Issues in Categorization and Management of Pediatric Patients with Myeloproliferative Neoplasms (2014)

Abstract Myeloproliferative Neoplasms (MPN) are well characterized in adults, with symptoms including thrombotic episodes, severe bleeding episodes, splenomegaly, and transformation to AML. Accepted treatment algorithms are available for management and multiple clinical trials are being done in adult patients. Much has been done to understand the pathogenesis in adults, and mutations in JAK2, MPL, and most recently CALR are established as causative lesions in these disorders. In contrast, knowledge of these disorders in children is more rudimentary, with limited information available regarding long-term clinical outcomes in children. Children have a lower frequency of the known mutations; studies to identify alternative driver mutations in children are ongoing. Eight pediatric patients with MPN have been seen at Cornell during their illness. Seven were diagnosed with Essential Thrombocytosis (ET) and the eighth had an initial diagnosis of ET but later was diagnosed with myelofibrosis (MF). One patient did not have bone marrow testing but was diagnosed by her primary hematologist on the basis of extreme thrombocytosis, and JAK2V617F positive testing on peripheral blood when no cause of reactive thrombocytosis was identified. Table 1 summarizes key features of these patients. The average age of diagnosis for these children is 10 years and 3 months. The oldest patient was diagnosed in 2006 and has had the longest consecutive period of thrombocytosis, 8 years. These patients presented with a variety of symptoms, including headache, abdominal pain, fatigue, and bleeding. All the children experienced extreme thrombocytosis (platelet count > 1,000 x 109/L) during their illness. Despite the presence of acquired von Willebrand's disease in at least three patients, none have experienced severe bleeding symptoms. There have been no reported severe thrombotic episodes, and any evaluations done for complaints of headache, chest pain, or palpitations have shown no CNS infarcts or cardiac abnormalities. One child developed pseudo tumor cerebri with no cerebral venous sinus thrombosis or CNS lesion detected. Four children have been treated with aspirin with no significant bleeding complications. Six of the eight had been treated with cytoreductive therapy (Hydroxyurea) by their primary hematologist at some point in their course, for various findings including extreme thrombocytosis, fatigue, erythromelalgia, and recurrent headache. All showed a good response in platelet count to Hydroxyurea treatment, none developed dose-limiting side effects, and the highest dose that was needed to relieve symptoms at any point was 35mg/kg. Four patients remain on therapy with Hydroxyurea. Genetic sequencing was positive for JAK2V617F in three of eight patients. All of these patients have received Hydroxyurea treatment, and the child with pseudotumor cerebri was JAK2V617F positive. Of the five patients who are negative for JAK2 mutation, four were tested for MPLW515K/L and all are negative. Two of these patients have had sequencing sent for CALR mutations, and one patient is negative for CALR mutation as well (one patient is pending.) Figure 1 summarizes the sequencing completed to date on these patients. This cohort of pediatric patients shows a lower frequency of the known causative mutations than their adult counterparts. There is variation in how these patients were managed by their primary hematologists, likely due to the lack of treatment guidelines in this patient population (Kucine et al, 2014.) With the apparent differences in clinical course and genetic drivers from adults with MPN, there is a clear need for further research on the outcomes and pathogenesis in pediatric patients with MPN. Our group is currently working to answer some of the questions regarding pathogenesis and outcomes in pediatric patients with MPN to allow for individualization of treatment recommendations and family guidance in these children. Table 1. Summary of Eight Pediatric MPN Patients Patient Age at Diagnosis (years) Diagnosis Initial Symptoms A 9 ET Weakness, Paresthesias B 7 ET Headache C 10 ET Headache, Fatigue D 7 ET Headache E 8 ET Bleeding F 13 MF Abdominal Pain, Splenomegaly G 10 ET Headache H 19 ET Fatigue, Itching Figure 1. Clinical Sequence of Genetic Testing For Pediatric Cohort Figure 1. Clinical Sequence of Genetic Testing For Pediatric Cohort References Kucine N, Chastain KM, Mahler MB, Bussel JB. Primary thrombocytosis in children. Haematologica. 2014;99(4)620-28. Disclosures Off Label Use: Hydroxyurea use in certain children with MPN is accepted practice but is technically off-label.