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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 -
Journal of Clinical and Experimental... 2018In 2017, the revised World Health Organization was published. Regarding myeloproliferative neoplasms, histological findings of bone marrow biopsy is becoming more... (Review)
Review
In 2017, the revised World Health Organization was published. Regarding myeloproliferative neoplasms, histological findings of bone marrow biopsy is becoming more important for diagnosis. This article highlights particularly the morphology of megakaryocytes and evaluation of myelofibrosis for pathological diagnosis, and immunohistochemistry which can detect somatic mutation.
Topics: Biopsy; Bone Marrow; Histological Techniques; Humans; Megakaryocytes; Primary Myelofibrosis
PubMed: 29998975
DOI: 10.3960/jslrt.18006 -
Oncotarget Aug 2016Identification of somatic frameshift mutations in exon 9 of the calreticulin gene (CALR) in myeloproliferative neoplasms (MPNs) in December of 2013 has been a remarkable...
Identification of somatic frameshift mutations in exon 9 of the calreticulin gene (CALR) in myeloproliferative neoplasms (MPNs) in December of 2013 has been a remarkable finding. It has provided a new molecular diagnostic marker, particularly in essential thrombocythemia (ET) and primary myelofibrosis (PMF), where is the second most common altered gene after JAK2V617F. There are two main types of CALR mutants, type 1 and type 2, and there is evidence about their distinct clinical/prognostic implications, for instances, it is believed that favorable outcome might be restricted to type-1 in PMF. By using reasoned approaches, very recent publications have supported classifying the alternative mutants in type-1-like or type-2-like. If further studies confirm these results, new considerations may be taken into account in the molecular diagnosis of MPNs. This implies that precise mutation characterization must be performed and caution should be taken in screening technique selection. In this Editorial we summarize the current information regarding all this issues.
Topics: Calreticulin; DNA Mutational Analysis; Genetic Testing; Humans; Mutation; Primary Myelofibrosis; Prognosis; Thrombocythemia, Essential
PubMed: 27384487
DOI: 10.18632/oncotarget.10376 -
Annals of Hematology Apr 2023Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by mutations (most frequently in JAK2, CALR, or MPL), burdensome symptoms, splenomegaly, cytopenia, and... (Review)
Review
Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by mutations (most frequently in JAK2, CALR, or MPL), burdensome symptoms, splenomegaly, cytopenia, and shortened life expectancy. In addition to other clinical manifestations, patients with MF often develop anemia, which can either be directly related to MF pathogenesis or a result of MF treatment with Janus kinase (JAK) inhibitors, such as ruxolitinib and fedratinib. Although symptoms and clinical manifestations can be similar between the 2 anemia types, only MF-related anemia is prognostic of reduced survival. In this review, I detail treatment and patient management approaches for both types of anemia presentations and provide recommendations for the treatment of MF in the presence of anemia.
Topics: Humans; Primary Myelofibrosis; Janus Kinase 2; Splenomegaly; Nitriles; Anemia; Pyrrolidines; Sulfonamides
PubMed: 36786879
DOI: 10.1007/s00277-023-05126-4 -
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 -
Haematologica Feb 2024
Topics: Humans; Primary Myelofibrosis; Pyrimidines; Nitriles; Janus Kinase 2; Benzamides; Pyrazoles
PubMed: 37259556
DOI: 10.3324/haematol.2023.283106 -
Clinical Lymphoma, Myeloma & Leukemia Sep 2020Splenomegaly, which may range from a few centimeters below the left costal border to massive dimensions, is one of the most characteristic features in patients with... (Review)
Review
Splenomegaly, which may range from a few centimeters below the left costal border to massive dimensions, is one of the most characteristic features in patients with advanced myelofibrosis (MF). Splenectomy may offer an effective therapeutic option for treating massive splenomegaly in patients with MF, and especially in cases of disease refractory to conventional drugs, but it is associated with a number of complications as well as substantial morbidity and mortality. Whether splenectomy should be performed before allogeneic hematopoietic stem-cell transplantation is also controversial, and there is a lack of prospective randomized clinical trials that assess the role of splenectomy before hematopoietic stem-cell transplantation in patients with MF. Although splenectomy is not routinely performed before transplantation, it may be appropriate in patients with massive splenomegaly and related symptoms, so long as the higher risk of graft failure in such cases is taken into account. This review aims to describe the efficacy, indications, and complications of splenectomy in patients with MF; and to evaluate the long-term impact of splenectomy on patient survival and risk of disease transformation.
Topics: Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Primary Myelofibrosis; Splenectomy; Transplantation Conditioning; Treatment Outcome
PubMed: 32482540
DOI: 10.1016/j.clml.2020.04.015 -
Blood Sep 2022
Topics: Humans; Primary Myelofibrosis
PubMed: 36173658
DOI: 10.1182/blood.2022015663 -
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 -
British Journal of Haematology Oct 2018The 2016 World Health Organization (WHO) classification for myeloproliferative neoplasms (MPN) divided myelofibrosis (MF) into pre-fibrotic (pre-MF) and overt-MF... (Review)
Review
The 2016 World Health Organization (WHO) classification for myeloproliferative neoplasms (MPN) divided myelofibrosis (MF) into pre-fibrotic (pre-MF) and overt-MF categories. This new classification, particularly the entity pre-MF, has been a subject of discussion between experts. Important questions have been raised in recent years, such as the need for bone marrow trephine for diagnosis; how this is interpreted and the weighting given to it in assigning a diagnosis; determination of prognosis for pre-MF patients; including which scoring system to use and, ultimately, an evidence-based management plan for this group of patients. Many pre-MF patients present as young adults, with thrombocytosis, elevated lactate dehydrogenase levels and increased bone marrow fibrosis (i.e. ≥ grade 1). Current management strategies differ in view of age, comorbidities and bone marrow features and the opinion of the managing clinicians. Prognostic scoring systems have some limitations regarding this entity, and at the present time there is limited information about the overall survival and incidence of progression to overt-MF and acute leukaemia for pre-MF. In this clinically focussed article, we review the main characteristics of this new disease category in view of the current published literature and illustrate our discussion with some real patient cases. Lastly, we propose a management strategy for patients to whom this diagnostic label is applied.
Topics: Disease Management; Fibrosis; Humans; Myeloproliferative Disorders; Primary Myelofibrosis; Prognosis; World Health Organization
PubMed: 30328618
DOI: 10.1111/bjh.15562