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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 -
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 -
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 -
Clinical Lymphoma, Myeloma & Leukemia Dec 2022Patients with myelofibrosis (MF) frequently develop thrombocytopenia as a consequence of bone marrow fibrosis, splenic sequestration, and myelosuppression from an... (Review)
Review
Patients with myelofibrosis (MF) frequently develop thrombocytopenia as a consequence of bone marrow fibrosis, splenic sequestration, and myelosuppression from an inflammatory microenvironmental milieu. Thrombocytopenia occurs frequently at diagnosis, worsens with disease progression, is an independent adverse prognostic factor, and limits effective dosing of JAK2 inhibitors. Recently, pacritinib was approved for patients with MF and extreme thrombocytopenia. However, this JAK2/IRAK1 inhibitor is not primarily used to attain improvement in platelet count. In this narrative review, we discuss strategies to specifically address thrombocytopenia in MF patients including immunomodulatory drugs, synthetic androgens, hypomethylating agents and splenectomy, all of which have only modest efficacy in alleviating thrombocytopenia. We also detail transfusion approaches, including diagnostic and therapeutic consideration for platelet transfusion refractoriness. We end by discussing novel therapies, including TGFβ traps and recombinant pentraxin-2, which may increase platelet counts in MF patients. Despite recent therapeutic advancements in MF, there remains a near paucity of agents that can effectively alleviate thrombocytopenia.
Topics: Humans; Primary Myelofibrosis; Janus Kinase 2; Protein Kinase Inhibitors; Thrombocytopenia; Anemia
PubMed: 36117043
DOI: 10.1016/j.clml.2022.08.011 -
European Journal of Haematology Nov 2023Autoimmune myelofibrosis (AIMF) is a rare cause of bone marrow fibrosis (BMF) occurring in the presence or absence of a defined autoimmune disease (secondary or primary... (Review)
Review
BACKGROUND AND OBJECTIVES
Autoimmune myelofibrosis (AIMF) is a rare cause of bone marrow fibrosis (BMF) occurring in the presence or absence of a defined autoimmune disease (secondary or primary AIMF, sAIMF/pAIMF, respectively). Unlike primary myelofibrosis (PMF), AIMF responds well to immunosuppressive therapy with a benign clinical course. Diagnostic criteria for AIMF in opposition to PMF have been lacking, though recent work has helped better characterise molecular and pathological features of AIMF, improving diagnostic precision.
METHODS
Using a modern clinical and pathophysiological understanding of AIMF, we apply scoping review methodology and rigorous case-criteria to retrospectively analyse the case literature. We examine its patient-population, describing patient-associated factors, presentation, bone marrow pathology, genetics, treatment and outcomes.
RESULTS
Fifty-five studies were identified, describing 139 AIMF patients. Patients were mostly young females (~4:1 ratio female:male, median age 40.8 years) and typically presented with cytopenias. Splenomegaly was rare. sAIMF was more common than pAIMF (~3:1 ratio), and most cases responded well to immunosuppressive therapy.
CONCLUSIONS
Our results strengthen the emerging picture of AIMF's patient population, natural history and response to treatment. Further work should continue to use reproducible diagnostic criteria, and explore AIMF's pathophysiology, response to different therapies, and sequelae over larger timescales, as well as differences between pAIMF, sAIMF and PMF.
Topics: Humans; Male; Female; Adult; Primary Myelofibrosis; Retrospective Studies; Bone Marrow; Autoimmune Diseases; Immunosuppression Therapy
PubMed: 37515415
DOI: 10.1111/ejh.14064 -
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 -
Haematologica Dec 2022
Topics: Humans; Leukemia, Megakaryoblastic, Acute; Primary Myelofibrosis; Megakaryocytes; Chronic Disease; Leukemia
PubMed: 35295083
DOI: 10.3324/haematol.2022.280838 -
Hematology/oncology Clinics of North... Oct 2003MMM is a chronic myeloproliferative disorder characterized by bone marrow fibrosis and neoangiogenesis, constitutive release ofa high number of CD34+ stem cells from the... (Review)
Review
MMM is a chronic myeloproliferative disorder characterized by bone marrow fibrosis and neoangiogenesis, constitutive release ofa high number of CD34+ stem cells from the bone marrow, and extramedullary hematopoiesis. It presents with heterogeneous clinical features in which anemia and progression to symptomatic splenomegaly dominate. The pathogenesis is undefined, but the dual action of deregulation of the bFGF pathway may influence myeloproliferation, myelofibrosis, and neoangiogenesis. Animal models suggest that chronic exposure to high doses of thrombopoietin or impairment of the capacity of megakaryocytes to differentiate into platelets, as occurs in the GATA-1(low) mice, is a necessary event for myelofibrosis. Allogeneic stem cell transplantation offers a chance of cure, and low conditioning regimens may extend the age of transplantable patients with lower mortality. Autologus stem cell transplantation and splenectomy are risky procedures that may be considered in patients with advanced disease when conventional therapies for correcting anemia (danazol, recombinant human erythropoietin, or cyclosporine) or chemotherapy for splenomegaly and myeloproliferation (hydroxyurea or interferon alfa) have failed. Thalidomide has been tested in numerous series, and its capacity to improve anemia and thrombocytopenia while reducing splenomegaly has been documented.
Topics: Diagnosis, Differential; Humans; Incidence; Primary Myelofibrosis
PubMed: 14560783
DOI: 10.1016/s0889-8588(03)00080-7 -
The New England Journal of Medicine Apr 2000
Review
Topics: Antineoplastic Agents; Bone Marrow; Diagnosis, Differential; Hematopoietic Stem Cell Transplantation; Humans; Hydroxyurea; Primary Myelofibrosis; Prognosis; Splenectomy; Suramin
PubMed: 10781623
DOI: 10.1056/NEJM200004273421706 -
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