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Expert Opinion on Pharmacotherapy 2024As an increasingly popular therapeutic option, testosterone replacement therapy (TRT) has gained significant notoriety for its health benefits in indicated populations,... (Review)
Review
INTRODUCTION
As an increasingly popular therapeutic option, testosterone replacement therapy (TRT) has gained significant notoriety for its health benefits in indicated populations, such as those suffering from hypogonadism.
AREAS COVERED
Benefits such as improved libido, muscle mass, cognition, and quality of life have led to widened public interest in testosterone as a health supplement. No therapy exists without side effects; testosterone replacement therapy has been associated with side effects such as an increased risk of polycythemia, benign prostate hypertrophy (BPH), prostate cancer, gynecomastia, testicular atrophy, and infertility. Testosterone replacement therapy is often accompanied by several prophylactic co-therapies aimed at reducing the prevalence of these side effects. Literature searches for sections on the clinical benefits and risks associated with TRT were performed to include clinical trials, meta-analyses, and systematic reviews from the last 10 years.
EXPERT OPINION
Data from clinical studies over the last decade suggest that the benefits of this therapy outweigh the risks and result in overall increased quality of life and remission of symptoms related to hypogonadism. With this in mind, the authors of this review suggest that carefully designed clinical trials are warranted for the investigation of TRT in symptomatic age-related hypogonadism.
Topics: Male; Humans; Quality of Life; Testosterone; Hypogonadism; Prostatic Neoplasms; Libido
PubMed: 38229462
DOI: 10.1080/14656566.2024.2306832 -
World Journal of Cardiology Nov 2023Myeloproliferative neoplasms (MPNs) are a heterogeneous group of hematologic malignancies characterized by an abnormal proliferation of cells of the myeloid lineage.... (Review)
Review
Myeloproliferative neoplasms (MPNs) are a heterogeneous group of hematologic malignancies characterized by an abnormal proliferation of cells of the myeloid lineage. Affected individuals are at increased risk for cardiovascular and thrombotic events. Myocardial infarction (MI) may be one of the earliest clinical manifestations of MPNs or may be a thrombotic complication that develops during the natural course of the disease. In the present review, we examine the epidemiology, pathogenesis, clinical presentation, and management of MI in MPNs based on the available literature. Moreover, we review potential biomarkers that could mediate the MI-MPNs crosstalk, from classical biochemical tests, , lactate dehydrogenase, creatine kinase and troponins, to pro-inflammatory cytokines, oxidative stress markers, and clonal hematopoiesis.
PubMed: 38058401
DOI: 10.4330/wjc.v15.i11.571 -
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 -
Leukemia Oct 2023
Topics: Humans; Polycythemia Vera; Progression-Free Survival; Recombinant Proteins
PubMed: 37634011
DOI: 10.1038/s41375-023-02008-6 -
Faculty Reviews 2023Primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET) form the classical -negative myeloproliferative neoplasms (MPNs) that are driven... (Review)
Review
Primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET) form the classical -negative myeloproliferative neoplasms (MPNs) that are driven by a constitutive activation of JAK2 signaling. PMF as well as secondary MF (post-ET and post-PV MF) are the most aggressive MPNs. Presently, there is no curative treatment, except allogenic hematopoietic stem cell transplantation. JAK inhibitors, essentially ruxolitinib, are the therapy of reference for intermediate and high-risk MF. However, presently the current JAK inhibitors behave mainly as anti-inflammatory drugs, improving general symptoms and spleen size without major impact on disease progression. A better understanding of the genetics of MF, the biology of its leukemic stem cells (LSCs), the mechanisms of fibrosis and of cytopenia and the role of inflammatory cytokines has led to new approaches with the development of numerous therapeutic agents that target epigenetic regulation, telomerase, apoptosis, cell cycle, cytokines and signaling. Furthermore, the use of a new less toxic form of interferon-α has been revived, as it is presently one of the only molecules that targets the mutated clone. These new approaches have different aims: (a) to provide alternative therapy to JAK inhibition; (b) to correct cytopenia; and (c) to inhibit fibrosis development. However, the main important goal is to find new disease modifier treatments, which will profoundly modify the progression of the disease without major toxicity. Presently the most promising approaches consist of the inhibition of telomerase and the combination of JAK2 inhibitors (ruxolitinib) with either a BCL2/BCL-xL or BET inhibitor. Yet, the most straightforward future approaches can be considered to be the development of and/or selective inhibition of JAK2V617F and the targeting MPL and calreticulin mutants by immunotherapy. It can be expected that the therapy of MF will be significantly improved in the coming years.
PubMed: 37771602
DOI: 10.12703/r/12-23 -
Leukemia & Lymphoma Jun 2024There has been remarkable progress in the development of novel therapeutic approaches for patients with polycythemia vera (PV). Historically, therapy goals in PV were to... (Review)
Review
There has been remarkable progress in the development of novel therapeutic approaches for patients with polycythemia vera (PV). Historically, therapy goals in PV were to mitigate thrombotic risks and control blood counts and symptoms. There is now increased focus on disease modification through progressive attrition of -mutant stem/progenitor cells. The approval of ropeginterferon, a novel monoPEGylated interferon, coupled with findings from LOW-PV and longer-term data from CONTINUATION-PV that strongly support a disease-modifying effect for interferon therapy, have transformed the treatment paradigm for this disorder. Results from MAJIC-PV demonstrate that disease modification can also be induced with JAK inhibitors, suggesting an urgent need to incorporate prospective molecular monitoring into PV trials. Novel agents, such as hepcidin mimetics, aim to help patients with PV restore normal hematocrit levels and become phlebotomy-free. In this review, we will summarize past, current and future approaches to PV management and highlight findings from key clinical studies.
PubMed: 38871488
DOI: 10.1080/10428194.2024.2361836 -
American Journal of Therapeutics
Topics: Humans; Polycythemia; Phenylurea Compounds; Quinolines
PubMed: 36989234
DOI: 10.1097/MJT.0000000000001606 -
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 -
ELife Aug 2023Erythroblasts possess unique characteristics as they undergo differentiation from hematopoietic stem cells. During terminal erythropoiesis, these cells incorporate large...
Erythroblasts possess unique characteristics as they undergo differentiation from hematopoietic stem cells. During terminal erythropoiesis, these cells incorporate large amounts of iron in order to generate hemoglobin and ultimately undergo enucleation to become mature red blood cells, ultimately delivering oxygen in the circulation. Thus, erythropoiesis is a finely tuned, multifaceted process requiring numerous properly timed physiological events to maintain efficient production of 2 million red blood cells per second in steady state. Iron is required for normal functioning in all human cells, the erythropoietic compartment consuming the majority in light of the high iron requirements for hemoglobin synthesis. Recent evidence regarding the crosstalk between erythropoiesis and iron metabolism sheds light on the regulation of iron availability by erythroblasts and the consequences of insufficient as well as excess iron on erythroid lineage proliferation and differentiation. In addition, significant progress has been made in our understanding of dysregulated iron metabolism in various congenital and acquired malignant and non-malignant diseases. Finally, we report several actual as well as theoretical opportunities for translating the recently acquired robust mechanistic understanding of iron metabolism regulation to improve management of patients with disordered erythropoiesis, such as anemia of chronic inflammation, β-thalassemia, polycythemia vera, and myelodysplastic syndromes.
Topics: Humans; Erythropoiesis; Erythrocytes; Iron; beta-Thalassemia; Hemoglobins
PubMed: 37578340
DOI: 10.7554/eLife.90189 -
American Journal of Kidney Diseases :... Apr 2024Erythrocytosis or polycythemia is defined as an increase in red blood cell concentration above the age- and sex-specific normal levels. Unlike anemia, which is very... (Review)
Review
Erythrocytosis or polycythemia is defined as an increase in red blood cell concentration above the age- and sex-specific normal levels. Unlike anemia, which is very common in patients with chronic kidney disease (CKD), erythrocytosis is less frequent but requires specific understanding by health care professionals in order to provide the best care. Erythrocytosis, especially when undiagnosed and untreated, can lead to serious thrombotic events and higher mortality. Classic causes of erythrocytosis associated with CKD include cystic kidney diseases, kidney or other erythropoietin-secreting neoplasms, high-altitude renal syndrome, overdosage of erythropoietin-stimulating agents, androgen therapy, heavy smoking, chronic lung disease, obstructive sleep apnea, IgA nephropathy, post-kidney transplant erythrocytosis, renal artery stenosis, and congenital etiologies. After ruling out the common acquired causes of erythrocytosis and/or in the presence of suggestive parameters, primary erythrocytosis or polycythemia vera (PV) should be considered, and patients should be screened for JAK2V617F somatic mutation. The newest entity inducing erythrocytosis is linked to the use of sodium/glucose cotransporter 2 (SGLT2) inhibitors that hypothetically activate hypoxia-inducible factor 2α (HIF-2α) and in some cases unmask PV. This Review focuses on the pathogenesis, renal manifestations and management of PV, the pathophysiology of erythrocytosis induced by SGLT2 inhibitors and the relevance of timely JAK2 mutation screening in these patients.
PubMed: 38621632
DOI: 10.1053/j.ajkd.2024.02.015