Ropeginterferon alfa-2b treatment in a young patient with multi-refractory polycythemia vera and double JAK2 gene mutation: a case report.

This case report presents a 3-year-old female patient initially diagnosed with polycythemia vera (PV) in 2001. The patient exhibited elevated red blood cell (RBC) counts, high hemoglobin (Hb) levels, hyperleukocytosis, and moderate thrombocytosis, with sporadic abdominal pain and significant splenomegaly. Despite various treatments, including phlebotomies, hydroxyurea, and alpha-interferon, the patient struggled to maintain optimal hematocrit levels and experienced persistent symptoms. Subsequent genomic analysis revealed a rare JAK2 G301R mutation alongside the canonical JAK2 V617F mutation, potentially contributing to disease severity. In 2023, the patient started Ropeginterferon alfa-2b, leading to improved hematological parameters and symptom relief. The case underscores the challenges in managing PV, particularly in young patients, and highlights the potential clinical significance of additional JAK2 mutations/variants and the potential benefits of Ropeginterferon alfa-2b in achieving better disease control.

Stiffer Spleen Predicts Higher Bone Marrow Fibrosis and Higher JAK2 Allele Burden in Patients With Myeloproliferative Neoplasms.

A total of 63 myeloproliferative neoplasms [MPN; 9 polycythemia vera (PV), 32 essential thrombocythemia (ET), and 22 myelofibrosis (MF)] underwent spleen stiffness (SS) measurement by vibration-controlled transient elastography equipped with a novel spleen-dedicated module. Higher SS values significantly correlated with grade 2-3 bone marrow (BM) fibrosis (p=0.035), with hemoglobin level <10 g/dl (p=0.014) and with white blood cells ≥10,000/µl (p=0.008). Median SS was significantly higher in MF patients compared to ET and PV (p=0.015). SS also correlated with higher JAK2 variant allele frequency (p=0.02). This study identifies SS as a potential noninvasive tool that reflects BM fibrosis and the mutational burden in MPN.

A case of subcapsular renal hematoma status post celiac artery thrombectomy.

INTRODUCTION: 30 year old male with no significant past medical history presenting to the hospital with significant left-sided abdominal pain. CASE PRESENTATION: Patient was found to have a thrombus within the celiac artery for which he underwent a catheter assisted thrombolysis procedure. Hypercoagulable work-up revealed evidence of a JAK 2 V617F mutation which is indicative of Polycythemia Vera. The patient returned the following day with considerable left-sided flank pain associated with shortness of breath, nausea, and vomiting. CT performed showed evidence of an expanding left renal subcapsular hematoma. Patient was treated conservatively with IV fluids and pain medication before he was discharged hemodynamically stable after a few days. DISCUSSION/CONCLUSION: Accessory renal vessels can be a rare finding coming of the celiac artery and so, care must be taken to evaluate vascular anatomy to avoid iatrogenic injuries; a bleed from one of these vessels could lead to the development of a hematomas, as seen with this patient.

Beyond Hemoglobin: When and How to Work Up Possible Polycythemia Vera.

BACKGROUND: World Health Organization (WHO) 2017 diagnostic criteria for hemoglobin levels in polycythemia vera (PV) were lowered from 185 g/L to 165 g/L for men and from 165 g/L to 160 g/L for women, but these cutoffs were not designed for screening. OBJECTIVES: The primary aim of this study was to assess the value of laboratory and clinical parameters in deciding whether to further pursue a diagnosis of PV. A secondary aim was to explore the diagnostic utility of bone marrow morphology. METHODS: We evaluated clinical and laboratory parameters that may be useful when considering further diagnostic work-up, emphasizing PV vs. secondary erythrocytosis (SE). We classified 200 patients with JAK2 V617F testing using WHO criteria. RESULTS: Patients with myeloproliferative neoplasms (MPN) were rarely under age 40 and uncommonly obese (BMI ≥ 30 kg/m2). Current smoking history favored SE, and these patients rarely had a platelet count ≥ 450 × 103/uL. Laboratory parameters suggesting greater PV likelihood were: RBC > 6.8 × 106 for men or > 5.9 × 106 for women; low erythropoietin; and low MCV or low ferritin. Bone marrow morphology (available in 111 cases) was generally more cellular in PV vs. SE and assessed disease progression. CONCLUSIONS: Readily accessible clinical and laboratory data can assist in considering a PV workup, and a possible diagnostic algorithm is presented. These preliminary findings warrant larger studies to develop a more formal PV-risk scoring system with optimal cutoffs and weighting.

The Role of New Technologies in Myeloproliferative Neoplasms.

The hallmark of BCR-ABL1-negative myeloproliferative neoplasms (MPNs) is the presence of a driver mutation in JAK2, CALR, or MPL gene. These genetic alterations represent a key feature, useful for diagnostic, prognostic and therapeutical approaches. Molecular biology tests are now widely available with different specificity and sensitivity. Recently, the allele burden quantification of driver mutations has become a useful tool, both for prognostication and efficacy evaluation of therapies. Moreover, other sub-clonal mutations have been reported in MPN patients, which are associated with poorer prognosis. ASXL1 mutation appears to be the worst amongst them. Both driver and sub-clonal mutations are now taken into consideration in new prognostic scoring systems and may be better investigated using next generation sequence (NGS) technology. In this review we summarize the value of NGS and its contribution in providing a comprehensive picture of mutational landscape to guide treatment decisions. Finally, discussing the role that NGS has in defining the potential risk of disease development, we forecast NGS as the standard molecular biology technique for evaluating these patients.

Molecular biomarkers of thrombosis in myeloproliferative neoplasms.

JAK2 mutations define polycythemia vera (PV), CALR and MPL mutations are specific to JAK2 unmutated essential thrombocythemia (ET) and primary myelofibrosis (PMF). We overviewed the current knowledge on the relationship between these phenotypic driver mutations and thrombotic complications that are major cause of morbidity and mortality in patients with myeloproliferative neoplasms (MPN) particularly PV and ET. The JAK2 mutation is found in 50-60% of patients with ET and PMF. The International Prognostic Score for Thrombosis in ET (IPSET-thrombosis) identified JAK2 mutation as an independent risk factor and a 3-tiered prognostic model was devised. IPSET-thrombosis model outperformed the 2-tiered conventional risk stratification that includes age and thrombotic history. PV is usually associated with a JAK2 mutation and studies looking at the role of JAK2V617F allele burden associated with thrombosis are so far inconclusive. In PMF, the rate of major thrombosis is around 2%pt-yr and JAK2 mutation emerged as an independent risk factor for these events. Calreticulin/MPL (CALR) is the second most frequent mutation and occurs in half of JAK2 and MPL wild-type patients with ET and PMF. Despite the fact that these mutations are associated with high platelet counts, the risk of thrombosis compared with JAK2 and MPL mutated cases is significantly lower. The role of MPL in the prediction of thrombosis is of difficult demonstration due to the low frequency in ET and PMF. Therefore, these epidemiologic studies pointed out the role of JAK2V617F mutation as a major contributory factor for the pathogenesis of thrombosis in MPN. Abnormalities of blood cells arising from the clonal proliferation of hematopoietic stem cells may explain the switch to a procoagulant phenotype.

Analysis of JAK2V617F mutation in Jordanian patients with myeloproliferative neoplasms.

OBJECTIVE/BACKGROUND: Myeloproliferative neoplasms (MPNs) are heterogeneous clonal bone marrow stem cell disorders and include polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis (IMF) neoplasia. In 2005, the JAK2(V617F) mutation was identified in Philadelphia chromosome-negative patients. The aim of this study was to sequence coding exons 12 and 14 of the JAK2 gene in Jordanian patients with MPN. METHODS: Both exons 12 and 14 of the JAK2 gene were amplified using polymerase chain reaction from DNA extracted from 68 blood and bone marrow samples belonging to 57 MPN patients and subjected to DNA sequencing. RESULTS: JAK2(V617F) mutations were detected in 26 of 57 Jordanian patients (45%) with different MPNs. JAK2(V617F) was identified in 70%, 31%, and 14% of PV, ET, and IMF cases, respectively. Five men diagnosed with PV were homozygous for JAK2(V617F), whereas the other 21 patients were heterozygous for the mutation. Neither the JAK2(V617F) mutation nor any DNA polymorphism in exon 12 or exon 14 of the JAK2 gene was detected among the 40 leukemic patients. A rare single nucleotide polymorphism, c.1860C→T (rs375442615), was detected in one patient with ET. CONCLUSION: This study is the first molecular investigation of the JAK2 gene in Jordan. We successfully identified the JAK2(V617F) mutation in Jordanian patients with Philadelphia chromosome-negative MPNs. Our results provide a basis for the early detection of this mutation and simplify the diagnostic workup for these disorders at the molecular level.

Burning feet in polycythemia vera - peripheral sensorimotor axonal neuropathy with erythromelalgia.

Polycythemia vera is a rare myeloproliferative disease. Cutaneous symptoms are uncommon. We report about a 72-year-old female patient with JAK2(V617F) -positive polycythemia who developed peripheral sensorimotor axonal neuropathy and erythromelalgia. Possible causes and treatment are discussed.

Role of calreticulin mutations in the aetiological diagnosis of splanchnic vein thrombosis.

BACKGROUND & AIMS: Myeloproliferative neoplasms are the most common aetiological cause of splanchnic vein thrombosis (SVT). In these patients, the JAK2V617F mutation has facilitated the diagnosis of an underlying myeloproliferative neoplasm (MPN). Recently, somatic mutations of the calreticulin (CALR) gene have been identified in MPN patients lacking the JAK2 mutation. The aim of the present study was to ascertain whether CALR mutations could also play a role in the diagnosis of masked MPN in SVT. METHODS: We included 209 patients with SVT (140 with PVT and 69 with Budd-Chiari syndrome) who had a complete aetiological diagnostic work-out. They were investigated for CALR mutations. RESULTS: CALR mutations were found in 4 of the 209 patients (1.9%). They represented 5.4% of patients with an underlying MPN of whom all had already been diagnosed with a MPN using conventional criteria including bone marrow biopsy findings. CONCLUSIONS: In the screening of underlying MPNs in patients with SVT, given its high frequency in these disorders, the JAK2 mutation must be evaluated first and, if negative, CALR mutations should also be investigated. This approach would increase the diagnostic yield of masked MPNs by reducing the need for additional studies.

The JAK2(V617F) tyrosine kinase mutation in blood donors with upper-limit haematocrit levels.

BACKGROUND: It is not rare to observe in blood donors a level of haematocrit (Hct) above or close to the highest normal limit. In the case of blood donors the diagnosis and clinical evaluation of this alteration may be complicated by regular blood donations that can mask an underlying disease such as polycythaemia vera. Recently a single acquired mutation in the Janus kinase 2 gene (JAK2) on chromosome 9 was identified and it was found that the incidence of this mutation was high in patients with polycythaemia vera. MATERIAL AND METHODS: From the January 1, 2006 to December 31, 2006 all consecutive donors with a Hct above 50% if males (n=84) and 46% if females (n=19) underwent JAK2 mutation analysis. Seventy-nine donors (59 males and 20 females) whose Hct was normal at their last blood donation were randomly selected and used as controls. RESULTS: Among the group of blood donors with a high Hct, we identified one donor who was positive for the JAK2 mutation. This man had a Hct of 50.6% at his last donation, while his average Hct in the preceding year was 51.7%. The prevalence of the JAK2 mutation could be estimated to be 1%, 0.6% or 0.02% in the three different populations considered: donors with a Hct level above the upper limit of normal, all tested donors or the entire donor cohort attending our transfusion service, respectively. CONCLUSIONS: The present study suggests that apparently healthy subjects with repeatedly high levels of Hct may have the acquired mutation in JAK2. Laboratory screening tests for JAK2 may be offered to blood donors at transfusion services with expertise in molecular genetics.