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Midostaurin

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https://www.readbyqxmd.com/read/28424161/response-and-progression-on-midostaurin-in-advanced-systemic-mastocytosis-kit-d816v-and-other-molecular-markers
#1
Mohamad Jawhar, Juliana Schwaab, Nicole Naumann, Hans-Peter Horny, Karl Sotlar, Torsten Haferlach, Georgia Metzgeroth, Alice Fabarius, Peter Valent, Wolf-Karsten Hofmann, Nicholas C P Cross, Manja Meggendorfer, Andreas Reiter
In advanced systemic mastocytosis (advSM), disease evolution is often triggered by activating KIT mutations (D816V in >80% of cases) and by additional mutations, e.g. in SRSF2, ASXL1 and/or RUNX1 (S/A/R(pos), >60% of cases). In a recently reported phase-II-study, midostaurin, a multikinase/KIT inhibitor, demonstrated an overall response rate (ORR) of 60% in advSM but biomarkers predictive of response are lacking. We evaluated the impact of molecular markers (KIT D816V, S/A/R(pos)) at baseline and during follow-up in 38 midostaurin-treated advSM patients...
April 19, 2017: Blood
https://www.readbyqxmd.com/read/28397975/the-jak2-stat5-signaling-pathway-as-a-potential-therapeutic-target-in-canine-mastocytoma
#2
Alexandra Keller, Bettina Wingelhofer, Barbara Peter, Karin Bauer, Daniela Berger, Susanne Gamperl, Martin Reifinger, Sabine Cerny-Reiterer, Richard Moriggl, Michael Willmann, Peter Valent, Emir Hadzijusufovic
BACKGROUND: Mastocytoma are frequently diagnosed cutaneous neoplasms in dogs. In non-resectable mastocytoma patients, novel targeted drugs are often applied. The transcription factor STAT5 has been implicated in the survival of human neoplastic mast cells (MC). Our study evaluated the JAK2/STAT5 pathway as a novel target in canine mastocytoma. MATERIALS AND METHODS: We employed inhibitors of JAK2 (R763, TG101348, AZD1480, ruxolitinib) and STAT5 (pimozide, piceatannol) and evaluated their effects on 2 mastocytoma cell lines, C2 and NI-1...
April 11, 2017: Veterinary and Comparative Oncology
https://www.readbyqxmd.com/read/28286924/treatment-of-relapsed-refractory-acute-myeloid-leukemia
#3
REVIEW
Prithviraj Bose, Pankit Vachhani, Jorge E Cortes
Approximately 40-45% of younger and 10-20% of older adults with acute myeloid leukemia (AML) will be cured with current standard chemotherapy. The outlook is particularly gloomy for patients with relapsed and/or refractory disease (cure rates no higher than 10%). Allogeneic hematopoietic stem cell transplantation (HSCT), the only realistic hope of cure for these patients, is an option for only a minority. In recent years, much has been learned about the genomic and epigenomic landscapes of AML, and the clonal architecture of both de novo and secondary AML has begun to be unraveled...
March 2017: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/28270565/midostaurin-a-novel-protein-kinase-inhibitor-for-the-treatment-of-acute-myelogenous-leukemia-insights-from-human-absorption-metabolism-and-excretion-studies-of-a-bddcs-ii-drug
#4
Handan He, Phi Tran, Helen Gu, Vivienne Tedesco, Jin Zhang, Wen Lin, Ewa Gatlik, Kai Klein, Tycho Heimbach
The absorption, metabolism, and excretion of midostaurin, a potent class III tyrosine protein kinase inhibitor for acute myelogenous leukemia, were evaluated in healthy subjects. A microemulsion formulation was chosen to optimize absorption. After a 50-mg [(14)C]midostaurin dose, oral absorption was high (>90%) and relatively rapid. In plasma, the major circulating components were midostaurin (22%), CGP52421 (32.7%), and CGP62221 (27.7%). Long plasma half-lives were observed for midostaurin (20.3 hours), CGP52421 (495 hours), and CGP62221 (33...
May 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28255023/the-clinical-and-molecular-diversity-of-mast-cell-leukemia-with-or-without-associated-hematologic-neoplasm
#5
Mohamad Jawhar, Juliana Schwaab, Manja Meggendorfer, Nicole Naumann, Hans-Peter Horny, Karl Sotlar, Torsten Haferlach, Karla Schmitt, Alice Fabarius, Peter Valent, Wolf-Karsten Hofmann, Nicholas C P Cross, Georgia Metzgeroth, Andreas Reiter
Mast cell leukemia is a rare variant of advanced systemic mastocytosis characterized by ≥20% mast cells in a bone marrow smear. We evaluated clinical and molecular characteristics of 28 patients with (n=20, 71%) or without an associated hematologic neoplasm. De novo mast cell leukemia was diagnosed in 16/28 (57%) patients and secondary mast cell leukemia evolving from other advanced systemic mastocytosis subtypes in 12/28 (43%) patients, of which 7 patients progressed while on cytoreductive treatment. Median bone marrow mast cell infiltration was 65% and median serum tryptase was 565 microg/L...
March 2, 2017: Haematologica
https://www.readbyqxmd.com/read/28030373/what-are-the-most-promising-new-agents-in-acute-myeloid-leukemia
#6
David A Sallman, Jeffrey E Lancet
PURPOSE OF REVIEW: Although the treatment paradigm for acute myeloid leukemia (AML) had been largely unchanged for many years, in-depth molecular characterization has revolutionized our understanding of mutations that drive the disease, subsequently serving to guide current clinical investigation. Furthermore, recent advances in the field have highlighted the importance of optimizing known efficacious agents by improving drug delivery or bypassing resistance mechanisms. The current status of novel agents which are shaping the clinical management of AML patients are summarized in this review...
March 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28001095/antileukemic-effects-of-midostaurin-in-acute-myeloid-leukemia-the-possible-importance-of-multikinase-inhibition-in-leukemic-as-well-as-nonleukemic-stromal-cells
#7
REVIEW
Tor Henrik Tvedt, Ina Nepstad, Øystein Bruserud
Midostaurin is a multikinase inhibitor that inhibits receptor tyrosine kinases (Flt3, CD117/c-kit, platelet-derived growth factor receptor, vascular endothelial growth factor receptor 2) as well as non-receptor tyrosine kinases (Frg, Src, Syk, Protein kinase C). Combination of midostaurin with conventional intensive chemotherapy followed by one year maintenance monotherapy was recently reported to improve the survival of acute myeloid leukemia (AML) patients with Flt3 mutations. Areas covered: Relevant publications were identified through literature searches in the PubMed database...
March 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28000291/the-role-of-flt3-inhibitors-in-the-treatment-of-flt3-mutated-acute-myeloid-leukemia
#8
REVIEW
Amir T Fathi, Yi-Bin Chen
FLT3 mutations are present in about one-third of patients with acute myeloid leukemia (AML). Several FLT3 inhibitors have been used in clinical trials, and these include midostaurin, sorafenib, quizartinib, crenolanib, and gilteritinib. Monotherapy with early tyrosine kinase inhibitors (TKIs) did not have much success; however, later generation agents have shown more promising results. Combination with conventional chemotherapy may have benefit as evidenced by recently presented results, and data from ongoing trials are eagerly awaited...
December 21, 2016: European Journal of Haematology
https://www.readbyqxmd.com/read/27942432/mast-cell-clonal-disorders-classification-diagnosis-and-management
#9
REVIEW
Merel C Onnes, Luciana K Tanno, Joanne N G Oude Elberink
Mast cell clonal disorders are characterized by the clonal proliferation of pathological mast cells as a result of somatic mutations in the KIT gene, most commonly the D816V mutation. Accumulation and degranulation of these cells causes a wide variety of symptoms. Mast cell clonal disorders can be divided into mastocytosis and monoclonal mast cell activation syndrome, depending of the level of clonality. The severity of mastocytosis varies from an indolent variant with a good prognosis, to an aggressive condition with short life expectancy...
2016: Current Treatment Options in Allergy
https://www.readbyqxmd.com/read/27908881/preclinical-studies-of-gilteritinib-a-next-generation-flt3-inhibitor
#10
LETTER
Lauren Y Lee, Daniela Hernandez, Trivikram Rajkhowa, Samuel C Smith, Jayant Ranganathan Raman, Bao Nguyen, Donald Small, Mark Levis
No abstract text is available yet for this article.
January 12, 2017: Blood
https://www.readbyqxmd.com/read/27856463/ccl-2-is-a-kit-d816v-dependent-modulator-of-the-bone-marrow-microenvironment-in-systemic-mastocytosis
#11
Georg Greiner, Nadine Witzeneder, Angelika Berger, Klaus Schmetterer, Gregor Eisenwort, Ana-Iris Schiefer, Simone Roos, Theresia Popow-Kraupp, Leonhard Müllauer, Johannes Zuber, Veronika Sexl, Lukas Kenner, Wolfgang R Sperr, Peter Valent, Matthias Mayerhofer, Gregor Hoermann
Systemic mastocytosis (SM) is characterized by abnormal accumulation of neoplastic mast cells harboring the activating KIT mutation D816V in the bone marrow and other internal organs. Similar to other myeloproliferative neoplasms, increased production of pro-fibrogenic and angiogenic cytokines and related alterations of the bone marrow microenvironment are commonly found in SM. However, only little is known about mechanisms and effector molecules triggering fibrosis and angiogenesis in SM. Here we show that KIT D816V promotes expression of the pro-angiogenic cytokine CCL-2 in neoplastic mast cells...
November 16, 2016: Blood
https://www.readbyqxmd.com/read/27835920/-acute-myeloid-leukemia
#12
REVIEW
Jan Braess
Acute myeloid leukemia (AML) has been genetically characterized extensively and can now be subdivided into 9 to 11 pathogenetically different subtypes according to their profile of driver mutations. In clinical practice karyotyping and molecular analysis of NPM1, cEBPa and FLT3-ITD are required for treatment stratification and potentially genotype specific treatment. Some markers such as NPM1 not only offer prognostic information but can also serve as markers of minimal residual disease and thus have the potential to guide therapy in the future...
November 2016: Deutsche Medizinische Wochenschrift
https://www.readbyqxmd.com/read/27775694/inhibition-of-flt3-in-aml-a-focus-on-sorafenib
#13
REVIEW
A Antar, Z K Otrock, J El-Cheikh, M A Kharfan-Dabaja, G Battipaglia, R Mahfouz, M Mohty, A Bazarbachi
FMS-like tyrosine kinase 3 (FLT3) is one of the most commonly mutated genes in AML. FLT3 is mutated in ~30% of patients with AML, either by internal tandem duplications (FLT3-ITD) of the juxta-membrane domain or by a point mutation, usually involving the tyrosine kinase domain. Several FLT3 tyrosine kinase inhibitors are being evaluated in multiple studies aiming at improving outcomes. The most widely used is sorafenib, a potent multikinase inhibitor approved for hepatocellular carcinoma and renal cell carcinoma...
October 24, 2016: Bone Marrow Transplantation
https://www.readbyqxmd.com/read/27769267/activation-of-hiv-1-expression-in-latently-infected-cd4-t-cells-by-the-small-molecule-pkc412
#14
Zhujun Ao, Rong Zhu, Xiaoli Tan, Lisa Liu, Liyu Chen, Shuiping Liu, XiaoJian Yao
BACKGROUND: HIV-1 latency is a major obstacle for HIV-1 eradication. Extensive efforts are being directed toward the reactivation of latent HIV reservoirs with the aim of eliminating latently infected cells via the host immune system and/or virus-mediated cell lysis. RESULTS: We screened over 1,500 small molecules and kinase inhibitors and found that a small molecule, PKC412 (midostaurin, a broad-spectrum kinase inhibitor), can stimulate viral transcription and expression from the HIV-1 latently infected ACH2 cell line and primary resting CD4+ T cells...
October 21, 2016: Virology Journal
https://www.readbyqxmd.com/read/27762455/systemic-mastocytosis-in-adults-2017-update-on-diagnosis-risk-stratification-and-management
#15
Animesh Pardanani
Disease overview:Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extra-cutaneous organs. DIAGNOSIS: The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. Risk stratification: The 2008 World Health Organization (WHO) classification of SM has been shown to be prognostically relevant...
November 2016: American Journal of Hematology
https://www.readbyqxmd.com/read/27450971/flt3-inhibitors-for-treating-acute-myeloid-leukemia
#16
REVIEW
Mona Hassanein, Muhamad H Almahayni, Syed O Ahmed, Sameh Gaballa, Riad El Fakih
FLT3 (Fms-like tyrosine kinase 3) inhibitors are tyrosine kinase inhibitors. The first-generation FLT3 inhibitors were developed several years ago and include midostaurin, lestaurtinib, sunitinib, and sorafenib. They are relatively nonspecific for FLT3, with other potential targets that include platelet-derived growth factor receptor, vascular endothelial growth factor receptor, KIT, and Janus kinase 2. The second-generation inhibitors, including quizartinib, crenolanib, PLX3397, and ASP2215, are more potent and selective than the first-generation inhibitors...
October 2016: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/27355533/efficacy-and-safety-of-midostaurin-in-advanced-systemic-mastocytosis
#17
MULTICENTER STUDY
Jason Gotlib, Hanneke C Kluin-Nelemans, Tracy I George, Cem Akin, Karl Sotlar, Olivier Hermine, Farrukh T Awan, Elizabeth Hexner, Michael J Mauro, David W Sternberg, Matthieu Villeneuve, Alice Huntsman Labed, Eric J Stanek, Karin Hartmann, Hans-Peter Horny, Peter Valent, Andreas Reiter
BACKGROUND: Advanced systemic mastocytosis comprises rare hematologic neoplasms that are associated with a poor prognosis and lack effective treatment options. The multikinase inhibitor midostaurin inhibits KIT D816V, a primary driver of disease pathogenesis. METHODS: We conducted an open-label study of oral midostaurin at a dose of 100 mg twice daily in 116 patients, of whom 89 with mastocytosis-related organ damage were eligible for inclusion in the primary efficacy population; 16 had aggressive systemic mastocytosis, 57 had systemic mastocytosis with an associated hematologic neoplasm, and 16 had mast-cell leukemia...
June 30, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27186148/midostaurin-an-emerging-treatment-for-acute-myeloid-leukemia-patients
#18
REVIEW
Molly Megan Gallogly, Hillard M Lazarus
Acute myeloid leukemia (AML) is a hematologic malignancy that carries a poor prognosis and has garnered few treatment advances in the last few decades. Mutation of the internal tandem duplication (ITD) region of fms-like tyrosine kinase (FLT3) is considered high risk for decreased response and overall survival. Midostaurin is a Type III receptor tyrosine kinase inhibitor found to inhibit FLT3 and other receptor tyrosine kinases, including platelet-derived growth factor receptors, cyclin-dependent kinase 1, src, c-kit, and vascular endothelial growth factor receptor...
2016: Journal of Blood Medicine
https://www.readbyqxmd.com/read/27137475/prolonged-cellular-midostaurin-retention-suggests-potential-alternative-dosing-strategies-for-flt3-itd-positive-leukemias
#19
D B Lipka, M-C Wagner, M Dziadosz, T Fischer
No abstract text is available yet for this article.
October 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27131865/consensus-opinion-on-allogeneic-hematopoietic-cell-transplantation-in-advanced-systemic-mastocytosis
#20
Celalettin Ustun, Jason Gotlib, Uday Popat, Andrew Artz, Mark Litzow, Andreas Reiter, Ryotaro Nakamura, Hanneke C Kluin-Nelemans, Srdan Verstovsek, James Gajewski, Miguel-Angel Perales, Tracy George, Tsiporah Shore, Wolfgang Sperr, Wael Saber, Vamsi Kota, Akif Selim Yavuz, Vinod Pullarkat, John Rogosheske, William Hogan, Koen Van Besien, Hans Hagglund, Gandhi Damaj, Michel Arock, Hans-Peter Horny, Dean D Metcalfe, H Joachim Deeg, Steven Devine, Daniel Weisdorf, Cem Akin, Peter Valent
No abstract text is available yet for this article.
August 2016: Biology of Blood and Marrow Transplantation
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