Evaluation Of Myeloproliferative Neoplasms In Pediatric Patients

OBJECTIVE: Myeloproliferative Neoplasms are rare, poorly understood diseases in children, and the outcomes, causative lesions, and management strategies for children with these diseases are not clearly defined. The purpose of this study was to evaluate clinical findings and management practices in children with MPN, and identify alternative genetic lesions that could contribute to disease pathogenesis in these patients. METHODS: Patients were identified as eligible if they were diagnosed with a BCR-ABL negative classical MPN. They were enrolled and provided our team with clinical information, including age of presentation, bone marrow pathology results, and treatments utilized. Blood and buccal samples were collected (and bone marrow if available.) Monocytes and granulocytes were separated from blood and marrow samples, and DNA was extracted from all three types of tissue (tumor samples = granulocytes and monocytes; normal tissue = buccal cells.) Next-generation sequencing was performed on these samples for a pre-determined panel of genes known to be relevant in hematologic malignancies and myeloproliferative neoplasms. RESULTS: Ten patients were enrolled on study but two were removed when their bone marrow biopsies ruled out a myeloproliferative neoplasm. Of the eight children eligible to remain in the study, known causative mutations were identified on clinical testing in three of them to date. Next-generation sequencing did not show alternative mutations in JAK2, MPL, or CALR. No children have yet had major thrombotic or hemorrhagic complications. Six children received hydroxyurea for their symptoms. None of the 8 subjects have developed leukemia at this time. CONCLUSIONS: Children with myeloproliferative neoplasms may have lower rates of severe complications and known genetic mutations than adults with similar diseases. More study is needed of this rare population of patients to better quantify clinical outcomes, genetic lesions, and allow for development of appropriate treatment algorithms

Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis

The discovery of JAK2 and MPL mutations in patients with myeloproliferative neoplasms (MPNs) provided important insight into the genetic basis of these disorders and led to the development of JAK2 kinase inhibitors for MPN therapy. Although recent studies have shown that JAK2 kinase inhibitors demonstrate efficacy in a JAK2V617F murine bone marrow transplantation model, the effects of JAK2 inhibitors on MPLW515L-mediated myeloproliferation have not been investigated. In this report, we describe the in vitro and in vivo effects of INCB16562, a small-molecule JAK2 inhibitor. INCB16562 inhibited proliferation and signaling in cell lines transformed by JAK2 and MPL mutations. Compared with vehicle treatment, INCB16562 treatment improved survival, normalized white blood cell counts and platelet counts, and markedly reduced extramedullary hematopoeisis and bone marrow fibrosis. We observed inhibition of STAT3 and STAT5 phosphorylation in vivo consistent with potent inhibition of JAK-STAT signaling. These data suggest JAK2 inhibitor therapy may be of value in the treatment of JAK2V617F-negative MPNs. However, we did not observe a decrease in the size of the malignant clone in the bone marrow of treated mice at the end of therapy, which suggests that JAK2 inhibitor therapy, by itself, was not curative in this MPN model