Natalia, Bellini, Marta, Betti, Silvia, Harrison, Claire, Rambaldi, Alessandro, Vannucchi, Alessandro Maria, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Barbui T, Masciulli A, Carobbio A] FROM Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy. [De Stefano V] Section of Hematology, Department of Radiological and Hematological Sciences, Catholic University, Fondazione Policlinico 'A. Gemelli' IRCCS, Rome, Italy. [Alvarez-Larran A] Hospital Clinic de Barcelona, Barcelona, Spain. [Iurlo A] Hematology Division, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy. [Fox ML] Servei d’Hematologia, Vall d’Hebron Institute of Oncology (VHIO), Barcelona Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
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Male ,COVID-19 (Malaltia) - Factors de risc ,030204 cardiovascular system & hematology ,Gastroenterology ,Cohort Studies ,Otros calificadores::Otros calificadores::/complicaciones [Otros calificadores] ,Myeloproliferative disease ,0302 clinical medicine ,Polycythemia vera ,Antithrombotic ,virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES] ,Cumulative incidence ,Trombosi ,enfermedades cardiovasculares::enfermedades vasculares::embolia y trombosis::tromboembolia::tromboembolia venosa [ENFERMEDADES] ,Aged, 80 and over ,Univariate analysis ,Mortality rate ,Cardiovascular Diseases::Vascular Diseases::Embolism and Thrombosis::Thromboembolism::Venous Thromboembolism [DISEASES] ,Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES] ,Hematology ,Venous Thromboembolism ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Thrombosis ,3. Good health ,Europe ,Myeloid leukemia ,Oncology ,030220 oncology & carcinogenesis ,Infectious diseases ,Female ,Thrombocythemia, Essential ,medicine.medical_specialty ,Leucèmia mieloide ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Myelofibrosis ,Pandemics ,Tromboembolisme ,Aged ,Retrospective Studies ,Myeloproliferative Disorders ,Essential thrombocythemia ,business.industry ,SARS-CoV-2 ,COVID-19 ,medicine.disease ,Risk factors ,business ,Bone Marrow Neoplasms ,Other subheadings::Other subheadings::/complications [Other subheadings] - Abstract
Blood cancer journal 11(2), 21 (2021). doi:10.1038/s41408-021-00417-3, Published by Nature Publishing Group, London [u.a.]
- Published
- 2021
7. Imetelstat in intermediate-2 or high-risk myelofibrosis refractory to JAK inhibitor: IMpactMF phase III study design.
- Author
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Mascarenhas, John, Harrison, Claire N, Kiladjian, Jean-Jacques, Komrokji, Rami S, Koschmieder, Steffen, Vannucchi, Alessandro M, Berry, Tymara, Redding, Denise, Sherman, Laurie, Dougherty, Souria, Peng, Lixian, Sun, Libo, Huang, Fei, Wan, Ying, Feller, Faye M, Rizo, Aleksandra, and Verstovsek, Srdan
- Abstract
Imetelstat, a first-in-class telomerase inhibitor, demonstrated meaningful clinical benefit including a robust symptom response rate and potential overall survival benefit in IMbark, a phase II study in intermediate-2 or high-risk myelofibrosis (MF) patients who have relapsed after or are refractory to JAK inhibitors. We describe the rationale and design for the phase III trial, IMpactMF (NCT04576156), an open-label evaluation of imetelstat versus best available therapy, excluding JAK inhibitors, in MF patients refractory to JAK inhibitor. Imetelstat 9.4 mg/kg is administered as an intravenous infusion every 21 days. Primary objective is to assess overall survival. Secondary objectives include symptom and spleen responses, progression-free survival, clinical response assessment, bone marrow fibrosis reduction, safety and pharmacokinetics. Biomarker, cytogenetics and mutation analyses will be performed. Imetelstat is a new type of treatment being studied in patients with myelofibrosis (MF). Encouraging clinical benefits were seen in a phase II clinical trial of imetelstat in higher risk MF. This article discusses the ongoing phase III trial, called IMpactMF. IMpactMF is comparing imetelstat to best available therapy (BAT) in MF patients not responding to a specific type of treatment, a JAK inhibitor. Imetelstat is an intravenous infusion, given every 21 days. This study will determine if patients who receive imetelstat live longer than patients who are given BAT. It will also collect information on additional outcomes, including safety. Trial Registration Number: NCT04576156 (ClinicalTrials.gov) [ABSTRACT FROM AUTHOR]
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- 2022
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8. Favorable COVID‐19 course despite significant comorbidities in a ruxolitinib‐treated patient with primary myelofibrosis.
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Koschmieder, Steffen, Jost, Edgar, Cornelissen, Christian, Müller, Tobias, Schulze‐Hagen, Maximilian, Bickenbach, Johannes, Marx, Gernot, Kleines, Michael, Marx, Nikolaus, Brümmendorf, Tim H., and Dreher, Michael
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COVID-19 , *COMORBIDITY , *CYTOKINE release syndrome , *MYELOFIBROSIS , *ADULT respiratory distress syndrome , *CHRONIC kidney failure - Abstract
COVID‐19 carries a high risk of severe disease course, particularly in patients with comorbidities. Therapy of severe COVID‐19 infection has relied on supportive intensive care measures. More specific approaches including drugs that limit the detrimental "cytokine storm", such as Janus‐activated kinase (JAK) inhibitors, are being discussed. Here, we report a compelling case of a 55‐yo patient with proven COVID‐19 pneumonia, who was taking the JAK1/2 inhibitor ruxolitinib in‐label for co‐existing primary myelofibrosis for 15 months prior to coronavirus infection. The patient had significant comorbidities, including chronic kidney disease, arterial hypertension, and obesity, and our previous cohort suggested that he was thus at high risk for acute respiratory distress syndrome (ARDS) and death from COVID‐19. Since abrupt discontinuation of ruxolitinib may cause fatal cytokine storm and ARDS, ruxolitinib treatment was continued and was well tolerated, and the patient´s condition remained stable, without the need for mechanical ventilation or vasopressors. The patient became negative for SARS‐CoV‐2 and was discharged home after 15 days. In conclusion, our report provides clinical evidence that ruxolitinib treatment is feasible and can be beneficial in patients with COVID‐19 pneumonia, preventing cytokine storm and ARDS. [ABSTRACT FROM AUTHOR]
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- 2020
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9. Transcriptional alteration of DNA repair genes in Philadelphia chromosome negative myeloproliferative neoplasms.
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Kirschner, Martin, Bornemann, Anne, Schubert, Claudia, Gezer, Deniz, Kricheldorf, Kim, Isfort, Susanne, Brümmendorf, Tim H., Schemionek, Mirle, Chatain, Nicolas, Skorski, Tomasz, and Koschmieder, Steffen
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PHILADELPHIA chromosome ,DNA repair ,POLYCYTHEMIA vera ,CHROMOSOMES ,MYELOFIBROSIS ,CANCER ,GENE expression ,CURATIVE medicine - Abstract
Philadelphia negative (Ph-neg) myeloproliferative neoplasms (MPN) are a heterogenous group of clonal stem cell disorders. Approved treatment options include hydroxyurea, anagrelide, and ruxolitinib, which are not curative. The concept of synthetic lethality may become an additional therapeutic strategy in these diseases. In our study, we show that DNA repair is altered in classical Ph-neg MPN, as analyzed by gene expression analysis of 11 genes involved in the homologous recombination repair pathway (HRR), the non-homologous end-joining pathway (NHEJ), and the single-strand break repair pathway (SSB). Altogether, peripheral blood-derived cells from 57 patients with classical Ph-neg MPN and 13 healthy controls were analyzed. LIG3 as an essential part of the SSB was significantly lower expressed compared to controls in all three entities (essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF)). In addition, while genes of other DNA-repair pathways showed-possibly compensatory-increased expression in ET (HRR, NHEJ) and PV (NHEJ), MF samples displayed downregulation of all genes involved in NHEJ. With regard to the JAK2 mutational status (analyzed in ET and MF only), no upregulation of the HRR was detected. Though further studies are needed, based on these findings, we conclude that synthetic lethality may become a promising strategy in treating patients with Ph-neg MPN. [ABSTRACT FROM AUTHOR]
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- 2019
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10. Emerging translational science discoveries, clonal approaches, and treatment trends in chronic myeloproliferative neoplasms.
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Mughal, Tariq I., Pemmaraju, Naveen, Radich, Jerald P., Deininger, Michael W., Kucine, Nicole, Kiladjian, Jean‐Jacques, Bose, Prithviraj, Gotlib, Jason, Valent, Peter, Chen, Chih‐Cheng, Barbui, Tiziano, Rampal, Raajit, Verstovsek, Srdan, Koschmieder, Steffen, Saglio, Giuseppe, Van Etten, Richard A., Kiladjian, Jean-Jacques, and Chen, Chih-Cheng
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SCIENTIFIC discoveries ,TUMORS ,MYELOFIBROSIS ,TRANSLATIONAL research ,OPEN-ended questions - Abstract
The 60th American Society of Hematology (ASH) held in San Diego in December 2018 was followed by the 13th Post-ASH chronic myeloproliferative neoplasms (MPNs) workshop on December 4 and 5, 2018. This closed annual workshop, first introduced in 2006 by Goldman and Mughal, was organized in collaboration with Alpine Oncology Foundation and allowed experts in preclinical and clinical research in the chronic MPNs to discuss the current scenario, including relevant presentations at ASH, and address pivotal open questions that impact translational research and clinical management. This review is based on the presentations and deliberations at this workshop, and rather than provide a resume of the proceedings, we have selected some of the important translational science and treatment issues that require clarity. We discuss the experimental and observational evidence to support the intimate interaction between aging, inflammation, and clonal evolution of MPNs, the clinical impact of the unfolding mutational landscape on the emerging targets and treatment of MPNs, new methods to detect clonal heterogeneity, the challenges in managing childhood and adolescent MPN, and reflect on the treatment of systemic mastocytosis (SM) following the licensing of midostaurin. [ABSTRACT FROM AUTHOR]
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- 2019
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11. The impact of myeloproliferative neoplasms (MPNs) on patient quality of life and productivity: results from the international MPN Landmark survey.
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Harrison, Claire, Koschmieder, Steffen, Foltz, Lynda, Guglielmelli, Paola, Flindt, Tina, Koehler, Michael, Mathias, Jonathan, Komatsu, Norio, Boothroyd, Robert, Spierer, Amber, Perez Ronco, Julian, Taylor-Stokes, Gavin, Waller, John, Mesa, Ruben, Harrison, Claire N, Boothroyd, Robert N, and Mesa, Ruben A
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MYELOFIBROSIS , *POLYCYTHEMIA vera , *THROMBOCYTOSIS , *TUMORS , *QUALITY of life , *FATIGUE (Physiology) , *MYELOPROLIFERATIVE neoplasms , *COMPARATIVE studies , *ECONOMIC aspects of diseases , *RESEARCH methodology , *MEDICAL cooperation , *PHYSICIAN-patient relations , *RESEARCH , *EVALUATION research , *THERAPEUTICS - Abstract
Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPNs) associated with high disease burden, reduced quality of life (QOL), and shortened survival. To assess how MPNs affect patients, we conducted a global MPN Landmark survey. This online survey of patients with MPNs and physicians was conducted in Australia, Canada, Germany, Japan, Italy, and the United Kingdom. The survey measured MPN-related symptoms and the impact of MPNs on QOL and the ability to work as well as disease-management strategies. Overall, 219 physicians and 699 patients (MF, n = 174; PV, n = 223; ET, n = 302) completed the survey; 90% of patients experienced MPN-related symptoms. The most frequent and severe symptom was fatigue. Most patients experienced a reduction in QOL, including those with low symptom burden or low-risk scores. A substantial proportion of patients reported impairment at work and in overall activity. Interestingly, physician feedback and blood counts were the most important indicators of treatment success among patients, with improvements in symptoms and QOL being less important. Regarding disease management, our study revealed a lack of alignment between physician and patient perceptions relating to communication and disease management, with patients often having different treatment goals than physicians. Overall, our study suggested that therapies that reduce symptom burden and improve QOL in patients with MPNs are crucial in minimizing disease impact on patient daily lives. Additionally, our findings showed a need for improved patient-physician communication, standardized monitoring of symptoms, and agreement on treatment goals. [ABSTRACT FROM AUTHOR]
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- 2017
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12. Activated fibronectin-secretory phenotype of mesenchymal stromal cells in pre-fibrotic myeloproliferative neoplasms.
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Schneider, Rebekka K., Ziegler, Susanne, Leisten, Isabelle, Ferreira, Monica S. V., Schumacher, Anne, Rath, Björn, Fahrenkamp, Dirk, Müller-Newen, Gerhard, Crysandt, Martina, Wilop, Stefan, Jost, Edgar, Koschmieder, Steffen, Knüchel, Ruth, Brümmendorf, Tim H., and Ziegler, Patrick
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MESENCHYMAL stem cells ,MYELOPROLIFERATIVE neoplasms ,FIBRONECTINS ,CELL proliferation ,HEMATOPOIETIC stem cells ,PROGENITOR cells ,BONE marrow - Abstract
We characterized bone marrow stromal cells (BMSC) from patients with pre-fibrotic myeloproliferative neoplasms (MPN). MPN-BMSC showed decreased capacity to stimulate the proliferation of colony-forming units of normal hematopoietic stem and progenitor cells and displayed increased matrix remodelling (in particular fibronectin deposition) compared to control BMSC. This finding was confirmed in pre-fibrotic MPN bone marrow biopsies in a tissue microarray (n = 34), which stained positive for fibronectin in the absence of reticulin as a standard myelofibrosis marker. Fibronectin expression correlated significantly with reduced haemoglobin levels in MPN-patients (p = 0.007; R2 = 0.42). Our data show significant cellintrinsic alterations in MPN-MSC and suggest that Fibronectin expression might be applicable as a biomarker for the identification of early myelofibrotic transformation in reticulin-negative MPN. [ABSTRACT FROM AUTHOR]
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- 2014
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13. JAK Inhibition Impairs NK Cell Function in Myeloproliferative Neoplasms.
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Schonberg, Kathrin, Rudolph, Janna, Vonnahme, Maria, Yajnanarayana, Sowmya Parampalli, Cornez, Isabelle, Hejazi, Maryam, Manser, Angela R., Uhrberg, Markus, Verbeek, Walter, Koschmieder, Steffen, Brümmendorf, Tim H., Brossart, Peter, Heine, Annkristin, and Wolf, Dominik
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JANUS kinases , *KINASE inhibitors , *KILLER cells , *MYELOFIBROSIS , *CELL proliferation , *CYTOKINES , *CELLULAR signal transduction - Abstract
Ruxolitinib is a small-molecule inhibitor of the )AK kinases, which has been approved for the treatment of myelofibrosis, a rare myeloproliferative neoplasm (MPN), but clinical trials are also being conducted in inflammatory-driven solid tumors. Increased infection rates have been reported in ruxolitinib- treated patients, and natural killer (NK) cells are immune effector cells known to eliminate both virus-infected and malignant cells. On this basis, we sought to compare the effects of IAK inhibition on human NK cells in a cohort of 28 MPN patients with or without ruxolitinib treatment and 24 healthy individuals. NK cell analyses included cell frequency, receptor expression, proliferation, immune synapse formation, and cytokine signaling. We found a reduction in NK cell numbers in ruxolitinib-treated patients that was linked to the appearance of clinically relevant infections. This reduction was likely due to impaired maturation of NK cells, as reflected by an increased ratio in immature to mature NK cells. Notably, the endogenous functional defect of NK cells in MPN was further aggravated by ruxolitinib treatment. In vitro data paralleled these in vivo results, showing a reduction in cytokine-induced NK cell activation. Further, reduced killing activity was associated with an impaired capacity to form lytic synapses with NK target cells. Taken together, our findings offer compelling evidence that ruxolitinib impairs NK cell function in MPN patients, offering an explanation for increased infection rates and possible longterm side effects associated with ruxolitinib treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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