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Haematologica Oct 2023Under normal conditions, iron metabolism is carefully regulated to sustain normal cellular functions and the production of hemoglobin in erythroid cells. Perturbation to... (Review)
Review
Under normal conditions, iron metabolism is carefully regulated to sustain normal cellular functions and the production of hemoglobin in erythroid cells. Perturbation to the erythropoiesis-iron metabolism axis can result in iron imbalances and cause anemia or organ toxicity. Various congenital and acquired diseases associated with abnormal red cell production are characterized by aberrant iron absorption. Several recent studies have shown that improvements in red blood cell production also ameliorate iron metabolism and vice versa. Many therapeutics are now under development with the potential to improve a variety of hematologic diseases, from β-thalassemia and iron-refractory iron deficiency anemia to anemia of inflammation and polycythemia vera. This review summarizes selected mechanisms related to red cell production and iron metabolism and describes potential therapeutics and their current uses. We also consider the potential application of the discussed therapeutics on various diseases, alone or in combination. The vast repertoire of drugs under development offers new opportunities to improve the clinical care of patients suffering from congenital or acquired red blood cell disorders with limited or no treatment options.
Topics: Humans; Erythropoiesis; Erythrocytes; Anemia, Iron-Deficiency; Iron; beta-Thalassemia; Hematologic Diseases
PubMed: 37345473
DOI: 10.3324/haematol.2023.283057 -
Annals of Hematology Jul 2023The classic BCR-ABL1-negative myeloproliferative neoplasm (MPN) is a highly heterogeneous hematologic tumor that includes three subtypes, namely polycythemia vera (PV),...
The classic BCR-ABL1-negative myeloproliferative neoplasm (MPN) is a highly heterogeneous hematologic tumor that includes three subtypes, namely polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). Despite having the same JAK2 mutation, the clinical manifestations of these three subtypes of MPN differ significantly, which suggests that the bone marrow (BM) immune microenvironment may also play an important role. In recent years, several studies have shown that peripheral blood monocytes play an important role in promoting MPN. However, to date, the role of BM monocytes/macrophages in MPN and their transcriptomic alterations remain incompletely understood. The purpose of this study was to clarify the role of BM monocytes/macrophages in MPN patients with the JAK2 mutation. MPN patients with the JAK2 mutation were enrolled in this study. We investigated the roles of monocytes/macrophages in the BM of MPN patients, using flow cytometry, monocyte/macrophage enrichment sorting, cytospins and Giemsa-Wright staining, and RNA-seq. Pearson correlation coefficient analysis was also used to detect the correlation between BM monocytes/macrophages and the MPN phenotype. In the present study, the proportion of CD163 monocytes/macrophages increased significantly in all three subtypes of MPN. Interestingly, the percentages of CD163 monocytes/macrophages are positively correlated with HGB in PV patients and PLT in ET patients. In contrast, the percentages of CD163 monocytes/macrophages are negatively correlated with HGB and PLT in PMF patients. It was also found that CD14CD16 monocytes/macrophages increased and correlated with MPN clinical phenotypes. RNA-seq analyses demonstrated that the transcriptional expressions of monocytes/macrophages in MPN patients are relatively distinct. Gene expression profiles of BM monocytes/macrophages suggest a specialized function in support of megakaryopoiesis in ET patients. In contrast, BM monocytes/macrophages yielded a heterogeneous status in the support or inhibition of erythropoiesis. Significantly, BM monocytes/macrophages shaped an inflammatory microenvironment, which, in turn, promotes myelofibrosis. Thus, we characterized the roles of increased monocytes/macrophages in the occurrence and progression of MPNs. Our findings of the comprehensive transcriptomic characterization of BM monocytes/macrophages provide important resources to serve as a basis for future studies and future targets for the treatment of MPN patients.
Topics: Humans; Bone Marrow; Monocytes; Myeloproliferative Disorders; Polycythemia Vera; Mutation; Bone Marrow Neoplasms; Thrombocythemia, Essential; Janus Kinase 2; Tumor Microenvironment
PubMed: 37233774
DOI: 10.1007/s00277-023-05284-5 -
Annals of Hematology Jun 2024Ruxolitinib is beneficial in patients with myelofibrosis (MF) and polycythemia vera (PV). Information on ruxolitinib adherence is scant. The Ruxolitinib Adherence in... (Clinical Trial)
Clinical Trial
Ruxolitinib is beneficial in patients with myelofibrosis (MF) and polycythemia vera (PV). Information on ruxolitinib adherence is scant. The Ruxolitinib Adherence in Myelofibrosis and Polycythemia Vera (RAMP) prospective multicenter study (NCT06078319) included 189 ruxolitinib-treated patients. Patients completed the Adherence to Refills and Medications Scale (ARMS) and Distress Thermometer and Problem List (DTPL) at the earliest convenience, after registration in the study, and at later timepoints. At week-0, low adherence (ARMS > 14) and high distress (DT ≥ 4) were declared by 49.7% and 40.2% of patients, respectively. The main reason for low adherence was difficult ruxolitinib supply (49%), intentional (4.3%) and unintentional (46.7%) non-take. In multivariable regression analysis, low adherence was associated to male sex (p = 0.001), high distress (p < 0.001), and treatment duration ≥ 1 year (p = 0.03). Over time, rates of low adherence and high distress remained stable, but unintentional non-take decreased from 47.9% to 26.0% at week-48. MF patients with stable high adherence/low distress were more likely to obtain/maintain the spleen response at week-24. Low adherence to ruxolitinib represents an unmet clinical need that require a multifaceted approach, based on reason behind it (patients characteristics and treatment duration). Its recognition may help distinguishing patients who are truly refractory and those in need of therapy optimization.
Topics: Humans; Primary Myelofibrosis; Nitriles; Pyrimidines; Pyrazoles; Male; Polycythemia Vera; Female; Prospective Studies; Aged; Middle Aged; Italy; Medication Adherence; Aged, 80 and over; Adult
PubMed: 38478023
DOI: 10.1007/s00277-024-05704-0 -
Cancers Aug 2023Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) arise due to acquired somatic driver mutations in stem cells and develop over 10-30 years... (Review)
Review
Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) arise due to acquired somatic driver mutations in stem cells and develop over 10-30 years from the earliest cancer stages (essential thrombocythemia, polycythemia vera) towards the advanced myelofibrosis stage with bone marrow failure. The mutation is the most prevalent driver mutation. Chronic inflammation is considered to be a major pathogenetic player, both as a trigger of MPN development and as a driver of disease progression. Chronic inflammation in MPNs is characterized by persistent connective tissue remodeling, which leads to organ dysfunction and ultimately, organ failure, due to excessive accumulation of extracellular matrix (ECM). Considering that MPNs are acquired clonal stem cell diseases developing in an inflammatory microenvironment in which the hematopoietic cell populations are progressively replaced by stromal proliferation-"a wound that never heals"-we herein aim to provide a comprehensive review of previous promising research in the field of circulating ECM fragments in the diagnosis, treatment and monitoring of MPNs. We address the rationales and highlight new perspectives for the use of circulating ECM protein fragments as biologically plausible, noninvasive disease markers in the management of MPNs.
PubMed: 37686599
DOI: 10.3390/cancers15174323 -
International Journal of Molecular... Oct 2023Splanchnic vein thrombosis (SVT) encompasses thrombosis in the vessels of the splanchnic basin and has a relatively rare occurrence with a reported frequency in the... (Review)
Review
Splanchnic vein thrombosis (SVT) encompasses thrombosis in the vessels of the splanchnic basin and has a relatively rare occurrence with a reported frequency in the general population of 1-2%. An episode of seemingly unprovoked SVT almost always triggers a diagnostic work-up for a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN), since atypical site thrombosis is a hallmark of MPN-associated thrombophilia. Primary myelofibrosis (PMF) is a rare MPN with an estimated incidence between 0.1 and 1/100,000 per year. Although prothrombotic tendency in PMF is not envisioned as a subject of specific therapeutic management, unlike other MPNs, such as polycythemia vera (PV) and essential thrombocythemia (ET), thrombotic risk and SVT prevalence in PMF may be comparably high. Additionally, unlike PV and ET, SVT development in PMF may depend more on procoagulant mechanisms involving endothelium than on blood cell activation. Emerging results from registry data also suggest that PMF patients with SVT may exhibit lower risk and better prognosis, thus highlighting the need for better thrombotic risk stratification and identifying a subset of patients with potential benefit from antithrombotic prophylaxis. This review highlights specific epidemiological, pathogenetic, and clinical features pertinent to SVT in myelofibrosis.
Topics: Humans; Primary Myelofibrosis; Myeloproliferative Disorders; Venous Thrombosis; Polycythemia Vera; Thrombosis; Thrombocythemia, Essential; Phenotype
PubMed: 37958701
DOI: 10.3390/ijms242115717 -
Turkish Journal of Haematology :... Aug 2023The impact of allele burden on clinical course in Philadelphia-negative (Ph-negative) myeloproliferative neoplasms (MPNs) is not clear. We analyzed the clinical impact...
OBJECTIVE
The impact of allele burden on clinical course in Philadelphia-negative (Ph-negative) myeloproliferative neoplasms (MPNs) is not clear. We analyzed the clinical impact of allele burden in a relatively large series of patients with Ph-negative MPNs and long-term follow-up.
MATERIALS AND METHODS
A total of 228 patients with Ph-negative MPNs, including 118 with essential thrombocythemia (ET), 84 with primary myelofibrosis (PMF), and 26 with polycythemia vera (PV), were analyzed. The JAK2 MutaScreen assay was used to quantify allele burden in genomic DNA.
RESULTS
In PV cases, high allele burden was associated with a trend towards inferior overall survival. In ET, high allele burden was associated with lower hemoglobin and hematocrit levels, higher lactate dehydrogenase (LDH) levels, larger spleen size, and increased bleeding and mortality rates. In PMF, high allele burden was associated with higher leukocyte counts and larger spleen size. In the entire cohort, high allele burden was associated with higher leukocyte and lower platelet counts, higher LDH levels, larger spleen size, higher percentage of bleeding events, higher death rate, and inferior overall survival.
CONCLUSION
Our results suggest that high allele burdens are associated with more severe disease in PV and ET. In PMF, high allele burdens were associated with more pronounced myeloproliferative phenotypes. In Ph-negative MPNs, high allele burdens were associated with more aggressive phenotypes. Our data with a long follow-up period support the possibility of allele burden being used as a marker for predicting clinical phenotype in cases of Ph-negative MPNs.
Topics: Humans; Alleles; Primary Myelofibrosis; Myeloproliferative Disorders; Polycythemia Vera; Thrombocythemia, Essential; Splenomegaly; Janus Kinase 2; Mutation
PubMed: 37584526
DOI: 10.4274/tjh.galenos.2023.2023.0169 -
Nature Cancer Aug 2023Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis-related somatic mutations and the development of myeloid malignancies,...
Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis-related somatic mutations and the development of myeloid malignancies, such as myeloproliferative neoplasms (MPNs). While cooperating mutations can cause transformation, it is unclear whether distinct bone marrow (BM) HSC-niches can influence the growth and therapy response of HSCs carrying the same oncogenic driver. Here we found different BM niches for HSCs in MPN subtypes. JAK-STAT signaling differentially regulates CDC42-dependent HSC polarity, niche interaction and mutant cell expansion. Asymmetric HSC distribution causes differential BM niche remodeling: sinusoidal dilation in polycythemia vera and endosteal niche expansion in essential thrombocythemia. MPN development accelerates in a prematurely aged BM microenvironment, suggesting that the specialized niche can modulate mutant cell expansion. Finally, dissimilar HSC-niche interactions underpin variable clinical response to JAK inhibitor. Therefore, HSC-niche interactions influence the expansion rate and therapy response of cells carrying the same clonal hematopoiesis oncogenic driver.
Topics: Humans; Aged; Myeloproliferative Disorders; Bone Marrow; Hematopoietic Stem Cells; Bone and Bones; Neoplasms; Tumor Microenvironment
PubMed: 37550517
DOI: 10.1038/s43018-023-00607-x -
Cancer Medicine Sep 2023Polycythemia vera (PV) and essential thrombocythemia (ET) are linked to increased risk of cardiovascular morbidity and mortality. In addition to the reduction in of...
BACKGROUND
Polycythemia vera (PV) and essential thrombocythemia (ET) are linked to increased risk of cardiovascular morbidity and mortality. In addition to the reduction in of arterial thrombotic events, statins may prevent venous thrombosis including among patients with cancer. As previous registry- and claims-based studies revealed that the use of statins may improve the survival of patients with various malignancies we evaluated their impact on outcomes of older adults with PV and ET.
METHODS
We identified 4010 older adults (aged 66-99 years at diagnosis) with PV (n = 1809) and ET (n = 2201) in a population-based cohort study using the Surveillance, Epidemiology, and End Results-Medicare database with median follow-up of 3.92 (interquartile range: 2.58-5.75) years. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) approaches were utilized to assess potential association between statins and overall survival. Multivariable competing risk models with death as a competing risk were used to evaluate possible relationship between statins and the incidence of thrombosis.
RESULTS
55.8% of the patients used statins within the first year after PV/ET diagnosis, and statin use was associated with a 22% reduction in all-cause mortality (PSM: hazard ratio [HR] = 0.78, 95% confidence interval [CI]: 0.63-0.98, p = 0.03; IPTW: HR = 0.79, 95% CI: 0.64-0.97, p = 0.03). Statins also reduced the risk of thrombosis in this patient population (PSM: HR = 0.63, 95% CI: 0.51-0.78, p < 0.01; IPTW: HR = 0.57, 95% CI: 0.49-0.66, p < 0.01) as well as in PV and ET subgroups.
CONCLUSIONS
These findings suggest that it may be important to incorporate statins into the therapeutic strategy for older adults with PV and ET.
Topics: United States; Humans; Aged; Polycythemia Vera; Thrombocythemia, Essential; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Cohort Studies; Risk Factors; Medicare; Thrombosis
PubMed: 37702132
DOI: 10.1002/cam4.6528 -
Clinical Cardiology Jan 2024Pulmonary arterial hypertension (PAH) is a widespread condition that affects around 1% of the global population, with a higher prevalence among older individuals. The... (Meta-Analysis)
Meta-Analysis Review
Pulmonary arterial hypertension (PAH) is a widespread condition that affects around 1% of the global population, with a higher prevalence among older individuals. The approach to managing PAH has undergone significant changes, requiring extensive treatment strategies. Sotatercept, an FDA-approved medication, has recently attracted attention for its potential role in PAH therapy. However, information on its safety and effectiveness is scarce. In this study, we performed a meta-analysis of existing randomized clinical trials to assess the impact of Sotatercept on PAH patients. Our findings revealed that those treated with Sotatercept showed greater improvement in pulmonary vascular resistance and World Health Organization functional class compared with placebo recipients. The occurrence of adverse events was similar between both groups. Importantly, the Sotatercept group displayed a considerably higher number of cases with an increase in hemoglobin levels. Considering that about 33% of PAH patients experience anemia and both anemia and polycythemia can adversely affect disease prognosis, additional research is necessary to establish the potential advantages and disadvantages of Sotatercept as a treatment choice, specifically regarding its erythropoietic properties.
Topics: Humans; Anemia; Prognosis; Pulmonary Arterial Hypertension; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins
PubMed: 37819149
DOI: 10.1002/clc.24173 -
International Journal of Molecular... Aug 2023The Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis... (Review)
Review
The Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are enduring and well-known conditions. These disorders are characterized by the abnormal growth of one or more hematopoietic cell lineages in the body's stem cells, leading to the enlargement of organs and the manifestation of constitutional symptoms. Numerous studies have provided evidence indicating that the pathogenesis of these diseases involves the dysregulation of the immune system and the presence of chronic inflammation, both of which are significant factors. Lately, the treatment of cancer including hematological malignancy has progressed on the agents aiming for the immune system, cytokine environment, immunotherapy agents, and targeted immune therapy. Immune checkpoints are the molecules that regulate T cell function in the tumor microenvironment (TME). The first line of primary immune checkpoints are programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4). Immune checkpoint inhibitor therapy (ICIT) exerts its anti-tumor actions by blocking the inhibitory pathways in T cells and has reformed cancer treatment. Despite the impressive clinical success of ICIT, tumor internal resistance poses a challenge for oncologists leading to a low response rate in solid tumors and hematological malignancies. A Phase II trial on nivolumab for patients with post-essential thrombocythemia myelofibrosis, primary myelofibrosis, or post-polycythemia myelofibrosis was performed (Identifier: NCT02421354). This trial tested the efficacy of a PD-1 blockade agent, namely nivolumab, but was terminated prematurely due to adverse events and lack of efficacy. A multicenter, Phase II, single-arm open-label study was conducted including pembrolizumab in patients with primary thrombocythemia, post-essential thrombocythemia or post-polycythemia vera myelofibrosis that were ineligible for or were previously treated with ruxolitinib. This study showed that pembrolizumab treatment did not have many adverse events, but there were no pertinent clinical responses hence it was terminated after the first stage was completed. To avail the benefits from immunotherapy, the paradigm has shifted to new immune checkpoints in the TME such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain immunoglobulin-containing suppressor of T cell activation (VISTA), and human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) forming the basis of next-generation ICIT. The primary aim of this article is to underscore and elucidate the significance of next-generation ICIT in the context of MPN. Specifically, we aim to explore the potential of monoclonal antibodies as targeted immunotherapy and the development of vaccines targeting specific MPN epitopes, with the intent of augmenting tumor-related immune responses. It is anticipated that these therapeutic modalities rooted in immunotherapy will not only expand but also enhance the existing treatment regimens for patients afflicted with MPN. Preliminary studies from our laboratory showed over-expressed MDSC and over-expressed VISTA in MDSC, and in progenitor and immune cells directing the need for more clinical trials using next-generation ICI in the treatment of MPN.
PubMed: 37569880
DOI: 10.3390/ijms241512502