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Blood Sep 2022
Topics: Humans; Primary Myelofibrosis
PubMed: 36173658
DOI: 10.1182/blood.2022015663 -
Cancer Mar 2016Primary myelofibrosis, the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), is a clonal disorder characterized by... (Review)
Review
Primary myelofibrosis, the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), is a clonal disorder characterized by often debilitating constitutional symptoms and splenomegaly, bone marrow fibrosis and resultant cytopenias, extramedullary hematopoiesis, risk of leukemic transformation, and shortened survival. Post-polycythemia vera and post-essential thrombocythemia myelofibrosis represent similar entities, although some differences are being recognized. Attempts to classify patients with myelofibrosis into prognostic categories have been made since the late 1980s, and these scoring systems continue to evolve as new information becomes available. Over the last decade, the molecular pathogenesis of MPNs has been elucidated considerably, and the Janus kinase (JAK) 1/2 inhibitor ruxolitinib is the first drug specifically approved by the US Food and Drug Administration to treat patients with intermediate-risk and high-risk myelofibrosis. This article reviews the evolution of prognostic criteria in myelofibrosis, emphasizing the major systems widely in use today, as well as recently described, novel systems that incorporate emerging data regarding somatic mutations. Risk factors for thrombosis and conversion to MPN blast phase also are discussed. Finally, the practical usefulness of the current prognostic classification systems in terms of clinical decision making is discussed, particularly within the context of some of their inherent weaknesses. Cancer 2016;122:681-692. © 2015 American Cancer Society.
Topics: Age Factors; Blast Crisis; Clinical Decision-Making; Hemoglobins; Humans; Leukocyte Count; Primary Myelofibrosis; Prognosis; Risk Factors; Thrombosis
PubMed: 26717494
DOI: 10.1002/cncr.29842 -
The Oncologist Oct 2015Primary myelofibrosis is a stem cell-derived clonal malignancy characterized by unchecked proliferation of myeloid cells, resulting in bone marrow fibrosis,... (Review)
Review
Primary myelofibrosis is a stem cell-derived clonal malignancy characterized by unchecked proliferation of myeloid cells, resulting in bone marrow fibrosis, osteosclerosis, and pathologic angiogenesis. Bone marrow fibrosis (BMF) plays a central role in the pathophysiology of the disease. This review describes current issues regarding BMF in primary myelofibrosis, including the pathophysiology and impact of abnormal deposition of excess collagen and reticulin fibers in bone marrow spaces, the modified Bauermeister and the European Consensus grading systems of BMF, and the prognostic impact of BMF on the overall outcome of patients with primary myelofibrosis. The impact of novel therapeutic strategies, including JAK-STAT inhibitors and allogeneic stem cell transplant, on BMF is discussed.
Topics: Bone Marrow Cells; Busulfan; Fibrosis; Humans; Janus Kinases; Nitriles; Primary Myelofibrosis; Prognosis; Pyrazoles; Pyrimidines; STAT Transcription Factors; Stem Cell Transplantation
PubMed: 26304912
DOI: 10.1634/theoncologist.2015-0094 -
Journal of Thrombosis and Haemostasis :... Apr 2020The risk of thromboembolism in myelofibrosis remains incompletely understood.
BACKGROUND
The risk of thromboembolism in myelofibrosis remains incompletely understood.
OBJECTIVES
To examine the association between myelofibrosis and each of venous and arterial thromboembolism.
METHODS
A cohort of 1 469 790 adults without a diagnosis of myelofibrosis was identified on 1 January 2007, from the electronic medical records of the largest health-care provider in Israel. Participants were followed until 31 December 2016 for the occurrence of myelofibrosis. Four randomly selected controls (without myelofibrosis) were matched to each case of myelofibrosis on age, sex, religious identification, and index date. The two groups were followed from the index date until 31 December 2017 for the occurrence of venous and arterial thromboembolism.
RESULTS
The study included 642 patients with myelofibrosis and 2568 matched controls. Myelofibrosis was independently associated with increased risk of venous thromboembolism but not with arterial thromboembolism. The propensity score adjusted hazard ratios (HRs) were 6.88 (95% confidence interval [CI], 2.02-23.45) for venous thromboembolism, and 0.94 (0.49-1.77) for arterial thromboembolism. Atypical sites of venous thromboembolism occurred almost exclusively in patients with myelofibrosis (four events of Budd Chiari versus none, and two mesenteric vein thrombosis events versus one) and were more likely to occur around the time of myelofibrosis diagnosis. No significant association was found between JAK2 inhibitor treatment (ruxolitinib) and the risk of venous HR 0.97 (0.30-3.12) or arterial thromboembolism 1.68 (0.78-3.62).
CONCLUSIONS
Myelofibrosis is associated with increased risk of venous thromboembolism but not of arterial thromboembolism. Atypical sites of venous thromboembolism are more frequent in myelofibrosis and are more likely to occur shortly after diagnosis.
Topics: Adult; Cohort Studies; Humans; Israel; Primary Myelofibrosis; Retrospective Studies; Risk Factors; Venous Thromboembolism
PubMed: 32017387
DOI: 10.1111/jth.14754 -
Journal of Translational Medicine Oct 2023Bone marrow fibrosis represents an important structural change in the marrow that interferes with some of its normal functions. The aetiopathogenesis of fibrosis is not... (Review)
Review
Bone marrow fibrosis represents an important structural change in the marrow that interferes with some of its normal functions. The aetiopathogenesis of fibrosis is not well established except in its primary form. The present review consolidates current understanding of marrow fibrosis. We searched PubMed without time restriction using key words: bone marrow and fibrosis as the main stem against the terms: growth factors, cytokines and chemokines, morphology, megakaryocytes and platelets, myeloproliferative disorders, myelodysplastic syndrome, collagen biosynthesis, mesenchymal stem cells, vitamins and minerals and hormones, and mechanism of tissue fibrosis. Tissue marrow fibrosis-related papers were short listed and analysed for the review. It emerged that bone marrow fibrosis is the outcome of complex interactions between growth factors, cytokines, chemokines and hormones together with their facilitators and inhibitors. Fibrogenesis is initiated by mobilisation of special immunophenotypic subsets of mesenchymal stem cells in the marrow that transform into fibroblasts. Fibrogenic stimuli may arise from neoplastic haemopoietic or non-hematopoietic cells, as well as immune cells involved in infections and inflammatory conditions. Autoimmunity is involved in a small subset of patients with marrow fibrosis. Megakaryocytes and platelets are either directly involved or are important intermediaries in stimulating mesenchymal stem cells. MMPs, TIMPs, TGF-β, PDGRF, and basic FGF and CRCXL4 chemokines are involved in these processes. Genetic and epigenetic changes underlie many of these conditions.
Topics: Humans; Bone Marrow; Primary Myelofibrosis; Cytokines; Fibrosis; Chemokines; Hormones
PubMed: 37814319
DOI: 10.1186/s12967-023-04393-z -
Cancer Control : Journal of the Moffitt... Oct 2012Myelofibrosis (MF) is a rare and serious hematologic malignancy classified as a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN). The disease is more... (Review)
Review
BACKGROUND
Myelofibrosis (MF) is a rare and serious hematologic malignancy classified as a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN). The disease is more common in males and in older individuals. Of the MPNs, MF presents with the most severe morbidity and greatest mortality. Although the cause of MF is unknown, it is thought to occur from acquired mutations that target the hematopoietic stem cell.
METHODS
We reviewed the current literature pertaining to the pathophysiology, clinical presentation, diagnosis, risk stratification, and treatment of MF. The strengths and limitations of present treatment options as well as the emerging clinical experience with Janus kinase 2 (JAK2) inhibitors are explored.
RESULTS
Diagnosis is often one of exclusion and is facilitated using the World Health Organization or International Working Group for Myelofibrosis Research and Treatment criteria, depending on whether primary or secondary MF is suspected. Treatment is complicated by a lack of disease familiarity of general practitioners and the advanced age of presenting patients. Although allogeneic stem cell transplant offers a potential cure, most treatments for this condition are limited to symptomatic management, with little to no effect on survival. Appropriate patient assessment and risk stratification are essential for predicting outcomes and allowing treating physicians to tailor therapy accordingly.
CONCLUSIONS
Significant advances have been made in understanding the pathophysiology of MF, leading to novel therapeutic approaches. The discovery of the JAK2 mutation and the development of JAK2 inhibitors provide clinicians with a new effective treatment option. Ruxolitinib is the first JAK1/2 inhibitor approved by the Food and Drug Administration (FDA) for the treatment of patients with intermediate- or high-risk MF. In clinical studies, ruxolitinib produced a significantly greater reduction in spleen size and improved quality of life compared with placebo or best available therapy. Several future therapies, including combination therapies with ruxolitinib, are currently under investigation.
Topics: Age Distribution; Enzyme Inhibitors; Humans; Janus Kinase 2; Nitriles; Primary Myelofibrosis; Pyrazoles; Pyrimidines; Risk Factors; Sex Distribution
PubMed: 23042420
DOI: 10.1177/107327481201904s04 -
Blood Reviews Jul 2020The myeloproliferative neoplasms (MPNs) encompass a heterogenous set of diseases that have variable survival, but in the setting of treatment refractory and progressive... (Review)
Review
The myeloproliferative neoplasms (MPNs) encompass a heterogenous set of diseases that have variable survival, but in the setting of treatment refractory and progressive disease, prognosis has been characteristically poor. JAK inhibition with ruxolitinib or fedratinib therapy has become the first line treatment for symptomatic or intermediate to high risk myelofibrosis. However, after three years of ruxolitinib therapy, approximately half of all patients with myelofibrosis will likely have stopped treatment. JAK inhibition failure represents a mixture of etiologies, including drug intolerance, suboptimal dosing, drug resistance, or progression of disease. JAK inhibition failure and accelerated/blast phase have now become the primary clinical challenges in the treatment of myelofibrosis and high risk polycythemia vera, and no phase III trials or clear treatment guidelines exist to guide management strategies in this setting. On the other hand, this represents an exciting time in treatment of JAK inhibitor failure and accelerated phase MPNs due to the advent of recently approved drugs as well as new targeted agents currently under investigation. In this article, we review the management options for these challenging clinical scenarios. We discuss the options for JAK inhibitor dose optimization and overcoming resistance by utilizing combinations of JAK inhibition, primarily ruxolitinib, with alternative commercially available therapies. For patients who have progressed, we discuss recent data regarding targeted therapy options approved for AML that represent potentially efficacious options in the progressive MPN setting. We also discuss the new clinical agents under development in MF and accelerated MPNs that may offer new therapeutic options in the years to come.
Topics: Animals; Disease Management; Disease Progression; Humans; Janus Kinase Inhibitors; Primary Myelofibrosis; Treatment Failure
PubMed: 32593470
DOI: 10.1016/j.blre.2020.100716 -
The Korean Journal of Internal Medicine Jul 2018Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) in which dysregulation of the Janus kinase/signal transducers and activators of transcription... (Review)
Review
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) in which dysregulation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways is the major pathogenic mechanism. Most patients with PMF carry a driver mutation in the JAK2, MPL (myeloproliferative leukemia), or CALR (calreticulin) genes. Mutations in epigenetic regulators and RNA splicing genes may also occur, and play critical roles in PMF disease progression. Based on revised World Health Organization diagnostic criteria for MPNs, both screening for driver mutations and bone marrow biopsy are required for a specific diagnosis. Clinical trials of JAK2 inhibitors for PMF have revealed significant efficacy for improving splenomegaly and constitutional symptoms. However, the currently available drug therapies for PMF do not improve survival. Although allogeneic stem cell transplantation is potentially curative, it is associated with substantial treatment-related morbidity and mortality. PMF is a heterogeneous disorder and decisions regarding treatments are often complicated, necessitating the use of prognostic models to determine the management of treatments for individual patients. This review focuses on the clinical aspects and outcomes of a cohort of Japanese patients with PMF, including discussion of recent advances in the management of PMF.
Topics: Humans; Janus Kinase 2; Mutation; Myeloproliferative Disorders; Primary Myelofibrosis; Protein Kinase Inhibitors; Splenomegaly
PubMed: 29665657
DOI: 10.3904/kjim.2018.033 -
Blood Cancer Journal Nov 2018Prefibrotic myelofibrosis (pre-PMF) is a distinct entity among chronic myeloproliferative neoplasm diagnosed according to the revised 2016 WHO classification. The... (Review)
Review
Prefibrotic myelofibrosis (pre-PMF) is a distinct entity among chronic myeloproliferative neoplasm diagnosed according to the revised 2016 WHO classification. The clinical picture is heterogeneous, ranging from isolated thrombocytosis, mimicking essential thrombocythemia (ET), to symptoms of high-risk PMF. Retrospective studies showed that survival of patients with pre-PMF is worse than that of ET and better than overt PMF. Whilst a specific prognostic score is lacking, the International Prognostic Scoring System is able to predict survival in pre-PMF patients, yet failing to separate intermediate-1 and -2 groups, and can be used in clinical practice. Each patient should be evaluated for, and interventions adapted to, both life-expectancy and the risk of bleeding and thrombosis. In low-risk patients with expected long survival, observation only is recommended; in cumulated intermediate-1 and -2 risk cases, whose median survival is projected at more than 10 years, treatment is based on symptoms; in high risk cases, with median survival lower than 5 years, intensive management is required. A pragmatic approach to address the risk of bleeding and thrombosis includes: no treatment or low-dose aspirin in asymptomatic patients; aspirin or oral anticoagulation if previous arterial or venous thrombosis, and hydroxyurea as first-line cytoreduction in case of thrombocytosis or leukocytosis.
Topics: Algorithms; Animals; Biomarkers; Disease Management; Female; Humans; Male; Mutation; Myeloproliferative Disorders; Outcome Assessment, Health Care; Phenotype; Primary Myelofibrosis; Risk Assessment; Risk Factors; Thrombocythemia, Essential
PubMed: 30405096
DOI: 10.1038/s41408-018-0142-z -
Haematologica Jun 2016Bone marrow fibrosis is a central pathological feature and World Health Organization major diagnostic criterion of myelofibrosis. Although bone marrow fibrosis is seen... (Review)
Review
Bone marrow fibrosis is a central pathological feature and World Health Organization major diagnostic criterion of myelofibrosis. Although bone marrow fibrosis is seen in a variety of malignant and non-malignant disease states, the deposition of reticulin and collagen fibrosis in the bone marrow of patients with myelofibrosis is believed to be mediated by the myelofibrosis hematopoietic stem/progenitor cell, contributing to an impaired microenvironment favoring malignant over normal hematopoiesis. Increased expression of inflammatory cytokines, lysyl oxidase, transforming growth factor-β, impaired megakaryocyte function, and aberrant JAK-STAT signaling have all been implicated in the pathogenesis of bone marrow fibrosis. A number of studies indicate that bone marrow fibrosis is an adverse prognostic variable in myeloproliferative neoplasms. However, modern myelofibrosis prognostication systems utilized in risk-adapted treatment approaches do not include bone marrow fibrosis as a prognostic variable. The specific effect on bone marrow fibrosis of JAK2 inhibition, and other rationally based therapies currently being evaluated in myelofibrosis, has yet to be fully elucidated. Hematopoietic stem cell transplantation remains the only curative therapeutic approach that reliably results in resolution of bone marrow fibrosis in patients with myelofibrosis. Here we review the pathogenesis, biological consequences, and prognostic impact of bone marrow fibrosis. We discuss the rationale of various anti-fibrogenic treatment strategies targeting the clonal hematopoietic stem/progenitor cell, aberrant signaling pathways, fibrogenic cytokines, and the tumor microenvironment.
Topics: Animals; Bone Marrow; Bone Marrow Cells; Cell Transformation, Neoplastic; Cellular Microenvironment; Disease Progression; Genetic Predisposition to Disease; Humans; Molecular Targeted Therapy; Primary Myelofibrosis; Prognosis; Severity of Illness Index
PubMed: 27252511
DOI: 10.3324/haematol.2015.141283