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Novel approaches to treating advanced systemic mastocytosis.
Clin Pharmacol 2019; 11:77-92CP

Abstract

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 KITD816V, 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.

Authors+Show Affiliations

Department of Pharmacotherapy, College of Pharmacy and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.Centre de Mathématiques et de Leurs Applications (CMLA-CNRS), ENS Paris-Saclay, Cachan 94235, France.Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

31372066

Citation

Gilreath, J A., et al. "Novel Approaches to Treating Advanced Systemic Mastocytosis." Clinical Pharmacology : Advances and Applications, vol. 11, 2019, pp. 77-92.
Gilreath JA, Tchertanov L, Deininger MW. Novel approaches to treating advanced systemic mastocytosis. Clin Pharmacol. 2019;11:77-92.
Gilreath, J. A., Tchertanov, L., & Deininger, M. W. (2019). Novel approaches to treating advanced systemic mastocytosis. Clinical Pharmacology : Advances and Applications, 11, pp. 77-92. doi:10.2147/CPAA.S206615.
Gilreath JA, Tchertanov L, Deininger MW. Novel Approaches to Treating Advanced Systemic Mastocytosis. Clin Pharmacol. 2019;11:77-92. PubMed PMID: 31372066.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel approaches to treating advanced systemic mastocytosis. AU - Gilreath,J A, AU - Tchertanov,L, AU - Deininger,M W, Y1 - 2019/07/10/ PY - 2019/02/24/received PY - 2019/04/26/accepted PY - 2019/8/3/entrez PY - 2019/8/3/pubmed PY - 2019/8/3/medline KW - BLU285 KW - KIT KW - avapritinib KW - systemic mastocytosis KW - tyrosine kinase inhibitor SP - 77 EP - 92 JF - Clinical pharmacology : advances and applications JO - Clin Pharmacol VL - 11 N2 - 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 KITD816V, 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. SN - 1179-1438 UR - https://www.unboundmedicine.com/medline/citation/31372066/Novel_approaches_to_treating_advanced_systemic_mastocytosis L2 - https://dx.doi.org/10.2147/CPAA.S206615 DB - PRIME DP - Unbound Medicine ER -