The World Health Organization’s semimolecular classification of eosinophilias emphasizes neoplasms driven by fusion tyrosine kinases. More than 80% of patients with systemic mastocytosis carry the KIT D816V mutation, the primary driver of disease pathogenesis. Genetic annotation of these diseases is critical and affords opportunities for targeted therapy. This article discusses our understanding of the mutated tyrosine kinome of eosinophilic neoplasms and systemic mast cell disease, and the successes and limitations of available therapies. Use of tyrosine kinase inhibitors as a bridge to hematopoietic stem cell transplantation, and development of more selective and potent tyrosine kinase inhibitors is also highlighted.
Key points
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Evaluation of eosinophilia-associated neoplasms and systemic mastocytosis requires diagnostic testing for rearrangements or point mutations involving tyrosine kinase genes.
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Imatinib is a highly effective, first-line therapy for myeloid/lymphoid neoplasms with eosinophilia characterized by PDGFRA or PDGFRB gene fusions.
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An unmet need exists for treatment of FGFR1 -rearranged and JAK2 -rearranged eosinophilic myeloid/lymphoid neoplasms in which currently available tyrosine kinase inhibitors demonstrate suboptimal efficacy.
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Novel agents with potent inhibitory activity against KIT D816V have demonstrated significant clinical benefit and reductions of bone marrow mast cell burden in patients with advanced systemic mastocytosis.
Introduction
Constitutive activation of tyrosine kinases (TKs) is a common theme among myeloproliferative neoplasms (MPNs), and typically occurs via point mutations or rearrangements. Well-known examples include BCR-ABL1 , which operationally defines chronic myeloid leukemia (CML), and Janus kinase 2 ( JAK2 ) V617F, which is a highly recurrent mutation among the classic Philadelphia chromosome–negative MPNs polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Among the primary (clonal) eosinophilias, a subset of patients belongs to the 2016 World Health Organization (WHO) category entitled, “Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA , PDGFRB , or FGFR1 , or with PCM1-JAK2 .” In addition to these TK genes, eosinophilic neoplasms may rarely be associated with rearrangement of FMS-like tyrosine kinase 3 ( FLT3 ) and ABL1 ( Table 1 ). In systemic mastocytosis (SM), the aspartate to valine mutation in codon 816 (D816 V) in the gene encoding the KIT receptor tyrosine kinase can be identified in approximately 80% to 90% of patients and is a primary driver of disease pathogenesis.
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