Kinase Inhibitors in the Treatment of Myeloid Malignancies

Aberrant signaling pathway activation is a central feature of myeloid malignancies. With the development of the tyrosine kinase inhibitor, imatinib, to treat chronic myelogenous leukemia (CML), the paradigm of targeted therapy in cancer was established. Imatinib inhibits ABL, KIT, and platelet-derived growth factor receptor signaling and as a result is approved for the treatment of CML and subsets of patients with systemic mastocytosis (SM) and hypereosinophilic syndrome. Activated JAK-STAT signaling is central to the pathogenesis of BCR-ABL- negative myeloproliferative neoplasms (MPN), and the JAK1/2 inhibitor, ruxolitinib, is approved for the treatment of myelofibrosis and polycythemia vera. Most recently, midostaurin, a multikinase inhibitor with activity against FLT3 and KIT, was approved for the treatment of FLT3 -mutant acute myeloid leukemia and advanced SM. In this issue, we present a series of reviews by leaders in the field, which describe the key research studies that led to the development and approval of these therapies and outline our current knowledge on mechanisms of resistance. We bookend these reviews with an article outlining key biological concepts underpinning the targeting of oncogenic kinases in myeloid malignancies and two articles describing some new developments in the field; the use of functional kinase inhibitor screens has uncovered novel therapeutic susceptibilities in myeloid blood cancers (eg, JAK inhibition in CSF3R -mutant chronic neutrophilic leukemia), and the application of genetic sequencing to histiocytic neoplasms has identified recurrent somatic mutations that activate mitogen-activated protein kinase signaling, which can be effectively targeted. We believe readers will find these reviews informative and timely, providing a comprehensive overview of the current role of kinase inhibitors in the treatment of myeloid malignancies.

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