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https://www.readbyqxmd.com/read/28030373/what-are-the-most-promising-new-agents-in-acute-myeloid-leukemia
#1
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...
December 26, 2016: 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
#2
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...
December 28, 2016: 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
#3
REVIEW
Amir T Fathi, Yi-Bin Chen
FLT3 mutations are present in about one third of patients with AML. Several FLT3 inhibitors have been used in clinical trials and these include midostaurin, sorafenib, quizartinib, crenolanib and gilteritinib. Monotherapy with early 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. Several trials are also evaluating TKI given after HSCT and a large international randomized trial is planned...
December 21, 2016: European Journal of Haematology
https://www.readbyqxmd.com/read/27942432/mast-cell-clonal-disorders-classification-diagnosis-and-management
#4
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/pre-clinical-studies-of-gilteritinib-a-next-generation-flt3-inhibitor
#5
Lauren Y Lee, Daniela Hernandez, Trivikram Rajkhowa, Samuel C Smith, Jayant Ranganathan Raman, Bao Nguyen, Donald Small, Mark Levis
Activating mutations in the receptor tyrosine kinase FLT3 comprise approximately one-third of genetic lesions in acute myeloid leukemia (AML) and are associated with a poor prognosis. Internal tandem duplication (FLT3-ITD) mutations in particular are associated with a high relapse rate. Although FLT3 tyrosine kinase inhibitors (TKIs) appear to improve clinical outcomes for patients with FLT3-ITD AML, the development of early-generation FLT3 TKIs has been impeded by several obstacles such as low potency and selectivity, myelosuppression, and the emergence of resistance-conferring point mutations...
December 1, 2016: Blood
https://www.readbyqxmd.com/read/27856463/ccl-2-is-a-kit-d816v-dependent-modulator-of-the-bone-marrow-microenvironment-in-systemic-mastocytosis
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
D B Lipka, M-C Wagner, M Dziadosz, T Fischer
Leukemia accepted article preview online, 03 May 2016. doi:10.1038/leu.2016.127.
May 3, 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
#15
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
https://www.readbyqxmd.com/read/27014400/midostaurin-the-first-targeted-therapy-to-improve-survival-in-aml-potentially-practice-changing
#16
Phoebe Starr
No abstract text is available yet for this article.
February 2016: American Health & Drug Benefits
https://www.readbyqxmd.com/read/26823681/orlando-magic-report-from-the-57th-meeting-of-the-american-society-of-haematology-5-7-december-2015-orlando-usa
#17
Luca Mazzarella
The 57th American Society of Haematology (ASH) meeting held in Orlando, FL was certainly the year when myeloma management changed for good, with a plethora of newly Food and Drug Administration (FDA)-approved drugs showing impressive outcome improvements and the introduction of new techniques for disease monitoring. Also, chimeric antigen receptor (CAR) T cells continued their triumphal march, consolidating their success in lymphoma and chronic lymhocytic leukaemia (CLL) and venturing into new fields such as again multiple myeloma...
2016: Ecancermedicalscience
https://www.readbyqxmd.com/read/26784138/midostaurin-bortezomib-and-mec-in-relapsed-refractory-acute-myeloid-leukemia
#18
Alison R Walker, Hongyan Wang, Katherine Walsh, Bhavana Bhatnagar, Sumithira Vasu, Ramiro Garzon, Renee Canning, Susan Geyer, Yue-Zhong Wu, Steven M Devine, Rebecca Klisovic, William Blum, Guido Marcucci
Targeting aberrant tyrosine kinase activity may impact clinical outcome in acute myeloid leukemia (AML). We conducted a phase I study of the tyrosine kinase inhibitor midostaurin with bortezomib alone and in combination with chemotherapy in patients with AML. Patients on dose levels 1 and 2 (DL1 & 2) received midostaurin 50 mg bid and escalating doses of bortezomib (1 to 1.3 mg/m2). Patients on DL3 or higher received midostaurin and bortezomib following chemotherapy with mitoxantrone, etoposide, cytarabine (MEC)...
September 2016: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/26708910/-research-progress-on-treating-acute-myeloid-leukemia-by-midostaurin
#19
REVIEW
Yin-Ying Wang, Wan-Ling Sun
FLT3 gene mutations occurred in approximately 30% of acute myeloid leukemia (AML) patients, which is closely associated with the occurrence, development and poor prognosis of AML. The therapy targeting at FLT3 mutations might be a promising treatment for AML. Midostaurin can inhibit the activities of III receptor tyrosine kinase encoded by FLT3 gene, induce cell cycle arrest and has a apoptotic effect on primitive AML cells of FLT3 -mutant, FLT3 wild-type and the expression of FLT3 mutated receptor. In view of this, the association between FLT3 mutations and AML, and research advances and clinical applications of midostaurin on the treatment of AML especially for FLT3 mutated AML, are reviewed...
December 2015: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/26625890/design-of-flt3-inhibitor-gold-nanoparticle-conjugates-as-potential-therapeutic-agents-for-the-treatment-of-acute-myeloid-leukemia
#20
Timea Simon, Ciprian Tomuleasa, Anca Bojan, Ioana Berindan-Neagoe, Sanda Boca, Simion Astilean
BACKGROUND: Releasing drug molecules at the targeted location could increase the clinical outcome of a large number of anti-tumor treatments which require low systemic damage and low side effects. Nano-carriers of drugs show great potential for such task due to their capability of accumulating and releasing their payload specifically, at the tumor site. RESULTS: FLT3 inhibitor - gold nanoparticle conjugates were fabricated to serve as vehicles for the delivery of anti-tumor drugs...
December 2015: Nanoscale Research Letters
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