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Midostaurin

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https://www.readbyqxmd.com/read/29117990/simultaneous-physiologically-based-pharmacokinetic-pbpk-modeling-of-parent-and-active-metabolites-to-investigate-complex-cyp3a4-drug-drug-interaction-potential-a-case-example-of-midostaurin
#1
Helen Gu, Catherine Dutreix, Sam Rebello, Taoufik Ouatas, Lai Wang, Dung Yu Chun, Heidi J Einolf, Handan He
Midostaurin (PKC412) is being investigated for the treatment of acute myeloid leukemia (AML) and advanced systemic mastocytosis (advSM). It is extensively metabolized by cytochrome P450 (CYP) 3A4 to form 2 major active metabolites, CGP52421 and CGP62221. In vitro and clinical drug-drug interaction (DDI) studies indicated that midostaurin and its metabolites are substrates, reversible and time-dependent inhibitors, and inducers of CYP3A4. A simultaneous pharmacokinetic model of parent and active metabolites was initially developed by incorporating data from in vitro, preclinical, and clinical pharmacokinetic studies in healthy volunteers and in patients with AML or advSM...
November 8, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29117486/midostaurin-in-flt3-mutated-acute-myeloid-leukemia
#2
LETTER
Richard M Stone, Richard A Larson, Hartmut Döhner
New England Journal of Medicine, Volume 377, Issue 19, Page 1901-1903, November 2017.
November 9, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29070106/-sensitivity-of-aml-cells-with-flt3-to-pkc412-in-vitro
#3
Yin-Ying Wang, Cong-Yan Liu, Wei Zhang, Jing-Juan He, Li Su, Wan-Ling Sun
OBJECTIVE: To explore the clinical value of PKC412 (midostaurin) in treatment of AML patients with FLT3(-). METHODS: The bone marrow or peripheral blood were collected and heparinized from 21 newly diagnosed FLT3(-) AML patients, then the mononuclear cells from bone marrow or peripheral blood were isolated by density-gradient method. The sensitivity of leukemia cells to PKC412 of 8 concentration in vitro was detected by ATP-bioluminescence-tumor chemosensitivity assay (ATP-TCA), and the relationship among sensitivity results in vitro, risk stratification and therapeutic efficacy was analyzed...
October 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/29069942/midostaurin-pkc412-for-the-treatment-of-newly-diagnosed-flt3-mutation-positive-acute-myeloid-leukemia
#4
Marlise R Luskin, Daniel J DeAngelo
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with inadequate treatment options. Approximately one-third of cases have a FLT3-ITD or FLT3-TKD mutation which leads to constitutive tyrosine kinase activation which contributes to leukemogenesis. The FLT3-ITD mutation is associated with a particularly poor prognosis. Midostaurin is a multi-kinase inhibitor active against the FLT3 receptor. Midostaurin was approved by the US FDA in April 2017 for treatment of newly diagnosed FLT3-mutant AML in combination with chemotherapy...
October 30, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/29051803/midostaurin-a-novel-therapeutic-agent-for-patients-with-flt3-mutated-acute-myeloid-leukemia-and-systemic-mastocytosis
#5
REVIEW
Molly M Gallogly, Hillard M Lazarus, Brenda W Cooper
The development of FLT3-targeted inhibitors represents an important paradigm shift in the management of patients with highly aggressive fms-like tyrosine kinase 3-mutated (FLT3-mut) acute myeloid leukemia (AML). Midostaurin is an orally administered type III tyrosine kinase inhibitor which in addition to FLT3 inhibits c-kit, platelet-derived growth factor receptors, src, and vascular endothelial growth factor receptor. Midostaurin is the first FLT3 inhibitor that has been shown to significantly improve survival in younger patients with FLT3-mut AML when given in combination with standard cytotoxic chemotherapy based on the recently completed RATIFY study...
September 2017: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/29051180/midostaurin-enasidenib-cpx-351-gemtuzumab-ozogomycin-and-venetoclax-bring-new-hope-to-aml
#6
Andrew H Wei, Ing S Tiong
In 2017, four new drugs have so far received FDA marketing approval for the treatment of acute myeloid leukemia (AML), including targeted therapies for mutant FLT3 (midostaurin) and IDH2 (enasidenib), a novel liposomal cytarabine-daunorubicin formulation (CPX-351) for therapy-related AML and AML with myelodysplasia-related changes and finally, resurgence of an antibody-drug conjugate designed to target CD33 (gemtuzumab ozogomycin; GO). Promising results also emerged for the BCL-2 inhibitor venetoclax combined with low-intensity therapy in older patients with AML unfit for intensive chemotherapy...
October 19, 2017: Blood
https://www.readbyqxmd.com/read/29043985/from-the-observation-of-atypical-cells-on-blood-smear-to-the-diagnosis-of-mast-cell-leukemia-a-case-report-in-a-79-year-old-woman-consulting-for-anemia
#7
Julien Decker, Sabine Meyer, Véronique Latger-Cannard, Sorin Visanica, Elena Loppinet, Jean-François Lesesve, Blandine Bénet
Mast cell leukemia is an extremely rare disease, which belongs to the systemic mastocytosis group (WHO 2016). We are reporting the case of a 79-year-old woman, without any hematological particular history consulting for hyperthermia, repeated malaise and subacute anemia. Her clinical examination was normal. Unusual cells were seen on blood and bone marrow smears. They represent more than 10% of blood nucleated cells end more than 20% of the bone marrow nucleated cells. Bone marrow immunophenotyping was performed to characterize these cells...
October 18, 2017: Annales de Biologie Clinique
https://www.readbyqxmd.com/read/29018296/pharmaceutical-approval-update
#8
Michele B Kaufman
L-glutamine oral powder (Endari) for reducing the acute complications of sickle cell disease; edaravone (Radicava) for the treatment of amyotrophic lateral sclerosis; and midostaurin (Rydapt) for the treatment of acute myeloid leukemia in combination with chemotherapy.
October 2017: P & T: a Peer-reviewed Journal for Formulary Management
https://www.readbyqxmd.com/read/29017371/cytarabine-and-daunorubicin-for-the-treatment-of-acute-myeloid-leukemia
#9
Tracy Murphy, Karen W L Yee
Acute myeloid leukemia (AML) is the most common acute forms of leukemia in adults. It has a poor long-term survival with a high relapse rate and at relapse, is commonly resistant to available therapies. The current combination of daunorubicin (DNR) for three days and cytarabine (Ara-C) as a continuous infusion for seven days, more commonly known as '3 + 7' has remained essentially unaltered over the last forty-four years and remains the standard induction regimen internationally. Areas covered: This paper will briefly review clinically important trials related to '3 + 7'...
October 20, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28978722/acquired-resistance-to-fgfr-inhibitor-in-diffuse-type-gastric-cancer-through-an-akt-independent-pkc-mediated-phosphorylation-of-gsk3%C3%AE
#10
Wen Min Lau, Eileen Teng, Kie Kyon Huang, Jin Wei Tan, Kakoli Das, Zhijiang Zang, Tania Chia, Ming Teh, Koji Kono, Wei Peng Yong, Asim Shabbir, Amy Tay, Niam Sin Phua, Patrick Tan, Shing Leng Chan, Jimmy Bok Yan So
Preclinical models of diffuse type gastric cancer (DGC) that reliably predict clinical activity of novel compounds are lacking. To overcome the problem of poor tumor cellularity in DGC, we used cells from malignant ascites to establish diffuse type gastric cancer patient-derived xenograft (PDX) models that recapitulate the primary cancer. Cells in PDX model GAGA6 with FGFR2 amplification were sensitive to AZD4547, a potent FGFR inhibitor that is being clinically evaluated for FGFR-aberrant cancer types. Intermittent in vivo treatment of GAGA6 tumors with AZD4547 gave rise to PDX tumors with acquired resistance to AZD4547, GAGA6-R...
October 4, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28976600/midostaurin-a-new-oral-agent-targeting-flt3-mutant-acute-myeloid-leukemia
#11
Lindsay C Stansfield, Daniel A Pollyea
Acute myeloid leukemia (AML), a clonal hematologic malignancy that results in bone marrow failure, is the most common acute leukemia in adults (median age of diagnosis 67 years), and treatment options, especially in the elderly population, are limited. Induction chemotherapy with 7+3, the combination of continuous-infusion cytarabine and intermittent dosing of an anthracycline administered over 7 and 3 days, respectively, has remained the standard of care since its introduction in 1973 in the United States...
October 4, 2017: Pharmacotherapy
https://www.readbyqxmd.com/read/28960095/midostaurin-treatment-in-flt3-mutated-acute-myeloid-leukemia-and-systemic-mastocytosis
#12
REVIEW
Sabine Kayser, Mark J Levis, Richard F Schlenk
A number of tyrosine kinase inhibitors (TKIs) have been developed that inhibit the constitutively activated kinase activity caused by activating tyrosine kinase mutations, such as FLT3 or KIT, thus interrupting signaling pathways. Currently, midostaurin is the only approved TKI as monotherapy for aggressive systemic mastocytosis (SM), SM with associated hematological neoplasm, or mast cell leukemia displaying a KIT mutation as well as in combination with standard intensive chemotherapy for adult patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML)...
November 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28949951/emerging-treatments-in-acute-myeloid-leukemia-current-standards-and-unmet-challenges
#13
Mary-Elizabeth Percival, Elihu Estey
Acute myeloid leukemia (AML) is rare and difficult to treat. Although remission is achieved in most patients with newly diagnosed disease, relapse occurs in most cases. For more than 40 years, the standard up-front induction treatment has been a combination of continuous-infusion cytarabine and an anthracycline. Risk stratification by molecular and cytogenetic characteristics and measurable residual disease (MRD) status informs decisions regarding referral to consolidative allogeneic hematopoietic cell transplant...
August 2017: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/28945834/midostaurin-a-magic-bullet-that-blocks-mast-cell-expansion-and-activation
#14
P Valent, C Akin, K Hartmann, T I George, K Sotlar, B Peter, K V Gleixner, K Blatt, W R Sperr, P W Manley, O Hermine, H C Kluin-Nelemans, M Arock, H-P Horny, A Reiter, J Gotlib
Clinically relevant features in patients with systemic mastocytosis (SM) include the cosmetic burden of lesional skin, mediator-related symptoms, and organ damage resulting from mast cell (MC) infiltration in advanced forms of SM. Regardless of the SM variant, expansion of neoplastic MC in the skin and other organs is triggered by mutant forms of KIT, the most prevalent being D816V. Activation of MC with subsequent release of chemical mediators is often caused by IgE-dependent mechanisms in these patients. Midostaurin, also known as PKC412, blocks the kinase activity of wild-type KIT and KIT D816V, counteracts KIT-dependent growth of neoplastic MC, and inhibits IgE-dependent mediator secretion...
October 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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