Reflections on the unexpected laboratory finding of hemorheological alterations observed in some haematological disorders.

Hyperviscosity syndrome is a clinical condition characterized by the slowing of blood flow through the vessels and it may be associated with several diseases. The nosographic classification of primary hyperviscosity conditions (Wells classification 1970) divided the primary hyperviscosity syndromes in polycythaemic, sclerocytemic and sieric. Recent and personal laboratory observations have highlighted an unexpected behaviour of the erythrocyte deformability observed in some haematological disorders such as polycythemia vera, multiple myeloma and monoclonal gammopathy of undetermined significance. The interest of this observation depends on the fact that up to now, according to the Wells classification, the hemorheological alteration present in PV was related to the increase of RBC mass while that present in MM and MGUS was attributable to the abnormality of plasma or serum viscosity only. Through an extensive research among the literature, using MEDLINE/PubMed to identify all published reports on the hyperviscosity syndromes, issues that until now have been dealt with separately will therefore be analyzed in a unique paper, allowing a global view. The aim of this paper is to provide some suggestions for reflection and emphasizing the need of a nosographic framework of hyperviscosity that, probably, deserves to be reviewed.

The management, outcome, and postpartum disease course of 41 pregnancies in 20 women with polycythemia vera.

OBJECTIVES: Pregnancies in women with polycythemia vera (PV) are associated with an increased risk of PV-related maternal complications and often result in miscarriage. Recommendations for the management of PV pregnancies are mainly based on studies with a small number of patients. A correlation between pregnancy outcome and postpartum course has been reported for essential thrombocythemia, but corresponding data for PV are lacking so far. METHODS: In 41 PV pregnancies, the pregnancy outcome, the use of PV-specific therapies (ie, acetylsalicylic acid, low-molecular weight heparin and/or interferon-alpha), and the postpartum PV course were investigated. RESULTS: A live birth rate of 51.2% (21/41 pregnancies) was observed. 43.9% of pregnancies ended in spontaneous abortion and 4.9% in stillbirth. A significantly increased live birth rate occurred in pregnancies with PV-specific therapies compared to standard antenatal care (69.0% vs. 8.3%; P < .0019). The use of PV-specific therapy significantly increased the number of maternal hemorrhages (P = .021) without increasing the risk of fetal complications. During the median postpartum follow-up period of 1.2 years (range 0.1-13.7), complicated postpartum PV occurred significantly more often after miscarriages (P = .035). CONCLUSIONS: According to our analysis, PV-specific therapy improved the live birth rate. Significantly more complicated postpartum PV courses were observed after miscarriages.

Givinostat: an emerging treatment for polycythemia vera.

INTRODUCTION: Polycythemia vera (PV), a Philadelphia chromosome-negative myeloproliferative neoplasm, is characterized by panmyelosis, pancytosis, and a JAK2 mutation. Patients are at increased risk of thrombohemorrhagic events, and progression to myelofibrosis or acute leukemia. Current treatments include aspirin, phlebotomy, and cytoreductive drugs (most commonly hydroxyurea). Givinostat is a potent, class I/II histone deacetylase (HDAC) inhibitor that is in phase I/II clinical trials in PV. Givinostat was well tolerated and yielded promising clinico-hematological responses. A phase III study of givinostat versus hydroxyurea in high-risk PV patients is planned. AREAS COVERED: We present an overview of PV, current treatment guidelines, and the putative mechanism(s) of action of givinostat. We discuss the preclinical and clinical studies of givinostat in PV and briefly review approved and investigational competitor compounds. EXPERT OPINION: HDAC inhibitors have long been known to be active in PV, but chronic toxicities can be challenging. Givinostat, however, is active and well tolerated, and is entering a pivotal Phase III randomized trial. Givinostat offers the possibility of replacing hydroxyurea as the standard first-line cytoreductive choice for PV patients. This would completely change the current therapeutic paradigm and guidelines for PV management. Although surrogate clinical study endpoints may suffice for regulatory purposes, thrombosis reduction and prevention of disease progression remain most important to patients and clinicians.

Novel agents for the treatment of polycythemia vera: an insight into preclinical research and early phase clinical trials.

INTRODUCTION: Current treatment for polycythemia vera (PV) is limited and primarily targets thrombosis risk. Agents targeting distinct mechanisms of action within myeloproliferation are undergoing clinical evaluation to optimize efficacy, improve tolerance and augment long term disease complications. AREA COVERED: This article reviews the current data from completed early phase clinical trials in PV, either as monotherapy or in combination with the few currently approved agents. EXPERT OPINION: There remains an opportunity in PV management to improve efficacy and decrease risk of disease progression. Evolving data from use of long acting interferons are serving to clarifying the potential front line role of this therapy. JAK2 inhibition has made a significant impact on decreasing morbidity in patients with hydroxyurea resistant/refractory disease. New approaches may soon expand options including histone deactylase inhibitors (HDACi), either as monotherapy or combination therapy, which showed promising activity and symptomatic control of pruritus. Drugs targeting new molecular pathways (mammalian target of rapamycin, insulin receptor substrates 1/2, MDM2 protein) or the iron metabolism pathway are in early phase trial. Further translational studies assessing efficacy, long term complications, survival, and constitutional symptom control could pave a way for future success in PV drug development either as monotherapy or in combination.

Polycythemia vera: the current status of preclinical models and therapeutic targets.

INTRODUCTION: Polycythemia vera (PV) is the most common myeloproliferative neoplasm (MPN). PV is characterized by erythrocytosis, leukocytosis, thrombocytosis, increased hematocrit, and hemoglobin in the peripheral blood. Splenomegaly and myelofibrosis often occur in PV patients. Almost all PV patients harbor a mutation in the JAK2 gene, mainly represented by the JAK2V617F point mutation. AREAS COVERED: This article examines the recent in vitro and in vivo available models of PV and moreover, it offers insights on emerging biomarkers and therapeutic targets. The evidence from mouse models, resembling a PV-like phenotype generated by different technical approaches, is discussed. The authors searched PubMed, books, and clinicaltrials.gov for original and review articles and drugs development status including the terms Myeloproliferative Neoplasms, Polycythemia Vera, erythrocytosis, hematocrit, splenomegaly, bone marrow fibrosis, JAK2V617F, Hematopoietic Stem Cells, MPN cytoreductive therapy, JAK2 inhibitor, histone deacetylase inhibitor, PV-like phenotype, JAK2V617F BMT, transgenic JAK2V617F mouse, JAK2 physiologic promoter. EXPERT OPINION: Preclinical models of PV are valuable tools for enabling an understanding of the pathophysiology and the molecular mechanisms of the disease. These models provide new biological insights on the contribution of concomitant mutations and the efficacy of novel drugs in a 'more faithful' setting. This may facilitate an enhanced understanding of pathogenetic mechanisms and targeted therapy.

[Suspected hippocampal sclerosis in an european shorthair cat diagnosed with polycythemia vera]. / Verdacht auf Hippocampussklerose bei einer Europäisch-Kurzhaar-Katze mit der Diagnose Polycythaemia vera.

A 7-year-old male castrated cat was presented because of an acute onset of lethargy and vestibular ataxia. The cat was diagnosed with polycythemia vera. Later the patient developed additional clinical signs including orofacial twitching, aggressivity, hypersalivation, circling and a head tilt. A magnetic resonance imaging was performed and revealed hippocampal alterations compatible with hippocampal sclerosis. The presented case report describes the clinical signs and hematologic findings in a cat with polycythemia vera and the response of treatment. Another part is the discussion about the hypothesis that the hippocampal alterations were due to a cerebral hypoperfusion caused by the polycythemic condition.

EVALUATION OF BURDENSOME SYMPTOMS IN PATIENTS WITH RADIATION6ASSOCIATED AND SPONTANEOUS MYELOPROILIFERATIVE NEOPLASMS WITH THE USE OF OPTIMIZED SELF-ASSESSMENT MPN-SAF TSS. / OTsINKA OBTIaZhLYVYKh SYMPTOMIV U KhVORYKh NA RADIATsIINO-ASOTsIIOVANI TA SPONTANNI MIIeLOPROLIFERATYVNI NEOPLAZIÏ Z VYKORYSTANNIaM ADAPTOVANOÏ ShKALY SAMOOTsINKY MPN-SAF TSS.

OBJECTIVE: To investigate the intensity of burdensome symptoms using self-assessment MPN-SAF TSS in patientswith radiation-associated and spontaneous myeloproiliferative neoplasms (MPNs). MATERIALS AND METHODS: The study included 89 patients with radiation-associated and spontaneous MPNs, the bur-densome symptoms of MPN were determined using MPN-SAF TSS. RESULTS: The average score for complaints in patients with radiation-associated MPNs was significantly higher thanin patients with spontaneous MPNs - 43.46 and 25.04 points, respectively (p = 0.003). MPN patients classified bysubtypes also showed differences regarding intensity of burdensome MPN symptoms, demonstrating significantlyhigher average score of complaints among primary myelofibrosis patients (35.60), compared to polycythemia vera(29.60) and essential thrombocythemia (18.05) patients, (p = 0.005). Our study did not reveal any influence of theJAK2 V617F mutation on MPN burdensome symptoms intensity in MPN patients. CONCLUSIONS: We demonstrated a higher intensity of the MPN burdensome symptoms determined by the optimizedself-assessment MPN-SAF TSS in patients with radiation-associated, and in primary myelofibrosis patients, indicat-ing increased severity of patient's general conditions at the stage of diagnosis verification. It is advisable to usethe optimized MPN-SAF TSS at the moment of molecular genetic testing during the diagnosis of MPN for selectionor modifying treatment strategies in order to achieve better quality of life for patients.

Spinal cord infarction during physical exertion due to polycythemia vera and aortoiliac occlusive disease: A case report.

RATIONALE: Spinal cord infarction is rarely caused by hypercoagulable states. Polycythemia vera (PV) is a myeloproliferative neoplasm that can contribute to thrombotic events due to increased blood viscosity. We report a case of spinal cord infarction due to extensive aortic thrombosis caused by PV. PATIENT CONCERNS: A 56-year-old man presented with acute paraplegia and urinary retention during heavy physical exertion. DIAGNOSES: Imaging studies revealed spinal cord infarction at the T9 to T12 levels and aortoiliac occlusive disease. PV was diagnosed during workup for elevated hemoglobin level INTERVENTIONS:: The patient received intravenous hydration and anticoagulation for spinal cord infarction. PV was managed with phlebotomy and hydroxyurea. Courses of inpatient and outpatient rehabilitation programs were also given. OUTCOMES: The patient became urinary catheter-free 5 months after disease onset, and was able to walk with walker. The American Spinal Injury Association Impairment scale also improved from C at diagnosis to D during last follow-up. LESSONS: Etiologic workup is important for patients with spinal cord infarction to direct specific treatment strategies. Physical exertion may act as a trigger for infarction in patients at risk for thrombotic events, and monitoring of neurologic status during and after periods of exercise is warranted.

Polycythemia vera: diagnosis, clinical course, and current management

Very important developments related to polycythemia vera (PV) have occurred during the last two decades. The discovery of Janus kinase (JAK) 2 mutations has changed both the diagnosis and clinical management of PV. Currently JAK2 molecular testing is essential in the diagnostic work-up and JAK2 mutation positivity is a major diagnostic criterion. The discovery of JAK2 mutations suggested that abnormal JAK-STAT signaling was a pivotal feature in the pathogenesis of Philadelphia-negative myeloproliferative neoplasms. This idea led to the development of JAK inhibitors. Currently ruxolitinib, a JAK1/JAK2 inhibitor, is also approved for PV patients with hydroxyurea resistance or intolerance. International collaborations have made it possible to describe disease characteristics and evolution better. Presently it is possible to quantify the symptomatic burden of the disease and to estimate prognosis. In spite of these developments, management of PV still largely depends on estimation of thromboembolic risk and trying to decrease the risk with or without cytoreductive medications. Different approaches have been proposed by international disease experts for the diagnosis, thromboembolic risk estimation, and drug selection. This paper aims to review clinical aspects of PV and propose a management algorithm. The authors also point to still unresolved questions and unmet needs in diagnosis and management.

Polycythemia Vera.

OPINION STATEMENT: Polycythemia vera (PV) is the most common myeloproliferative neoplasm (MPN), the ultimate phenotype of the JAK2 V1617F mutation, the MPN with the highest incidence of thromboembolic complications, which usually occur early in the course of the disease, and the only MPN in which erythrocytosis occurs. The classical presentation of PV is characterized by erythrocytosis, leukocytosis, and thrombocytosis, often with splenomegaly and occasionally with myelofibrosis, but it can also present as isolated erythrocytosis with or without splenomegaly, isolated thrombocytosis or isolated leukocytosis, or any combination of these. When PV is present, the peripheral blood hematocrit (or hemoglobin) determination will not accurately represent the actual volume of red cells in the body, because in PV, in contrast to other disorders causing erythrocytosis, when the red cell mass increases, the plasma volume usually increases. In fact, unless the hematocrit is greater than 59%, true erythrocytosis cannot be distinguished from pseudoerythrocytosis due to plasma volume contraction. Usually, the presence of splenomegaly or leukocytosis or thrombocytosis establishes the diagnosis. However, when a patient presents with isolated thrombocytosis and a positive JAK2 V617F assay, particularly a young woman, the possibility of PV must always be considered because of plasma volume expansion. The WHO PV diagnostic guidelines are not helpful in this situation, since the hematocrit is invariably normal and a bone marrow examination will not distinguish ET from PV. Only a direct measurement of both the red cell mass and plasma volume can establish the correct diagnosis. In managing a PV patient, it is important to remember that PV is an indolent disorder in which life span is usually measured in decades, even when myelofibrosis is present, that chemotherapy is futile in eradicating the disease but does increase the incidence of acute leukemia and that hydroxyurea is not safe in this regard nor is it antithrombotic. Phlebotomy to a sex-specific normal hematocrit is the cornerstone of therapy and there now exist safe remedies for controlling leukocytosis, thrombocytosis, and extramedullary hematopoiesis and symptoms due to inflammatory cytokines when this is necessary.

Efficacy and safety of ruxolitinib after and versus interferon use in the RESPONSE studies.

Ruxolitinib was well tolerated and superior to best available therapy (including interferon [IFN]) in controlling hematocrit without phlebotomy eligibility, normalizing blood counts, and improving polycythemia vera-related symptoms in the Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care (RESPONSE) studies. This ad hoc analysis focuses on ruxolitinib in relation to IFN in the RESPONSE studies, with attention on the following: (1) safety and efficacy of ruxolitinib and best available therapy in patients who received IFN before study randomization, (2) safety and efficacy of IFN during randomized treatment in best available therapy arm, and (3) use of ruxolitinib after crossover from best available therapy in IFN-treated patients. IFN exposure before randomization had little effect on the efficacy or safety of ruxolitinib. In the randomized treatment arms, ruxolitinib was superior to IFN in efficacy [hematocrit control (RESPONSE = 60% of ruxolitinib vs 23% of IFN patients; RESPONSE-2 = 62% of ruxolitinib vs 15% of IFN patients)] and was tolerated better in hydroxyurea-resistant or hydroxyurea-intolerant patients. After crossing over to receive ruxolitinib, patients who had initially received IFN and did not respond had improved hematologic and spleen responses (62% of patients at any time after crossover) and an overall reduction in phlebotomy procedures. Rates and incidences of the most common adverse events decreased after crossover to ruxolitinib, except for infections (primarily grade 1 or 2). These data suggest that ruxolitinib is efficacious and well tolerated in patients who were previously treated with IFN. The RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036) studies were registered at clinicaltrials.gov .

Progression of primary myelofibrosis to polycythemia vera: A case report.

RATIONALE: This case report describes the progression of primary myelofibrosis (PMF) to polycythemia vera (PV), and discuss its potential mechanisms. PATIENT CONCERNS: The patient was admitted because of abdominal discomfort and enlarged spleen for 19 months. DIAGNOSIS: A case of PMF progressed to PV was retrospectively analyzed. There were 19 months between the diagnosis of PMF and PV. The JAK2 V617F mutation was positive before and after the diagnosis of PV; however, new chromosomal abnormalities were detected during the progression. INTERVENTIONS: For treatment of PMF, the danazol, calcitriol, and thalidomide were given. Then, the use of thalidomide and calcitriol was stopped, and hydroxyurea was started. For treatment of PV, interferon treatment was given, whereas hydroxyurea was continued. OUTCOMES: After 30 months of the progression (at the recent follow-up), this patient had no obvious symptoms or thrombosis. LESSONS: PMF rarely progresses to PV, however, the progression will significantly improve the quality of life and prognosis.

VEGF-A, sVEGFR-1, and sVEGFR-2 in BCR-ABL negative myeloproliferative neoplasms.

BACKGROUND AND OBJECTIVE: Data from the literature indicate the relationship between the bone marrow microvessel density and the blood parameters of angiogenesis. The aim of this study was to evaluate selected parameters of angiogenesis (VEGF-A, sVEGFR-1, and sVEGFR-2) and their correlations with white blood cells, platelets, and red blood cells. MATERIALS AND METHODS: The study included 72 patients (mean age, 61.84 years) with myeloproliferative neoplasms (MPNs): essential thrombocythemia (ET) (n=46), polycythemia vera (PV) (n=19), and primary myelofibrosis (PMF) (n=7). Serum VEGF-A, sVEGFR-1, and sVEGFR-2 were determined using the ELISA assay. RESULTS: We observed a significantly higher level of VEGF-A and reduced concentrations of sVEGFR-1 and sVEGFR-2 in the whole group of patients with MPNs as compared to controls. Detailed analysis confirmed significantly higher level of VEGF-A and lower concentration of sVEGFR-2 in each subgroups of MPNs patients. However, sVEGFR-1 concentrations were significantly lower only in PV and ET patients. CONCLUSIONS: The study showed an increased level of VEGF-A, which may indicate the intensity of neoangiogenesis in the bone marrow. Decreased sVEGFR-1 and sVEGFR-2 in the blood of patients with MPNs may reflect consumption of these soluble receptors.

Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms.

The genetic landscape of classical myeloproliferative neoplasm (MPN) is in large part elucidated. The MPN-restricted driver mutations, including those in JAK2, calreticulin (CALR), and myeloproliferative leukemia virus (MPL), abnormally activate the cytokine receptor/JAK2 pathway and their downstream effectors, more particularly the STATs. The most frequent mutation, JAK2V617F, activates the 3 main myeloid cytokine receptors (erythropoietin receptor, granulocyte colony-stimulating factor receptor, and MPL) whereas CALR or MPL mutants are restricted to MPL activation. This explains why JAK2V617F is associated with polycythemia vera, essential thrombocythemia (ET), and primary myelofibrosis (PMF) whereas CALR and MPL mutants are found in ET and PMF. Other mutations in genes involved in epigenetic regulation, splicing, and signaling cooperate with the 3 MPN drivers and play a key role in the PMF pathogenesis. Mutations in epigenetic regulators TET2 and DNMT3A are involved in disease initiation and may precede the acquisition of JAK2V617F. Other mutations in epigenetic regulators such as EZH2 and ASXL1 also play a role in disease initiation and disease progression. Mutations in the splicing machinery are predominantly found in PMF and are implicated in the development of anemia or pancytopenia. Both heterogeneity of classical MPNs and prognosis are determined by a specific genomic landscape, that is, type of MPN driver mutations, association with other mutations, and their order of acquisition. However, factors other than somatic mutations play an important role in disease initiation as well as disease progression such as germ line predisposition, inflammation, and aging. Delineation of these environmental factors will be important to better understand the precise pathogenesis of MPN.