-
Blood Apr 2023
Topics: Humans; Polycythemia Vera; Iron; Myeloproliferative Disorders; Phenotype; Janus Kinase 2
PubMed: 37103951
DOI: 10.1182/blood.2023020065 -
Leukemia Oct 2023
Topics: Humans; Polycythemia Vera; Progression-Free Survival; Recombinant Proteins
PubMed: 37634011
DOI: 10.1038/s41375-023-02008-6 -
Cancer Dec 2023The rapid pace of drug development in hematology has led to multiple approvals for myelofibrosis (MF) and polycythemia vera (PV) in recent years. Moreover, there are...
The rapid pace of drug development in hematology has led to multiple approvals for myelofibrosis (MF) and polycythemia vera (PV) in recent years. Moreover, there are many innovative agents and combinations being explored for myeloproliferative neoplasms (MPNs). In the past year, there have been several advances in MF, PV, and essential thrombocythemia. In MF, investigational approaches are focusing on strategies to optimize inhibition of signal transduction (including JAK inhibition), modify epigenetics, enhance apoptosis, target DNA replication, transform host immunity, and/or alter the tumor microenvironment. In PV, ropeginterferon alfa-2b has been introduced to the market in the United States, and data continue to accumulate to support the safety and efficacy of this treatment. Hepcidin mimesis is also emerging as a novel way to treat erythrocytosis. In essential thrombocythemia, ropeginterferon alfa-2b is being evaluated, as are therapies to modify epigenetics and inhibit CALR. The enhanced focus on MPNs brings hope that our field can improve morbidity and mortality in this group of diseases.
Topics: Humans; United States; Thrombocythemia, Essential; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis; Signal Transduction; Tumor Microenvironment
PubMed: 37768996
DOI: 10.1002/cncr.35028 -
Genes Apr 2022Polycythemia vera belongs to myeloproliferative neoplasms, essentially by affecting the erythroblastic lineage. JAK2 alterations have emerged as major driver mutations... (Review)
Review
Polycythemia vera belongs to myeloproliferative neoplasms, essentially by affecting the erythroblastic lineage. JAK2 alterations have emerged as major driver mutations triggering PV-phenotype with the mutation detected in nearly 98% of cases. That's why JAK2 targeting therapeutic strategies have rapidly emerged to counter the aggravation of the disease. Over decades of research, to go further in the understanding of the disease and its evolution, a wide panel of genetic alterations affecting multiple genes has been highlighted. These are mainly involved in alternative splicing, epigenetic, miRNA regulation, intracellular signaling, and transcription factors expression. If JAK2 mutation, irrespective of the nature of the alteration, is known to be a crucial event for the disease to initiate, additional mutations seem to be markers of progression and poor prognosis. These discoveries have helped to characterize the complex genomic landscape of PV, resulting in potentially new adapted therapeutic strategies for patients concerning all the genetic interferences.
Topics: Genetic Background; Humans; Janus Kinase 2; Mutation; Myeloproliferative Disorders; Phenotype; Polycythemia Vera
PubMed: 35456443
DOI: 10.3390/genes13040637 -
Best Practice & Research. Clinical... Jun 2022Polycythemia vera (PV) is characterized by clonal proliferation of a hematopoietic stem cell leading to erythrocytosis. Patients with PV have significantly higher... (Review)
Review
Polycythemia vera (PV) is characterized by clonal proliferation of a hematopoietic stem cell leading to erythrocytosis. Patients with PV have significantly higher morbidity and mortality compared to the general population due to increased risk of thrombosis, hemorrhage, and well-characterized microvascular and constitutional symptoms. There is also a propensity to transform to myelofibrosis and to an aggressive form of acute leukemia, further increasing morbidity and mortality. Current management is aimed at reducing the risk of thromboembolic events and improving symptom burden; however, none of the existing therapies have proven the ability to deplete the underlying malignant clone, or definitively reduce the risk of disease, progression leaving a large area of unmet need. In this review, we highlight the pathophysiology of PV, current management and limitations therein. We propose highly debated clinical practices that require further investigation. We conclude by discussing therapies in development and how these may fill unmet needs and be incorporated into the future PV treatment paradigm.
Topics: Humans; Polycythemia Vera; Janus Kinase 2; Primary Myelofibrosis; Hemorrhage
PubMed: 36333064
DOI: 10.1016/j.beha.2022.101370 -
The New England Journal of Medicine Feb 2024Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide, an injectable peptide mimetic of the master iron regulatory... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide, an injectable peptide mimetic of the master iron regulatory hormone hepcidin, restricts the availability of iron for erythropoiesis. The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown.
METHODS
In part 1 of the international, phase 2 REVIVE trial, we enrolled patients in a 28-week dose-finding assessment of rusfertide. Part 2 was a double-blind, randomized withdrawal period in which we assigned patients, in a 1:1 ratio, to receive rusfertide or placebo for 12 weeks. The primary efficacy end point was a response, defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Patient-reported outcomes were assessed by means of the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary (scores range from 0 to 10, with higher scores indicating greater severity of symptoms).
RESULTS
Seventy patients were enrolled in part 1 of the trial, and 59 were assigned to receive rusfertide (30 patients) or placebo (29 patients) in part 2. The estimated mean (±SD) number of phlebotomies per year was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). The mean maximum hematocrit was 44.5±2.2% during part 1 as compared with 50.0±5.8% during the 28 weeks before the first dose of rusfertide. During part 2, a response was observed in 60% of the patients who received rusfertide as compared with 17% of those who received placebo (P = 0.002). Between baseline and the end of part 1, rusfertide treatment was associated with a decrease in individual symptom scores on the MPN-SAF in patients with moderate or severe symptoms at baseline. During parts 1 and 2, grade 3 adverse events occurred in 13% of the patients, and none of the patients had a grade 4 or 5 event. Injection-site reactions of grade 1 or 2 in severity were common.
CONCLUSIONS
In patients with polycythemia vera, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo. (Funded by Protagonist Therapeutics; REVIVE ClinicalTrials.gov number, NCT04057040.).
Topics: Humans; Hematocrit; Hepcidins; Iron; Polycythemia; Polycythemia Vera; Peptides; Injections; Double-Blind Method; Hematologic Agents
PubMed: 38381675
DOI: 10.1056/NEJMoa2308809 -
Expert Review of Hematology Apr 2023Significant advances have been made in the diagnosis and management of patients with polycythemia vera (PV) over the past two decades, but a few important issues remain,...
INTRODUCTION
Significant advances have been made in the diagnosis and management of patients with polycythemia vera (PV) over the past two decades, but a few important issues remain, either overlooked or controversial.
AREAS COVERED
We discuss making an accurate diagnosis of PV with careful interpretation of hematocrit values, red cell count, and red cell mass when available, and bone marrow histomorphology to distinguish PV from other myeloproliferative neoplasms (MPNs). We cover aspects of initial PV treatment with phlebotomy (PHL), its drawbacks in the long term, and alternative strategies. We comprehensively discuss cytoreductive therapy using interferon-alpha or hydroxyurea, with emphasis on patient selection, treatment goals, clinical endpoints, biomarkers and, most importantly, event-free and overall survival.
EXPERT OPINION
A bone marrow biopsy in PV is essential for diagnosis and baseline histomorphology. Both hematocrit and red cell counts should be controlled with both phlebotomy (PHL) and cytoreductive agents. PHL alone is often inadequate in the long term, and cytoreduction is needed for most. Interferon is our preferred first-line agent due to improved survival outcomes. Short-term biomarkers predictive of long-term outcomes are needed to guide optimal therapy and development of new treatments.
Topics: Humans; Polycythemia Vera; Hydroxyurea; Myeloproliferative Disorders; Janus Kinase 2; Bone Marrow; Interferon-alpha
PubMed: 37013802
DOI: 10.1080/17474086.2023.2198698 -
Current Hematologic Malignancy Reports Apr 2020Polycythemia vera is a myeloproliferative neoplasm characterized by increased erythrocyte count, thrombotic potential, and transformation to myelofibrosis. Older... (Review)
Review
PURPOSE OF REVIEW
Polycythemia vera is a myeloproliferative neoplasm characterized by increased erythrocyte count, thrombotic potential, and transformation to myelofibrosis. Older patients and those who have a history of thrombosis require cytoreductive therapy, most commonly with hydroxyurea. Other currently available therapies include pegylated interferon alfa-2a and the JAK1/2 inhibitor ruxolitinib. However, there are limitations to these agents, including potential detrimental adverse effects. In this review, we will describe current therapeutic options for the treatment of PV and then detail new agents with available clinical trial data.
RECENT FINDINGS
A number of novel investigational therapies including MDM2 inhibitors, histone deacetylase inhibitors, and long-acting pegylated interferon alfa-2b are in various stages of clinical development with encouraging efficacy data. The therapeutic landscape for patients with PV is expanding. Novel agents are in development that not only reduce the thrombotic potential but also act directly on the malignant PV clone with the intention of significantly modifying disease progression.
Topics: Antineoplastic Agents; Humans; Molecular Targeted Therapy; Polycythemia Vera; Signal Transduction; Treatment Outcome
PubMed: 32034662
DOI: 10.1007/s11899-020-00564-7 -
Vascular Health and Risk Management 2023Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by aberrant myeloid lineage hematopoiesis with excessive red blood cell and pro-inflammatory... (Review)
Review
Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by aberrant myeloid lineage hematopoiesis with excessive red blood cell and pro-inflammatory cytokine production. Patients with PV present with a range of thrombotic and hemorrhagic symptoms that affect quality of life and reduce overall survival expectancy. Thrombotic events, transformation into acute myeloid leukemia, and myelofibrosis are largely responsible for the observed mortality. Treatment of PV is thus primarily focused on symptom control and survival extension through the prevention of thrombosis and leukemic transformation. Patients with PV frequently experience thrombotic events and have elevated cardiovascular risk, including hypertension, dyslipidemias, obesity, and smoking, all of which negatively affect survival. To reduce the risk of thrombotic complications, PV therapy should aim to normalize hemoglobin, hematocrit, and leukocytosis and, in addition, identify and modify cardiovascular risk factors. Herein, we review what is currently known about the associated cardiovascular risk and propose strategies for diagnosing and managing patients with PV.
Topics: Humans; Polycythemia Vera; Cardiovascular Diseases; Quality of Life; Janus Kinase 2; Risk Factors; Thrombosis; Heart Disease Risk Factors
PubMed: 38025519
DOI: 10.2147/VHRM.S429995 -
Blood Nov 2023Polycythemia vera (PV) belongs to the BCR-ABL1-negative myeloproliferative neoplasms and is characterized by activating mutations in JAK2 and clinically presents with...
Polycythemia vera (PV) belongs to the BCR-ABL1-negative myeloproliferative neoplasms and is characterized by activating mutations in JAK2 and clinically presents with erythrocytosis, variable degrees of systemic and vasomotor symptoms, and an increased risk of both thromboembolic events and progression to myelofibrosis and acute myeloid leukemia (AML). Treatment selection is based on a patient's age and a history of thrombosis in patients with low-risk PV treated with therapeutic phlebotomy and aspirin alone, whereas cytoreductive therapy with either hydroxyurea or interferon alfa (IFN-α) is added for high-risk disease. However, other disease features such as significant disease-related symptoms and splenomegaly, concurrent thrombocytosis and leukocytosis, or intolerance of phlebotomy can constitute an indication for cytoreductive therapy in patients with otherwise low-risk disease. Additionally, recent studies demonstrating the safety and efficacy (ie, reduction in phlebotomy requirements and molecular responses) of ropegylated IFN-α2b support its use for patients with low-risk PV. Additionally, emerging data suggest that early treatment is associated with higher rates of molecular responses, which might eventually enable time-limited therapy. Nonetheless, longer follow-up is needed to assess whether molecular responses associate with clinically meaningful outcome measures such as thrombosis and progression to myelofibrosis or AML. In this article, we provide an overview of the current and evolving treatment landscape of PV and outline our vision for a patient-centered, phlebotomy-free, treatment approach using time-limited, disease-modifying treatment modalities early in the disease course, which could ultimately affect the natural history of the disease.
Topics: Humans; Polycythemia Vera; Primary Myelofibrosis; Thrombocytosis; Hydroxyurea; Thrombosis; Interferon-alpha; Leukemia, Myeloid, Acute; Janus Kinase 2
PubMed: 37729609
DOI: 10.1182/blood.2023021503