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Midostaurin

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https://www.readbyqxmd.com/read/28881711/characterization-of-midostaurin-as-a-dual-inhibitor-of-flt3-and-syk-and-potentiation-of-flt3-inhibition-against-flt3-itd-driven-leukemia-harboring-activated-syk-kinase
#1
Ellen L Weisberg, Alexandre Puissant, Richard Stone, Martin Sattler, Sara J Buhrlage, Jing Yang, Paul W Manley, Chengcheng Meng, Michael Buonopane, John F Daley, Suzan Lazo, Renee Wright, David M Weinstock, Amanda L Christie, Kimberly Stegmaier, James D Griffin
Oncogenic FLT3 kinase is a clinically validated target in acute myeloid leukemia (AML), and both multi-targeted and selective FLT3 inhibitors have been developed. Spleen tyrosine kinase (SYK) has been shown to be activated and increased in FLT3-ITD-positive AML patients, and has further been shown to be critical for transformation and maintenance of the leukemic clone in these patients. Further, over-expression of constitutively activated SYK causes resistance to highly selective FLT3 tyrosine kinase inhibitors (TKI)...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28804680/treatment-of-older-patients-with-acute-myeloid-leukemia-aml-revised-canadian-consensus-guidelines
#2
REVIEW
Joseph M Brandwein, Nancy Zhu, Rajat Kumar, Brian Leber, Mitchell Sabloff, Irwindeep Sandhu, Jeannine Kassis, Harold J Olney, Mohamed Elemary, Andre C Schuh
The treatment of acute myeloid leukemia (AML) in older patients is undergoing rapid changes, with a number of important publications in the past five years. Because of this, a group of Canadian leukemia experts has produced an update to the Canadian Consensus Guidelines that were published in 2013, with several new agents recommended, subject to availability. Recent studies have supported the survival benefit of induction chemotherapy for patients under age 80, except those with major co-morbidities or those with adverse risk cytogenetics who are not candidates for allogeneic hematopoietic stem cell transplantation (HSCT)...
2017: American Journal of Blood Research
https://www.readbyqxmd.com/read/28744009/efficacy-and-safety-of-midostaurin-in-patients-with-advanced-systemic-mastocytosis-10-year-median-follow-up-of-a-phase-ii-trial
#3
D J DeAngelo, T I George, A Linder, C Langford, C Perkins, J Ma, P Westervelt, J D Merker, C Berube, S Coutre, M Liedtke, B Medeiros, D Sternberg, C Dutreix, P-A Ruffie, C Corless, T J Graubert, J Gotlib
Patients with advanced systemic mastocytosis (SM) (e.g. aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL)) have limited treatment options and exhibit reduced survival. Midostaurin is an oral multikinase inhibitor that inhibits D816V-mutated KIT, a primary driver of SM pathogenesis. We conducted a phase II trial of midostaurin 100 mg twice daily, administered as 28-day cycles, in 26 patients (ASM, n=3; SM-AHN, n= 17; MCL, n=6) with at least one sign of organ damage...
July 24, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28706155/characterization-of-midostaurin-as-a-dual-inhibitor-of-flt3-and-syk-and-potentiation-of-flt3-inhibition-against-flt3-itd-driven-leukemia-harboring-activated-syk-kinase
#4
Ellen L Weisberg, Alexandre Puissant, Richard Stone, Martin Sattler, Sara J Buhrlage, Jing Yang, Paul W Manley, Chengcheng Meng, Michael Buonopane, John F Daley, Suzan Lazo, Renee Wright, David M Weinstock, Amanda L Christie, Kimberly Stegmaier, James D Griffin
Oncogenic FLT3 kinase is a clinically validated target in acute myeloid leukemia (AML), and both multi-targeted and selective FLT3 inhibitors have been developed. Spleen tyrosine kinase (SYK) has been shown to be activated and increased in FLT3-ITD-positive AML patients, and has further been shown to be critical for transformation and maintenance of the leukemic clone in these patients. Further, over-expression of constitutively activated SYK causes resistance to highly selective FLT3 tyrosine kinase inhibitors (TKI)...
July 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28705853/a-molecular-roadmap-for-midostaurin-in-mastocytosis
#5
Jason Gotlib
No abstract text is available yet for this article.
July 13, 2017: Blood
https://www.readbyqxmd.com/read/28673395/mechanisms-of-resistance-to-flt3-inhibitors-and-the-role-of-the-bone-marrow-microenvironment
#6
REVIEW
Gabriel Ghiaur, Mark Levis
The presence of FLT3 mutations in acute myeloid leukemia (AML) carries a particularly poor prognosis, making the development of FLT3 inhibitors an imperative goal. The last decade has seen an abundance of clinical trials using these drugs alone or in combination with chemotherapy. This culminated with the recent approval by the US Food and Drug Administration of Midostaurin for the treatment of FLT3-mutated AML. Initial success has been followed by the emergence of clinical resistance. Although novel FLT3 inhibitors are being developed, studies into mechanisms of resistance raise hope of new strategies to prevent emergence of resistance and eliminate minimal residual disease...
August 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28673394/the-development-of-flt3-inhibitors-in-acute-myeloid-leukemia
#7
REVIEW
Jacqueline S Garcia, Richard M Stone
FLT3 mutations, generally associated with a poor prognosis, are found in approximately one-third of patients with acute myeloid leukemia (AML) and represent an attractive therapeutic target. FLT3 inhibitors undergoing clinical evaluation include first-generation relatively non-specific small molecules and second-generation compounds with higher potency and selectivity against mutant FLT3. Recently presented results from a prospective randomized clinical trial will likely lead to a change in the standard of care for younger patients with FLT3-mutated AML: addition of the multi-targeted FLT3 inhibitor midostaurin to standard induction and consolidation chemotherapy...
August 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28669736/midostaurin-in-flt3-mutated-acute-myeloid-leukaemia
#8
Manjulika Das
No abstract text is available yet for this article.
August 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28663576/setd2-and-histone-h3-lysine-36-methylation-deficiency-in-advanced-systemic-mastocytosis
#9
G Martinelli, M Mancini, C De Benedittis, M Rondoni, C Papayannidis, M Manfrini, M Meggendorfer, R Calogero, V Guadagnuolo, M C Fontana, L Bavaro, A Padella, E Zago, L Pagano, R Zanotti, L Scaffidi, G Specchia, F Albano, S Merante, C Elena, P Savini, D Gangemi, P Tosi, F Ciceri, G Poletti, L Riccioni, F Morigi, M Delledonne, T Haferlach, M Cavo, P Valent, S Soverini
The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy-neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM...
June 16, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28644114/midostaurin-plus-chemotherapy-for-acute-myeloid-leukemia-with-a-flt3-mutation
#10
RANDOMIZED CONTROLLED TRIAL
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...
August 3, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28612232/midostaurin-first-global-approval
#11
REVIEW
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]...
July 2017: Drugs
https://www.readbyqxmd.com/read/28610444/midostaurin-for-the-treatment-of-acute-myeloid-leukemia
#12
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...
September 2017: Future Oncology
https://www.readbyqxmd.com/read/28546144/midostaurin-approved-for-flt3-mutated-aml
#13
REVIEW
Mark Levis
Midostaurin was recently approved by the US 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 United States 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.
June 29, 2017: Blood
https://www.readbyqxmd.com/read/28526740/midostaurin-gets-fda-nod-for-aml
#14
(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
#15
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
#16
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 KIT mutations (D816V in >80% of cases) and by additional mutations (eg, in SRSF2, ASXL1, and/or RUNX1 [S/A/R(pos) in >60% of cases]). In a recently reported phase 2 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 at baseline and during follow-up in 38 midostaurin-treated advSM patients...
July 13, 2017: Blood
https://www.readbyqxmd.com/read/28397975/the-jak2-stat5-signaling-pathway-as-a-potential-therapeutic-target-in-canine-mastocytoma
#17
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
#18
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
#19
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
#20
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
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