Novel approaches to treating advanced systemic mastocytosis

JA Gilreath,1 L Tchertanov,2 MW Deininger31Department of Pharmacotherapy, College of Pharmacy and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; 2Centre de Mathématiques et de Leurs Applications (CMLA-CNRS), ENS Paris-Saclay, Cachan 94235, France; 3Division...

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Autores principales:	Gilreath JA, Tchertanov L, Deininger MW
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	Avapritinib BLU285 Systemic Mastocytosis KIT Tyrosine Kinase Inhibitor Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/3b950dcf31fb4f92945febf9a423a7bb
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spelling	oai:doaj.org-article:3b950dcf31fb4f92945febf9a423a7bb2021-12-02T00:19:04ZNovel approaches to treating advanced systemic mastocytosis1179-1438https://doaj.org/article/3b950dcf31fb4f92945febf9a423a7bb2019-07-01T00:00:00Zhttps://www.dovepress.com/novel-approaches-to-treating-advanced-systemic-mastocytosis-peer-reviewed-article-CPAAhttps://doaj.org/toc/1179-1438JA Gilreath,1 L Tchertanov,2 MW Deininger31Department of Pharmacotherapy, College of Pharmacy and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; 2Centre de Mathématiques et de Leurs Applications (CMLA-CNRS), ENS Paris-Saclay, Cachan 94235, France; 3Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USAAbstract: Mastocytosis is a myeloproliferative neoplasm characterized by expansion of abnormal mast cells (MCs) in various tissues, including skin, bone marrow, gastrointestinal tract, liver, spleen, or lymph nodes. Subtypes include indolent systemic mastocytosis, smoldering systemic mastocytosis and advanced systemic mastocytosis (AdvSM), a term collectively used for the three most aggressive forms of the disease: aggressive systemic mastocytosis, mast cell leukemia, and systemic mastocytosis with an associated clonal hematological non-mast cell disease (SM-AHNMD). MC activation and proliferation is physiologically controlled in part through stem cell factor (SCF) binding to its cognate receptor, KIT. Gain-of-function KIT mutations that lead to ligand-independent kinase activation are found in most SM subtypes, and the overwhelming majority of AdvSM patients harbor the KITD816V, mutation. Several approved tyrosine kinase inhibitors (TKIs), such as imatinib and nilotinib, have activity against wild-type KIT but lack activity against KITD816V,. Midostaurin, a broad spectrum TKI with activity against KIT,D816V has a 60% clinical response rate, and is currently the only drug specifically approved for AdvSM. While this agent improves the prognosis of AdvSM patients and provides proof of principle for targeting KITD816V, as a driver mutation, most responses are partial and/or not sustained, indicating that more potent and/or specific inhibitors are required. Avapritinib, a KIT and PDGFRα inhibitor, was specifically designed to inhibit KITD816V,. Early results from a Phase 1 trial suggest that avapritinib has potent antineoplastic activity in AdvSM, extending to patients who failed midostaurin. Patients exhibited a rapid reduction in both symptoms as well as reductions of bone marrow MCs, serum tryptase, and KITD816V, mutant allele burden. Adverse effects include expected toxicities such as myelosuppression and periorbital edema, but also cognitive impairment in some patients. Although considerable excitement about avapritinib exists, more data are needed to assess long-term responses and adverse effects of this novel TKI.Keywords: avapritinib, BLU285, systemic mastocytosis, KIT, tyrosine kinase inhibitorGilreath JATchertanov LDeininger MWDove Medical PressarticleAvapritinibBLU285Systemic MastocytosisKITTyrosine Kinase InhibitorTherapeutics. PharmacologyRM1-950ENClinical Pharmacology: Advances and Applications, Vol Volume 11, Pp 77-92 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Avapritinib BLU285 Systemic Mastocytosis KIT Tyrosine Kinase Inhibitor Therapeutics. Pharmacology RM1-950
spellingShingle	Avapritinib BLU285 Systemic Mastocytosis KIT Tyrosine Kinase Inhibitor Therapeutics. Pharmacology RM1-950 Gilreath JA Tchertanov L Deininger MW Novel approaches to treating advanced systemic mastocytosis
description	JA Gilreath,1 L Tchertanov,2 MW Deininger31Department of Pharmacotherapy, College of Pharmacy and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; 2Centre de Mathématiques et de Leurs Applications (CMLA-CNRS), ENS Paris-Saclay, Cachan 94235, France; 3Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USAAbstract: Mastocytosis is a myeloproliferative neoplasm characterized by expansion of abnormal mast cells (MCs) in various tissues, including skin, bone marrow, gastrointestinal tract, liver, spleen, or lymph nodes. Subtypes include indolent systemic mastocytosis, smoldering systemic mastocytosis and advanced systemic mastocytosis (AdvSM), a term collectively used for the three most aggressive forms of the disease: aggressive systemic mastocytosis, mast cell leukemia, and systemic mastocytosis with an associated clonal hematological non-mast cell disease (SM-AHNMD). MC activation and proliferation is physiologically controlled in part through stem cell factor (SCF) binding to its cognate receptor, KIT. Gain-of-function KIT mutations that lead to ligand-independent kinase activation are found in most SM subtypes, and the overwhelming majority of AdvSM patients harbor the KITD816V, mutation. Several approved tyrosine kinase inhibitors (TKIs), such as imatinib and nilotinib, have activity against wild-type KIT but lack activity against KITD816V,. Midostaurin, a broad spectrum TKI with activity against KIT,D816V has a 60% clinical response rate, and is currently the only drug specifically approved for AdvSM. While this agent improves the prognosis of AdvSM patients and provides proof of principle for targeting KITD816V, as a driver mutation, most responses are partial and/or not sustained, indicating that more potent and/or specific inhibitors are required. Avapritinib, a KIT and PDGFRα inhibitor, was specifically designed to inhibit KITD816V,. Early results from a Phase 1 trial suggest that avapritinib has potent antineoplastic activity in AdvSM, extending to patients who failed midostaurin. Patients exhibited a rapid reduction in both symptoms as well as reductions of bone marrow MCs, serum tryptase, and KITD816V, mutant allele burden. Adverse effects include expected toxicities such as myelosuppression and periorbital edema, but also cognitive impairment in some patients. Although considerable excitement about avapritinib exists, more data are needed to assess long-term responses and adverse effects of this novel TKI.Keywords: avapritinib, BLU285, systemic mastocytosis, KIT, tyrosine kinase inhibitor
format	article
author	Gilreath JA Tchertanov L Deininger MW
author_facet	Gilreath JA Tchertanov L Deininger MW
author_sort	Gilreath JA
title	Novel approaches to treating advanced systemic mastocytosis
title_short	Novel approaches to treating advanced systemic mastocytosis
title_full	Novel approaches to treating advanced systemic mastocytosis
title_fullStr	Novel approaches to treating advanced systemic mastocytosis
title_full_unstemmed	Novel approaches to treating advanced systemic mastocytosis
title_sort	novel approaches to treating advanced systemic mastocytosis
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/3b950dcf31fb4f92945febf9a423a7bb
work_keys_str_mv	AT gilreathja novelapproachestotreatingadvancedsystemicmastocytosis AT tchertanovl novelapproachestotreatingadvancedsystemicmastocytosis AT deiningermw novelapproachestotreatingadvancedsystemicmastocytosis
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Novel approaches to treating advanced systemic mastocytosis

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