A complete remission induced by valproic acid in a patient with essential thrombocytemia JAKV617F- positive

INTRODUCTION: Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are myeloproliferative neoplasms characterized by excessive proliferation of myeloid/erythroid lineage cells and JAK2V617F somatic mutation. Since current treatments of MPNs are unlikely to cure or offer remission to patients, there is a clear necessity of new therapies. Histone Deacetylase inhibitors (HDACi) are a new class of drugs with a potential activity in this group of disease. Among these, valproic acid (VPA) is a well tolerated and long since used drug for the treatment of epilepsy and bipolar disorders. At concentration equivalent to those used by neuro-psychiatrists (> 50 μg/ml), VPA acts as a powerful HDACi, that has been shown to be promising in the treatment of both solid and hematological tumors. Therefore herein we present a 52 years-old woman with JAK2V617F ET who received VPA for a bipolar disorder. METHODS: Diagnosis of ET, was done 2 years before our observation, at the time of an episode of angina pectoris treated with four coronary by-passes. Patient started treatment with antiplatelet drugs and hydrossiurea (HU). However, due to a severe intolerance, HU was intermittently assumed never reaching therapeutic concentration and disease control. During this period, the patient developed heightened mood (either euphoric or irritable), decreased need for sleep and hyperactivity. A psychiatric evaluation allowed to made the diagnosis of bipolar disorder type II. Thus the patient definitively stopped HU and started VPA at increasing doses, reaching a therapeutic serum level of 76 μg/ml after four months with a dosage of 1500 mg/day and achieving the complete remission of her manic phase of the bipolar disorder. RESULTS: As for the clinical course of ET, her hemochromocytometric values before VPA were: Hb 14.3 gr/dl, WBC count 11.3 x 109/L and platelets 793 x 109/L. Two months after reaching the VPA therapeutic level we observed a significant decrease in the values of Hb, WBC and Platelet that resulted 12.9 gr/dl, 6.3 x 109/l and 403 x 109/L, respectively. Since, these values are remained stable after more than one-year of VPA treatment, the patient has been classified in complete remission (CR) of disease (figure 1). Molecular monitoring of disease during VPA treatment was performed by evaluating JAK2 gene dosage and JAK2WT and JAK2V617F transcript levels at diagnosis and after 4, 8 and 12 month from the start of VPA. Although, the JAK2 gene dosage remained constant upon treatment,, JAK2WT and JAK2V617F transcript levels significantly increased at each time points. CONCLUSION: Data herein reported demonstrated, for the first time, the achievement of CR induced by the HDACi VPA in a ET patient intolerant to HU. The findings that JAK2WT and JAK2V617F transcript levels increased, despite the achievement of therapeutic response, support that JAK2 is not fully implicated in the pathogenesis of Ph(-) MPN.