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Blood May 2021
Topics: Basic Helix-Loop-Helix Transcription Factors; Erythropoietin; Humans; Hypertension, Pulmonary; Polycythemia
PubMed: 33956067
DOI: 10.1182/blood.2020010323 -
American Journal of Medical Genetics.... Nov 2021Hypoxia-inducible factors (HIFs) activate gene transcription in response to reduced O availability and play critical roles in development, physiology, and disease... (Review)
Review
Hypoxia-inducible factors (HIFs) activate gene transcription in response to reduced O availability and play critical roles in development, physiology, and disease pathogenesis. Mutations that dysregulate HIF activity are the genetic basis for tumor predisposition in the von Hippel-Lindau syndrome and excess red blood cell production in hereditary erythrocytosis.
Topics: Aryl Hydrocarbon Receptor Nuclear Translocator; Basic Helix-Loop-Helix Transcription Factors; Genetic Diseases, Inborn; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mutation; Oxygen; Polycythemia; von Hippel-Lindau Disease
PubMed: 34655169
DOI: 10.1002/ajmg.a.62521 -
American Journal of Medical Genetics.... Aug 2021Hypoxia-inducible factors (HIFs) activate gene transcription in response to reduced O availability and play critical roles in development, physiology, and disease... (Review)
Review
Hypoxia-inducible factors (HIFs) activate gene transcription in response to reduced O availability and play critical roles in development, physiology, and disease pathogenesis. Mutations that dysregulate HIF activity are the genetic basis for tumor predisposition in the von Hippel-Lindau syndrome and excess red blood cell production in hereditary erythrocytosis.
Topics: Biomarkers; Diagnosis, Differential; Genetic Association Studies; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Oxygen; Phenotype; Polycythemia; Signal Transduction; von Hippel-Lindau Disease
PubMed: 33973706
DOI: 10.1002/ajmg.a.62250 -
International Journal of Laboratory... May 2024An absolute erythrocytosis is present when the red cell mass is greater than 125% of the predicted. This is suspected when the hemoglobin or hematocrit is above the... (Review)
Review
An absolute erythrocytosis is present when the red cell mass is greater than 125% of the predicted. This is suspected when the hemoglobin or hematocrit is above the normal range. An erythrocytosis can be classified as primary or secondary and congenital or acquired. The commonest primary acquired disorder is polycythemia vera. The diagnostic criteria for PV have evolved over time and this is the main diagnosis managed in hematology clinics. There are a variety of rare congenital causes both primary and secondary. In particular in young patients and/or those with a family history a congenital cause is suspected. There remains a larger cohort with acquired erythrocytosis mainly with non-hematological pathology. In order to explore for a cause of erythrocytosis, measurement of the erythropoietin level is a first step. A low erythropoietin level indicates a primary cause and a normal or elevated level indicates a secondary etiology. Further investigation is then dictated by initial findings and includes mutational testing with PCR and NGS for those in whom a congenital cause is suspected. Following this possibly bone marrow biopsy, scans, and further investigation as indicated by history and initial findings. Investigation is directed toward the identification of those with a hematological disorder which would be best managed following guidelines in hematology clinics and referral elsewhere in those for whom there are non-hematological reasons for the elevated hemoglobin.
Topics: Humans; Polycythemia; Erythropoietin; Hemoglobins; Polycythemia Vera
PubMed: 38695361
DOI: 10.1111/ijlh.14298 -
The Lancet. Haematology Apr 2021
Topics: Attitude to Health; Cost of Illness; Delivery of Health Care; Female; Gender Identity; Health Personnel; Health Planning; Hormones; Humans; Male; Polycythemia; Quality of Life; Risk Factors; Sex Characteristics; Thrombosis; Transgender Persons
PubMed: 33770474
DOI: 10.1016/S2352-3026(21)00065-X -
Hematology (Amsterdam, Netherlands) Dec 2021Mean corpuscular volume (MCV) as a measure of the size of red blood cells (RBCs) has been pivotal in the diagnosis and morphologic classification of anemias for over a...
Mean corpuscular volume (MCV) as a measure of the size of red blood cells (RBCs) has been pivotal in the diagnosis and morphologic classification of anemias for over a century. Despite its ubiquitous use and time-honored diagnostic value, one essential attribute of MCV has remained under the radar. It has been long underappreciated that the size of RBC correlates with the amount of hemoglobin (Hb) that it accommodates and, therefore, is an important determining factor of the total Hb level. By scrutinizing this basic principle, it has become possible to uncover a hitherto obscured relationship between MCV, hematocrit (Hct) and RBCs described as a This principle is shown to be invaluable in interpreting RBC parameters, particularly for the evaluation of patients with polycythemia.
Topics: Aged; Erythrocyte Count; Erythrocyte Indices; Erythrocytes; Female; Hematocrit; Hemoglobins; Humans; Male; Middle Aged; Polycythemia
PubMed: 34753407
DOI: 10.1080/16078454.2021.1994173 -
The Lancet. Haematology Mar 2020Polycythaemia vera is a myeloproliferative neoplasm characterised by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow due... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Polycythaemia vera is a myeloproliferative neoplasm characterised by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow due to mutations in the Janus kinase 2 (JAK2) gene. Ruxolitinib, a JAK 1 and JAK 2 inhibitor, showed superiority over best available therapy in a phase 2 study in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. We aimed to compare the long-term safety and efficacy of ruxolitinib with best available therapy in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea.
METHODS
We report the 5-year results for a randomised, open-label, phase 3 study (RESPONSE) that enrolled patients at 109 sites across North America, South America, Europe, and the Asia-Pacific region. Patients (18 years or older) with polycythaemia vera who were resistant to or intolerant of hydroxyurea were randomly assigned 1:1 to receive either ruxolitinib or best available therapy. Patients randomly assigned to the ruxolitinib group received the drug orally at a starting dose of 10 mg twice a day. Single-agent best available therapy comprised hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or observation without pharmacological treatment. The primary endpoint, composite response (patients who achieved both haematocrit control without phlebotomy and 35% or more reduction from baseline in spleen volume) at 32 weeeks was previously reported. Patients receiving best available therapy could cross over to ruxolitinib after week 32. We assessed the durability of primary composite response, complete haematological remission, overall clinicohaematological response, overall survival, patient-reported outcomes, and safety after 5-years of follow-up. This study is registered with ClinicalTrials.gov, NCT01243944.
FINDINGS
We enrolled patients between Oct 27, 2010, and Feb 13, 2013, and the study concluded on Feb 9, 2018. Of 342 individuals screened for eligibility, 222 patients were randomly assigned to receive ruxolitinib (n=110, 50%) or best available therapy (n=112, 50%). The median time since polycythaemia vera diagnosis was 8·2 years (IQR 3·9-12·3) in the ruxolitinib group and 9·3 years (4·9-13·8) in the best available therapy group. 98 (88%) of 112 patients initially randomly assigned to best available therapy crossed over to receive ruxolitinib and no patient remained on best available therapy after 80 weeks of study. Among 25 primary responders in the ruxolitinib group, six had progressed at the time of final analysis. At 5 years, the probability of maintaining primary composite response was 74% (95% CI 51-88). The probability of maintaining complete haematological remission was 55% (95% CI 32-73) and the probability of maintaining overall clinicohaematological responses was 67% (54-77). In the intention-to-treat analysis not accounting for crossover, the probability of survival at 5 years was 91·9% (84·4-95·9) with ruxolitinib therapy and 91·0% (82·8-95·4) with best available therapy. Anaemia was the most common adverse event in patients receiving ruxolitinib (rates per 100 patient-years of exposure were 8·9 for ruxolitinib and 8·8 for the crossover population), though most anaemia events were mild to moderate in severity (grade 1 or 2 anaemia rates per 100 patient-years of exposure were 8·0 for ruxolitinib and 8·2 for the crossover population). Non-haematological adverse events were generally lower with long-term ruxolitinib treatment than with best available therapy. Thromboembolic events were lower in the ruxolitinib group than the best available therapy group. There were two on-treatment deaths in the ruxolitinib group. One of these deaths was due to gastric adenocarcinoma, which was assessed by the investigator as related to ruxolitinib treatment.
INTERPRETATION
We showed that ruxolitinib is a safe and effective long-term treatment option for patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea. Taken together, ruxolitinib treatment offers the first widely approved therapeutic alternative for this post-hydroxyurea patient population.
FUNDING
Novartis Pharmaceuticals Corporation.
Topics: Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Drug Therapy, Combination; Fibrinolytic Agents; Follow-Up Studies; Humans; Hydroxyurea; Interferon alpha-2; Interferon-alpha; Nitriles; Pipobroman; Polycythemia Vera; Polyethylene Glycols; Prognosis; Pyrazoles; Pyrimidines; Quinazolines; Recombinant Proteins; Survival Rate; Time Factors
PubMed: 31982039
DOI: 10.1016/S2352-3026(19)30207-8 -
Pediatrics and Neonatology Nov 2022Unlike in adults, there is no consensus on management and diagnosis of polycythemia in children. This study aims to evaluate the diagnosis and verify the algorithm in...
BACKGROUND
Unlike in adults, there is no consensus on management and diagnosis of polycythemia in children. This study aims to evaluate the diagnosis and verify the algorithm in children with polycythemia.
METHODS
Seventy-nine children with polycythemia were followed-up in our pediatric hematology-oncology clinic between December 15, 2019, and July 15, 2021. After eliminating secondary causes (hypoxia, pulmonary, cardiac diseases), we checked for genetic mutations, including congenital erythrocytosis gene panel (JAK, EPOR, EPAS1, EGNL1, HBB, HBA, BPGM, and VHL). We also compared parameters for secondary and idiopathic polycythemia groups.
RESULTS
Of the 79 children, thirty-five had secondary polycythemia (hypoxia, pulmonary, cardiac diseases), and one was diagnosed with a novel likely pathogenic mutation c.2089C > G; p.Pro697Ala in exon 13 of EPAS1 gene. Others (n = 35) had persistent and idiopathic polycythemia. Here, we compared the idiopathic and secondary cases. We found that the ratio of family history of polycythemia (n = 4 (9.5%) vs 0%, respectively) was higher in the second group (p = 0.009). In addition, the mean age (14.7 ± 3.52 vs 13.4 ± 4.67 respectively) (p = 0.042) and the ratio of erythroid hyperplasia in bone marrow [n = 3 (8.6%) vs 0% respectively] (p = 0.003) was higher in the idiopathic polycythemia group, compared to secondary polycythemia patients.
CONCLUSION
Finding the genetic defect in polycythemia is a significant issue. Due to being a rarity in children, the first line JAK mutation analysis should be performed in selected cases. This study is the first description of a Turkish patient with EPAS1 p.Pro697Ala mutation, thereby expanding our knowledge about the clinical features of the disease. However, new investigations are required to confirm its function.
Topics: Child; Humans; Heart Diseases; Hypoxia; Mutation; Polycythemia; Adolescent; Basic Helix-Loop-Helix Transcription Factors
PubMed: 36002380
DOI: 10.1016/j.pedneo.2022.06.006 -
Current Hematologic Malignancy Reports Oct 2023Chronic myeloproliferative neoplasms (MPN) represent a group of diseases characterised by constitutive activation of the JAK/STAT pathway in a clonal myeloid precursor.... (Review)
Review
PURPOSE OF REVIEW
Chronic myeloproliferative neoplasms (MPN) represent a group of diseases characterised by constitutive activation of the JAK/STAT pathway in a clonal myeloid precursor. The therapeutic approach aims to treat the symptom burden (headache, itching, debilitation), splenomegaly, slow down the fibrotic proliferation in the bone marrow and reduce the risk of thrombosis/bleeding whilst avoiding leukaemic transformation.
RECENT FINDINGS
In recent years, the advent of JAK inhibitors (JAKi) has significantly broadened treatment options for these patients. In myelofibrosis, symptom control and splenomegaly reduction can improve quality of life with improved overall survival, not impacting progression into acute leukaemia. Several JAKi are available and used worldwide, and combination approaches are now being explored. In this chapter, we review the approved JAKi, highlighting its strengths, exploring potential guidelines in choosing which one to use and reasoning towards future perspectives, where the combinations of therapies seem to promise the best results.
Topics: Humans; Janus Kinase Inhibitors; Polycythemia Vera; Janus Kinases; Splenomegaly; Quality of Life; Thrombocythemia, Essential; Signal Transduction; STAT Transcription Factors; Myeloproliferative Disorders
PubMed: 37395943
DOI: 10.1007/s11899-023-00702-x -
Revue Medicale de Liege Feb 2024Polycythemia is suspected when hemoglobin and/or hematocrit levels exceed established norms based on gender and age. This biological anomaly can arise from a...
Polycythemia is suspected when hemoglobin and/or hematocrit levels exceed established norms based on gender and age. This biological anomaly can arise from a myeloproliferative neoplasm known as polycythemia vera, or be secondary to excess erythropoietin (EPO) or decreased in plasma volume. Faced with polycythemia, the search for JAK2 mutations and measurement of serum EPO levels can guide toward the etiology. In polycythemia vera, thromboembolic events are the most lethal complications and unfortunately often the initial manifestation of the disease. The condition can also progress to myelofibrosis or acute leukemia. Management aims at reducing the hematocrit below 45 %, in order to limit, but not completely prevent, thrombo-embolic complications. This article elaborates on the clinical considerations around this biological anomaly, relevant complementary examinations, and briefly the therapeutic management.
Topics: Humans; Polycythemia; Polycythemia Vera; Janus Kinase 2; Thromboembolism
PubMed: 38356428
DOI: No ID Found