Abstract 37: An unusual case of myelofibrosis with a JAK2 H538QK539L mutation associated with nephrotic syndrome
Authors: Tung Moon Ley , Sran Hersharan Kaur 
Published: August 2018

Abstract
Introduction: Activating Janus kinase 2 (JAK2) mutations have been described in myeloproliferative neoplasms (MPNs) since 2005. Since its initial discovery, the JAK2 V617F mutation has been described in more than 95% of patients with polycythemia vera (PV) and in 50-60% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). Subsequent efforts were made to identify molecular mutations in MPN cases lacking the V617F mutation and further mutations in the exon 12 domain of the JAK2 were identified in PV patients. However, there have been only a few studies evaluating the presence of these JAK2 exon 12 mutations in PMF patients.
Case Report: A 60-year-old Malay gentleman with no known prior medical history of note presented at our Emergency Department with a 1-week history of bipedal edema and exertional dyspnea. Physical examination revealed bibasal coarse crepitations with moderate hepatosplenomegaly. Laboratory investigations revealed normochromic, normocytic anemia, thrombocytopenia, hypoalbuminemia, and elevated creatinine levels. A spot urine sample showed a protein to creatinine ratio of 93 mg/mmol with an estimated total urinary protein (TUP) of 0.8 g/day.
Further workup of his renal impairment, which included an autoimmune screen, hepatitis, and humman immunodeficiency tests, were all unremarkable. A myeloma screen revealed elevated immunoglobulin G levels of 29.18 g/L but with no monoclonal bands detected. Transthoracic echocardiography showed mild pulmonary hypertension with a pulmonary artery systolic pressure (PASP) of 45 mmHg, but the ejection fraction was normal at 65%. He was also noted incidentally to have a prolonged prothrombin time (PT), activated partial thromboplastic time (APTT), and thrombin clotting time. Fibrinogen levels were normal and a lupus anticoagulant was not detected.
Bone marrow aspiration and biopsy results were consistent with myelofibrosis and diffuse coarse reticulin fibers of grade 4 were reported. Quantitative BCR-ABL messenger ribonucleic acid (mRNA), JAK2 V617F, and calreticulin (CALR) mutations were negative. However, a JAK2 H538QK539L (mutation leading to a substitution of glutamine for histidine at position 538 and leucine for lysine at position 539) in exon 12 was detected. Incidentally, iron stores were absent on the bone marrow aspirate sample.
Ultrasound (US) and computed tomography (CT) scans showed the presence of hepatosplenomegaly with portal hypertension with no evidence of any venous thrombosis. A nonobstructive left renal calculi was seen but no other renal abnormality was detected.
He was started on low-salt diet, fluid restriction, diuretic, and iron supplements. Within 1 month, his hemoglobin increased from 7.7g/dL to 14 g/dL with a rise in hematocrit to 52.1%. His iron supplements were stopped and he required 3 sessions of venesection in total to control his hematocrit. Subsequently, he was commenced on hydroxyurea for cytoreduction. His spleen reduced in size and his proteinuria normalized after 10 months. However, he developed worsening anemia and hydroxyurea had to be stopped. On follow-up, his hemoglobin increased to 12 g/dL with a baseline platelet count of &gt; 100 X 109/L. Throughout this period, his bipedal edema remained chronic but he was not consistent with his renal follow-ups. Within 12 months, his proteinuria started increasing and is now within the nephrotic range.
Discussion: We describe here a patient who was diagnosed with a JAK2 V617F negative PMF. Subsequent analysis revealed that he was harboring a JAK2 exon12 mutation instead. This was associated with a deranged coagulation profile and proteinuria which responded to hydroxyurea. This patient was never diagnosed with PV previously and thus did not meet the criteria for post-PV myelofibrosis. Also, we believe that this is the first case of a JAK2 exon12 mutation occurring in a myelofibrotic patient. Given the recent description of MPN-related glomerulopathy and the response of this patient to hydroxyurea, we believe further investigations into the associations of triple-negative (JAK2 V617F, myeloproliferative leukemia virus oncogene (MPL) and CALR negative) PMF with JAK2 exon12 mutations and the associated organ involvements may increase our knowledge of the pathogenesis of this rare condition.
Citation Format: Moon Ley Tung, Hersharan Kaur Sran. An unusual case of myelofibrosis with a JAK2 H538QK539L mutation associated with nephrotic syndrome [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 37.