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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 -
Expert Opinion on Emerging Drugs Mar 2018Myelofibrosis (MF) is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN). It can be sub-categorized into primary myelofibrosis, post polycythemia vera... (Review)
Review
Myelofibrosis (MF) is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN). It can be sub-categorized into primary myelofibrosis, post polycythemia vera myelofibrosis and post essential thrombocythemia myelofibrosis. MF is a life-threatening hematologic malignancy characterized by dysregulation of the Janus associated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling network and a heightened inflammatory state. Areas covered: We cover the pathogenesis, clinical features, new prognostic models, current treatment of MF and discuss agents in development. We also cover market review and health care costs associated with some of these therapies. Expert opinion: There are many ongoing clinical trials evaluating novel therapeutic approaches, including selective JAK inhibitors, histone deacetylase/DNA methyltransferase inhibitors, PI3K-inhibitors, Hedgehog/mammalian target of rapamycin (MTOR) inhibitors, anti-fibrotic agents, immunomodulators, monoclonal antibodies and immune checkpoint inhibitors. Ruxolitinib, a potent oral JAK1/JAK2 inhibitor remains the only Food and Drug Administration (FDA)-approved medicinal therapy for the treatment of MF. Unmet needs include alleviation of limiting thrombocytopenia and anemia, halting disease progression to acute leukemia, and extending survival. The development of biomarker driven clinical trials of mechanism based novel therapeutics will usher in a new era of advances in the treatment of this chronic and progressive myeloid malignancy.
Topics: Biomarkers; Disease Progression; Drug Design; Humans; Janus Kinase Inhibitors; Nitriles; Primary Myelofibrosis; Pyrazoles; Pyrimidines
PubMed: 29480036
DOI: 10.1080/14728214.2018.1445718 -
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 -
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 -
Expert Review of Hematology Oct 2017Aberrant regulation of the immune system with up-regulation of pro-inflammatory cytokines contributes to disease pathophysiology in myelofibrosis (MF). Therapeutic... (Meta-Analysis)
Meta-Analysis Review
Aberrant regulation of the immune system with up-regulation of pro-inflammatory cytokines contributes to disease pathophysiology in myelofibrosis (MF). Therapeutic options for MF associated anemia, thrombocytopenia, and bone marrow fibrosis remain limited. Areas covered: This review focuses on immune based therapies in MF, including immunomodulatory imide drugs (IMiDs), interferons, monoclonal antibodies and targeted agents (SL-401), and checkpoint inhibitors. Published literature was reviewed using available databases (PubMed, Cochrane, Scopus) and web pages (clinicaltrials.gov). IMiDs, such as thalidomide, lenalidomide and pomalidomide, have demonstrated efficacy in treating MF associated cytopenias. Interferon-alpha may be beneficial in early phase MF due to its effects on neoplastic bone marrow. Monoclonal antibodies are designed to target overexpressed antigens on tumor cells and induce targeted cell death by either delivering a toxic payload, or to unleash anti-tumor T-cells by blocking T-cell inhibitory checkpoints. Expert commentary: Immune based therapy is being evaluated in a number of hematologic malignancies with encouraging data in Hodgkins, multiple myeloma, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Ongoing and planned clinical trials of these agents, either alone or in various combinations with other targeted therapies, such as JAK-STAT or histone deacetylase inhibitors, and anti-fibrotic agents, will reveal the full potential of immune therapies in MF.
Topics: Antibodies, Monoclonal; Clinical Trials as Topic; Humans; Immunologic Factors; Immunomodulation; Immunotherapy; Interferon-alpha; Molecular Targeted Therapy; Primary Myelofibrosis; T-Lymphocyte Subsets; Treatment Outcome
PubMed: 28799436
DOI: 10.1080/17474086.2017.1366853 -
Current Opinion in Hematology Mar 2015The myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia, and myelofibrosis. Of these, myelofibrosis often has the most aggressive course.... (Review)
Review
PURPOSE OF REVIEW
The myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia, and myelofibrosis. Of these, myelofibrosis often has the most aggressive course. There is, however, often significant clinical heterogeneity among patients with myelofibrosis. We seek to summarize recent clinical and biological findings in myelofibrosis as well as review the spectrum of clinically relevant mutation in myelofibrosis and their implications.
RECENT FINDINGS
The mutational spectrum in myelofibrosis includes driver mutations in genes such as JAK2, calreticulin, and myeloproliferative leukemia virus oncogene. In addition, recurrent mutations in epigenetic modifiers such as ASXL1 and TET2 have also been described. Importantly, several studies have indicated that specific mutations, as well as the number of mutations, that a patient bears may have important clinical consequences. The presence or absence of certain mutations may help to determine a patient's risk for thrombosis, leukemic transformation, and survival.
SUMMARY
Myelofibrosis often has variable outcomes among patients. Prognostic systems based on clinical observations have been developed in an attempt to predict risks of disease progression and transformation. The discovery of recurrent genomic alterations in myelofibrosis, and the observation that many of these alterations may help predict clinical outcomes, has heralded a new era in the biologic understanding and clinical approach to myelofibrosis.
Topics: Genetic Predisposition to Disease; Humans; Mutation; Primary Myelofibrosis; Prognosis
PubMed: 25635755
DOI: 10.1097/MOH.0000000000000122 -
Best Practice & Research. Clinical... Jun 2022Pre-Fibrotic Myelofibrosis is a frequently under-recognised entity that has distinct features separate to those of both Essential Thrombocythaemia and overt Primary... (Review)
Review
Pre-Fibrotic Myelofibrosis is a frequently under-recognised entity that has distinct features separate to those of both Essential Thrombocythaemia and overt Primary Myelofibrosis. Misdiagnosis is relatively common due to subtle differences in bone marrow trephine morphology and multidisciplinary approaches are required. The clinical phenotype and disease course is heterogeneous and hence management approaches tend to vary widely. Although patients may initially be asymptomatic, disease-related complications can include troublesome symptom burdens, increased incidence of both arterial and venous thromboses, haemorrhage, anaemia and an inherent risk of disease evolution to either overt myelofibrosis or blastic phase disease. Specific prognostic tools with high discriminatory power are lacking. Within this review we use case-based approaches to review the current literature, highlight challenges in both diagnostics and disease management and suggest contemporary approaches to improve patient outcomes.
Topics: Humans; Primary Myelofibrosis; Thrombocythemia, Essential; Bone Marrow; Prognosis; Disease Progression
PubMed: 36333067
DOI: 10.1016/j.beha.2022.101378 -
International Journal of Hematology May 2022In this review, we will outline dimensions in which outcome of patients with myelofibrosis undergoing curative treatment can be optimized: patient selection, transplant... (Review)
Review
In this review, we will outline dimensions in which outcome of patients with myelofibrosis undergoing curative treatment can be optimized: patient selection, transplant procedure, and posttransplant prevention or treatment of relapse. For patient selection, fortunately, as with several other hematologic malignancies, the management of patients with myelofibrosis has very much entered the molecular era, with the establishment of several driver and nondriver mutations, allowing more individualized selection for treatment. For the transplant procedure itself, different conditioning intensities do not seem to play a distinctive role with regards to outcome posttransplant but still need to be compared in the molecular era. While many patients nowadays may receive ruxolitinib before transplant, recent studies may facilitate fine-tuning and integration of ruxolitinib into the transplant algorithm. The role of novel inhibitors for the transplant setting remains unclear. For the posttransplant phase, evidence remains scarce, with experiences of donor-lymphocyte infusions for relapse management but more efforts are needed in understanding relapse and identifying and treating patients at high risk for relapse.
Topics: Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Neoplasm Recurrence, Local; Primary Myelofibrosis; Transplantation Conditioning; Transplantation, Homologous
PubMed: 35419771
DOI: 10.1007/s12185-022-03340-w -
Blood Sep 2022
Topics: Humans; Primary Myelofibrosis
PubMed: 36173658
DOI: 10.1182/blood.2022015663