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Midostaurin

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https://www.readbyqxmd.com/read/28644114/midostaurin-plus-chemotherapy-for-acute-myeloid-leukemia-with-a-flt3-mutation
#1
Richard M Stone, Sumithra J Mandrekar, Ben L Sanford, Kristina Laumann, Susan Geyer, Clara D Bloomfield, Christian Thiede, Thomas W Prior, Konstanze Döhner, Guido Marcucci, Francesco Lo-Coco, Rebecca B Klisovic, Andrew Wei, Jorge Sierra, Miguel A Sanz, Joseph M Brandwein, Theo de Witte, Dietger Niederwieser, Frederick R Appelbaum, Bruno C Medeiros, Martin S Tallman, Jürgen Krauter, Richard F Schlenk, Arnold Ganser, Hubert Serve, Gerhard Ehninger, Sergio Amadori, Richard A Larson, Hartmut Döhner
Background Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population. Methods We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo...
June 23, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28612232/midostaurin-first-global-approval
#2
Esther S Kim
Midostaurin (Rydapt(®)) is a multikinase inhibitor being developed by Novartis Pharmaceuticals. In April 2017, midostaurin was approved in the USA for the treatment of adult patients with newly diagnosed, FMS-like tyrosine kinase 3 (FLT3) mutation-positive acute myeloid leukaemia (AML) [in combination with standard cytarabine and daunorubicin induction, and cytarabine consolidation], or aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasm (SM-AHN) or mast cell leukaemia (MCL) [collectively known as advanced SM]...
June 13, 2017: Drugs
https://www.readbyqxmd.com/read/28610444/midostaurin-for-the-treatment-of-acute-myeloid-leukemia
#3
Mrinal M Patnaik
Midostaurin is a multikinase tyrosine kinase inhibitor acting against targets known to be expressed in hematologic malignancies, especially acute myeloid leukemia. Midostaurin combined with chemotherapy followed by single-agent maintenance therapy elicited statistically significant and clinically meaningful improvement in overall survival versus placebo in patients with newly diagnosed FLT3-mutant acute myeloid leukemia. Although gastrointestinal events were more common with midostaurin, overall the drug was relatively well tolerated...
June 14, 2017: Future Oncology
https://www.readbyqxmd.com/read/28546144/midostaurin-approved-for-flt3-mutated-aml
#4
Mark Levis
Midostaurin was recently approved by the U.S. Food and Drug Administration for the treatment of FLT3-mutant acute myeloid leukemia (AML). This is the first drug to receive regulatory approval for AML in the U.S. since the year 2000. Midostaurin is a small molecule kinase inhibitor with activity against the receptor tyrosine kinase FLT3, and its approval will hopefully mark the beginning of an era of targeted agents for the treatment of molecularly-defined subtypes of AML.
May 25, 2017: Blood
https://www.readbyqxmd.com/read/28526740/midostaurin-gets-fda-nod-for-aml
#5
(no author information available yet)
The FDA has approved the small-molecule inhibitor midostaurin in combination with chemotherapy to treat acute myeloid leukemia. It is the first approved drug for the disease that specifically targets FLT3 mutations, which occur in about a quarter of all AML cases and are associated with particularly poor outcomes.
May 19, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28484168/current-diagnosis-and-treatment-for-acute-myeloid-leukemia
#6
Yukio Kobayashi
Genomic studies of acute myeloid leukemia have been extensively in progress. In patients with therapy-related myeloid neoplasms, peripheral blood before chemotherapy was found to have a minute clone with mutated oncogenes and tumor suppressor genes. Patients who were in complete remission showed a fraction of mutated genes. This status involves clonal hematopoiesis of indeterminate potential and demonstrates that a fraction of cells with mutated genes cannot result in leukemia. Regarding treatment, the results of two phase 3 studies have shown efficacy; midostaurin is effective in combination with the standard 7+3 therapy, and another mixed compound comprising micellized cytarabine and daunorubicin at a mixing molar ratio of 5 : 1 is more effective than the standard 7+3 therapy...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28424161/response-and-progression-on-midostaurin-in-advanced-systemic-mastocytosis-kit-d816v-and-other-molecular-markers
#7
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
#8
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
#9
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
#10
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
#11
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 at least 20% of 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 of 28 (57%) patients and secondary mast cell leukemia evolving from other advanced systemic mastocytosis subtypes in 12 of 28 (43%) patients, of which 7 patients progressed while on cytoreductive treatment...
June 2017: Haematologica
https://www.readbyqxmd.com/read/28030373/what-are-the-most-promising-new-agents-in-acute-myeloid-leukemia
#12
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
#13
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
#14
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...
April 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/27942432/mast-cell-clonal-disorders-classification-diagnosis-and-management
#15
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
#16
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
#17
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
#18
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
#19
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...
March 2017: 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
#20
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
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