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Expert Review of Hematology Jul 2018The 2016 WHO classification comprises two stages of primary myelofibrosis (PMF): early/prefibrotic primary myelofibrosis (pre-PMF) and overt fibrotic PMF (overt PMF).... (Review)
Review
The 2016 WHO classification comprises two stages of primary myelofibrosis (PMF): early/prefibrotic primary myelofibrosis (pre-PMF) and overt fibrotic PMF (overt PMF). Diagnostic criteria rely on bone marrow morphology, fibrosis grade (0-1 in pre-PMF, 2-3 in overt PMF), and clinical features (leukoerythroblastosis, anemia, leucocytosis, increased lactate dehydrogenase, and palpable splenomegaly). An accurate differentiation from essential thrombocythemia (ET) is pivotal because the two entities show different clinical presentation and outcome, in terms of survival, leukemic evolution, and rates of progression to overt myelofibrosis. Areas covered: The current review provides an overview on how to diagnose and stratify patients with pre-PMF, taking into account their definite and peculiar risk of vascular event, which is often neglected, and their milder disease course, compared with overt PMF, with the aim of improving and individualizing their counseling and management. Expert commentary: Pre-PMF is a new entity characterized by a unique combination of both a thrombo-hemorrhagic risk (that brings it closer to PV and ET) and a definite risk of disease evolution (that places pre-PMF somewhat closer to the overt PMF variant).
Topics: Humans; Precision Medicine; Primary Myelofibrosis
PubMed: 29862872
DOI: 10.1080/17474086.2018.1484280 -
Annals of Hematology Apr 2017Primary myelofibrosis is a unique entity among BCR-ABL-negative myeloproliferative diseases, manifesting as bone marrow fibrosis and pancytopenia. Considerable evidence... (Review)
Review
Primary myelofibrosis is a unique entity among BCR-ABL-negative myeloproliferative diseases, manifesting as bone marrow fibrosis and pancytopenia. Considerable evidence indicates that genetic and epigenetic abnormalities can result in defective clonal hematopoietic stem cell proliferation in addition to bone marrow microenvironment alteration. The "bad seeds in bad soil" theory illustrates the orchestrating efforts of hematopoietic stem cells, stromal cells, and their surrounding signaling molecules in myelofibrosis progression and malignancy transformation, though the exact mechanism of myelofibrosis is still not clear. This study reviews current concepts and questions regarding the pathogenesis of primary myelofibrosis and discusses the emerging targeted therapy aimed at restoring normal bone marrow environment and halting bone marrow fibrotic deterioration.
Topics: Animals; Clinical Trials as Topic; Drug Delivery Systems; Hematopoietic Stem Cell Transplantation; Humans; Janus Kinases; Nitriles; Primary Myelofibrosis; Pyrazoles; Pyrimidines
PubMed: 27539616
DOI: 10.1007/s00277-016-2785-9 -
Expert Review of Hematology Nov 2018Despite the dramatic progress made in the treatment of patients with myelofibrosis since the introduction of the JAK1/2 inhibitor ruxolitinib, a therapeutic option that... (Review)
Review
Despite the dramatic progress made in the treatment of patients with myelofibrosis since the introduction of the JAK1/2 inhibitor ruxolitinib, a therapeutic option that can modify the natural history of the disease and prevent evolution to blast-phase is still lacking. Recent investigational treatments including immunomodulatory drugs and histone deacetylase inhibitors benefit some patients but these effects have proven modest at best. Several novel agents do show promising activity in preclinical studies and early-phase clinical trials. We will illustrate a snapshot view of where the management of myelofibrosis is evolving, in an era of personalized medicine and advanced molecular diagnostics. Areas covered: A literature search using MEDLINE and recent meeting abstracts was performed using the keywords below. It focused on therapies in active phases of development based on their scientific and preclinical rationale with the intent to highlight agents that have novel biological effects. Expert commentary: The most mature advances in treatment of myelofibrosis are the development of second-generation JAK1/2 inhibitors and improvements in expanding access to donors for transplantation. In addition, there are efforts to identify drugs that target pathways other than JAK/STAT signaling that might improve the survival of myelofibrosis patients, and limit the need for stem-cell transplantation.
Topics: Animals; Biomarkers; Combined Modality Therapy; Disease Management; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy; Interferon-alpha; Molecular Targeted Therapy; Mutation; Primary Myelofibrosis; Protein Kinase Inhibitors; Signal Transduction; Transplantation, Homologous; Treatment Outcome
PubMed: 30324817
DOI: 10.1080/17474086.2018.1536538 -
Blood Reviews Jul 2020Myelofibrosis is classified as a 'Philadelphia-chromosome negative' clonal myeloproliferative disorder. The heterogeneity of this condition and patient population and... (Review)
Review
Myelofibrosis is classified as a 'Philadelphia-chromosome negative' clonal myeloproliferative disorder. The heterogeneity of this condition and patient population and array of often challenging clinical manifestations can frequently make therapeutic decisions challenging. Despite many advances in therapy with targeted and combination approaches, following an enhanced understanding of underlying disease pathogenesis, cure only remains achievable with allogeneic stem cell transplant. This option is often limited to a small group of younger transplant-eligible patients with more advanced disease who have both a suitable donor and no or few co-morbidities. In this article, we will discuss up-to-date disease prognostication, common clinical challenges associated with myelofibrosis and both standard and novel therapeutic approaches. Increasingly complex prognostic modelling utilises patient-specific, haematological and genomic parameters to improve the accuracy of risk assessment and predict disease progression. We will also focus on difficult clinical scenarios such as disease-associated anaemia, thrombocytopenia and extremes of age. Future and evolving therapies within this field are highly anticipated and novel JAK inhibitor and non-JAK inhibitor-based therapy will also be discussed, including the new challenge of how to switch from one JAK inhibitor therapy to another.
Topics: Clinical Trials as Topic; Disease Management; Disease Progression; Humans; Primary Myelofibrosis; Prognosis
PubMed: 32536371
DOI: 10.1016/j.blre.2020.100715 -
Clinical Advances in Hematology &... Sep 2018Bone marrow fibrosis (BMF) is a histologic finding in a wide range of diseases, including malignancies, endocrine disorders, autoimmune diseases, and infections.... (Review)
Review
Bone marrow fibrosis (BMF) is a histologic finding in a wide range of diseases, including malignancies, endocrine disorders, autoimmune diseases, and infections. Autoimmune myelofibrosis (AIMF) is an uncommon etiology of BMF; it can be secondary to a defined autoimmune disease, or it can be primary in the absence of a clinically diagnosed autoimmune disease but the presence of serologic evidence of autoantibodies. Distinguishing between primary myelofibrosis (PMF) and non-neoplastic AIMF is of the utmost importance because the prognosis and therapeutic options are different. This distinction, however, can be complicated by overlapping findings in the 2 disease entities. Here, using the case of a patient with BMF in the setting of idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia, we present a systematic approach to distinguishing between PMF and AIMF.
Topics: Autoimmune Diseases; Female; Humans; Male; Primary Myelofibrosis
PubMed: 30256778
DOI: No ID Found -
Current Hematologic Malignancy Reports Jun 2018Cytopenias, particularly anemia, are frequently encountered in patients with myelofibrosis. Management of cytopenias in myelofibrosis can be very challenging because... (Review)
Review
PURPOSE OF REVIEW
Cytopenias, particularly anemia, are frequently encountered in patients with myelofibrosis. Management of cytopenias in myelofibrosis can be very challenging because current therapeutic interventions are only of modest efficacy and ruxolitinib, the only approved drug for myelofibrosis, is myelosuppressive. Yet, dose optimization of ruxolitinib is important for its survival benefit in patients with advanced disease. We sought to summarize the data on treatments for cytopenias available at present and review promising agents in development and emerging strategies.
RECENT FINDINGS
The activin receptor ligand traps hold considerable promise for the treatment of anemia and could represent an attractive combination strategy with ruxolitinib. Low-dose thalidomide, which could offset both anemia and thrombocytopenia caused by ruxolitinib, represents another potential partner for ruxolitinib. The anti-fibrotic agent PRM-151 produced sustained improvements in cytopenias in some patients, and further data on this drug are eagerly awaited. Finally, several preclinical leads with translational potential are worthy of clinical investigation as strategies to halt/reverse bone marrow fibrosis and thereby improve cytopenias. Cytopenias remain a significant hurdle in myelofibrosis management, but several novel investigational agents hold considerable promise for the future.
Topics: Anemia; Disease-Free Survival; Humans; Nitriles; Primary Myelofibrosis; Pyrazoles; Pyrimidines; Survival Rate; Thrombocytopenia
PubMed: 29796726
DOI: 10.1007/s11899-018-0447-9 -
Blood Cancer Journal Jul 2018Two novel prognostic systems for primary myelofibrosis (PMF) were recently unveiled: GIPSS (genetically inspired prognostic scoring system) and MIPSS70... (Review)
Review
Two novel prognostic systems for primary myelofibrosis (PMF) were recently unveiled: GIPSS (genetically inspired prognostic scoring system) and MIPSS70 (mutation-enhanced international prognostic scoring system for transplant-age patients). GIPSS is based exclusively on genetic markers: mutations and karyotype. MIPSS70 includes mutations and clinical risk factors. In its most recent adaptation, the prognostic value of MIPSS70 has been bolstered by the inclusion of a three-tiered cytogenetic risk stratification and use of hemoglobin thresholds that are adjusted for sex and severity (MIPSS70+ version 2.0). GIPSS features four, MIPSS70 three, and MIPSS70+ version 2.0 five risk categories. MIPSS70 is most useful in the absence of cytogenetic information. MIPSS70+ version 2.0 is more comprehensive than MIPSS70 and is the preferred model in the presence of cytogenetic information. Both MIPSS70 and MIPSS70+ version 2.0 require an online score calculator ( http://www.mipss70score.it ). GIPPS offers a lower complexity prognostic tool that reliably identifies candidates for allogeneic stem cell transplant (GIPSS high-risk disease) or long-term observation with little or no therapeutic intervention (GIPSS low-risk disease). Ultimately, we favor a step-wise prognostication approach that starts with GIPSS but also considers MIPSS70+ version 2.0 for confirming the most appropriate treatment approach for the individual patient.
Topics: Algorithms; Disease Management; Humans; Practice Guidelines as Topic; Primary Myelofibrosis; Prognosis; Risk Factors
PubMed: 30065290
DOI: 10.1038/s41408-018-0109-0 -
Haematologica Apr 2015
Topics: Humans; Nitriles; Primary Myelofibrosis; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines
PubMed: 25828084
DOI: 10.3324/haematol.2015.124099 -
Clinical Advances in Hematology &... Feb 2018Myelofibrosis is one of the BCR-ABL-negative clonal disorders that collectively are known as myeloproliferative neoplasms (MPNs). It is caused by the proliferation of... (Review)
Review
Myelofibrosis is one of the BCR-ABL-negative clonal disorders that collectively are known as myeloproliferative neoplasms (MPNs). It is caused by the proliferation of clonal hematopoietic stem cells, which over time leads to characteristic clinical features. The disease presentation is heterogeneous, however, with 30% of patients initially asymptomatic. This variation in clinical phenotype warrants careful risk stratification to guide appropriate management, and prognostic risk scores are continually being refined. Considerable advancements have been made in the understanding of MPN pathogenesis, in particular recognition of the driver mutations JAK2 V617F, CALR, and MPL, which has led to the development of ruxolitinib, an inhibitor of Janus kinase 1 (JAK1) and JAK2 that has transformed therapy for myelofibrosis. Although ruxolitinib decreases symptoms and is associated with a survival advantage, it has no clear disease-altering activity, and allogeneic hematopoietic stem cell transplant remains the sole curative option for myelofibrosis. Ongoing studies are evaluating newer JAK inhibitors, combinations of ruxolitinib with other targeted drugs, and targeted therapies that do not inhibit JAK. This review provides further detail regarding the clinical features, pathogenesis, risk stratification, and current management of myelofibrosis, including older and newer targeted treatments.
Topics: Biomarkers; Biopsy; Cell Transformation, Neoplastic; Combined Modality Therapy; Disease Management; Disease Progression; Humans; Primary Myelofibrosis; Prognosis; Treatment Outcome
PubMed: 29741513
DOI: No ID Found -
Current Hematologic Malignancy Reports Dec 2017The purpose of the review was to provide a contemporary update of novel agents and targets under investigation in myelofibrosis in the Janus kinase (JAK) inhibitor era. (Review)
Review
PURPOSE OF REVIEW
The purpose of the review was to provide a contemporary update of novel agents and targets under investigation in myelofibrosis in the Janus kinase (JAK) inhibitor era.
RECENT FINDINGS
Myelofibrosis (MF) is a clonal stem cell disease characterized by marrow fibrosis and a heterogeneous disease phenotype with a variable degree of splenomegaly, cytopenias, and constitutional symptoms that significantly impact quality of life and survival. Overactive JAK/STAT signaling is a hallmark of MF. The only approved therapy for MF, JAK1/2 inhibitor ruxolitinib, can ameliorate splenomegaly, improve symptoms, and prolong survival in some patients. Therapeutic challenges remain, however. Myelosuppression limits the use of ruxolitinib in some patients, eventual drug resistance is common, and the underlying malignant clone persists despite therapy. A deeper understanding of the pathogenesis of MF has informed the development of additional agents. Promising targets under investigation include JAK1 and JAK2 and downstream intermediates in related signaling pathways, epigenetic modifiers, pro-inflammatory cytokines, and immune regulators.
Topics: Humans; Primary Myelofibrosis
PubMed: 29098608
DOI: 10.1007/s11899-017-0403-0