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La Revue de Medecine Interne Feb 2021Myelofibrosis is a BCR-ABL1-negative chronic myeloproliferative neoplasm that includes primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential... (Review)
Review
Myelofibrosis is a BCR-ABL1-negative chronic myeloproliferative neoplasm that includes primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. It is characterized by stem cell-derived clonal proliferation that is often, but not always, accompanied by somatic mutations, which are classified into driver mutations (JAK2, CALR, or MPL), subclonal mutations and fibrosis on bone marrow biopsy. Myelofibrosis commonly demonstrates splenomegaly, constitutional symptoms, anemia, thrombocytosis, or thrombocytopenia. Patients may also be asymptomatic. Complications as thromboembolic or hemorrhagic events can reveal the disease. Primary myelofibrosis is the least common myeloproliferative neoplasm but is associated with poor survival and acute leukemic transformation. In contrast to the significant progress made in understanding the disease's pathogenesis, treatment for myelofibrosis remains largely palliative. The JAK2 inhibitor, ruxolitinib is not sufficient in eliminating the underlying myeloid progenitor clone, as disease inevitably returns with therapy discontinuation. Allogeneic hematopoietic stem cell transplantation is the only therapeutic option that offers potential cure. The development of novel treatment strategies aimed at slowing or even reversing disease progression, prolonging patient survival and preventing evolution to blast-phase are still lacking.
Topics: Fusion Proteins, bcr-abl; Humans; Mutation; Polycythemia Vera; Primary Myelofibrosis; Splenomegaly
PubMed: 33243417
DOI: 10.1016/j.revmed.2020.08.018 -
American Journal of Hematology Jan 2021Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation that is often but not always accompanied... (Review)
Review
DISEASE OVERVIEW
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR, or MPL mutations. Additional disease features include bone marrow reticulin/collagen fibrosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival.
DIAGNOSIS
Bone marrow morphology is the primary basis for diagnosis. Presence of JAK2, CALR, or MPL mutation, expected in around 90% of the patients, is supportive but not essential for diagnosis; these mutations are also prevalent in the closely related MPNs, namely polycythemia vera (PV) and essential thrombocythemia (ET). The 2016 World Health Organization classification system distinguishes "prefibrotic" from "overtly fibrotic" PMF; the former might mimic ET in its presentation. Furthermore, approximately 15% of patients with ET or PV might progress into a PMF-like phenotype (post-ET/PV MF) during their clinical course.
ADVERSE MUTATIONS
SRSF2, ASXL1, and U2AF1-Q157 mutations predict inferior survival in PMF, independent of each other and other risk factors. RAS/CBL mutations predicted resistance to ruxolitinib therapy.
ADVERSE KARYOTYPE
Very high risk abnormalities include -7, inv (3), i(17q), +21, +19, 12p-, and 11q-.
RISK STRATIFICATION
Two new prognostic systems for PMF have recently been introduced: GIPSS (genetically-inspired prognostic scoring system) and MIPSS70+ version 2.0 (MIPSSv2; mutation- and karyotype-enhanced international prognostic scoring system). GIPSS is based exclusively on mutations and karyotype. MIPSSv2 includes, in addition, clinical risk factors. GIPSS features four and MIPSSv2 five risk categories.
RISK-ADAPTED THERAPY
Observation alone is advised for MIPSSv2 "low" and "very low" risk disease (estimated 10-year survival 56%-92%); allogeneic hematopoietic stem cell transplant (AHSCT) is the preferred treatment for "very high" and "high" risk disease (estimated 10-year survival 0%-13%); treatment-requiring patients with intermediate-risk disease (estimated 10-year survival 30%) are best served by participating in clinical trials. In non-transplant candidates, conventional treatment for anemia includes androgens, prednisone, thalidomide, and danazol; for symptomatic splenomegaly, hydroxyurea and ruxolitinib; and for constitutional symptoms, ruxolitinib. Fedratinib, another JAK2 inhibitor, has now been FDA-approved for use in ruxolitinib failures. Splenectomy is considered for drug-refractory splenomegaly and involved field radiotherapy for non-hepatosplenic EMH and extremity bone pain.
NEW DIRECTIONS
A number of new agents, alone or in combination with ruxolitinib, are currently under investigation for MF treatment (ClinicalTrials.gov); preliminary results from some of these clinical trials were presented at the 2020 ASH annual meeting and highlighted in the current document.
Topics: Disease-Free Survival; Humans; Mutation; Primary Myelofibrosis; Risk Assessment; Survival Rate
PubMed: 33197049
DOI: 10.1002/ajh.26050 -
British Journal of Haematology Oct 2020Myelofibrosis is an enigmatic myeloproliferative neoplasm, despite noteworthy strides in understanding its genetic underpinnings. Driver mutations involving JAK2, CALR... (Review)
Review
Myelofibrosis is an enigmatic myeloproliferative neoplasm, despite noteworthy strides in understanding its genetic underpinnings. Driver mutations involving JAK2, CALR or MPL in 90% of patients mediate constitutive JAK-STAT signaling which, in concert with epigenetic alterations (ASXL1, DNMT3A, SRSF2, EZH2, IDH1/2 mutations), play a fundamental role in disease pathogenesis. Aberrant immature megakaryocytes are a quintessential feature, exhibiting reduced GATA1 protein expression and secreting a plethora of pro-inflammatory cytokines (IL-1 ß, TGF-ß), growth factors (b-FGF, PDGF, VEGF) in addition to extra cellular matrix components (fibronectin, laminin, collagens). The ensuing disrupted interactions amongst the megakaryocytes, osteoblasts, endothelium, stromal cells and myofibroblasts within the bone marrow culminate in the development of fibrosis and osteosclerosis. Presently, prognostic assessment tools for primary myelofibrosis (PMF) are centered on genetics, with incorporation of cytogenetic and molecular information into the mutation-enhanced (MIPSS 70-plus version 2.0) and genetically-inspired (GIPSS) prognostic scoring systems. Both models illustrate substantial clinical heterogeneity in PMF and serve as the crux for risk-adapted therapeutic decisions. A major challenge remains the dearth of disease-modifying drugs, whereas allogeneic transplant offers the chance of long-term remission for some patients. Our review serves to synopsise current appreciation of the pathogenesis of myelofibrosis together with emerging management strategies.
Topics: Gene Expression Regulation; Humans; Mutation; Myofibroblasts; Primary Myelofibrosis
PubMed: 32196650
DOI: 10.1111/bjh.16576 -
Blood Reviews Jan 2021Although understanding of the pathogenesis and molecular biology of primary myelofibrosis continues to improve, treatment options are limited, and several biological... (Review)
Review
Although understanding of the pathogenesis and molecular biology of primary myelofibrosis continues to improve, treatment options are limited, and several biological features remain unexplained. With an appropriate clinical history, exam, laboratory evaluation, and bone marrow biopsy, the diagnosis can often be established. Recent studies have better characterized prognostic factors and driver mutations in myelofibrosis, facilitated by use of next-generation sequencing. These advances have facilitated development of a management strategy that is based on both risk factors and clinical phenotype. For low-risk patients, treatment will depend on symptom severity. For patients with higher-risk disease, several treatments are available including JAK inhibitors, allogeneic hematopoietic stem cell transplant, and clinical trials using novel molecularly targeted therapies and rational drug combinations. In this review, we outline what is known about the disease pathogenesis, discuss an approach to reaching the diagnosis, review the prognosis of myelofibrosis, and detail current therapeutic strategies.
Topics: Animals; Biomarkers; Biopsy; Combined Modality Therapy; Disease Management; Disease Susceptibility; Genetic Predisposition to Disease; Humans; Molecular Diagnostic Techniques; Practice Guidelines as Topic; Primary Myelofibrosis; Prognosis; Symptom Assessment; Treatment Outcome
PubMed: 32354563
DOI: 10.1016/j.blre.2020.100691 -
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 -
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 -
Clinical Lymphoma, Myeloma & Leukemia May 2022Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm characterized by anemia, extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly,... (Review)
Review
Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm characterized by anemia, extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly, constitutional symptoms and acute myeloid leukemia progression. Currently, allogeneic haematopoietic stem cell transplantation (AHSCT) therapy is the only curative option for MF patients. However, AHSCT is strictly limited due to the high rates of morbidity and mortality. Janus kinase 2 (JAK2) inhibitor Ruxolitinib is the first-line treatment for intermediate-II or high-risk MF patients with splenomegaly and constitutional symptoms, but most MF patients develop resistance or intolerance to Ruxolitinib. Therefore, MF treatment is a challenge for the medical community. This review summarizes 3 investigated directions for MF therapy: monotherapies of JAK inhibitors, monotherapies of non-JAK targeted agents, combination therapies of Ruxolitinib and other agents. We emphasize combination of Ruxolitinib and other agents is a promising strategy.
Topics: Anemia; Hematopoiesis; Humans; Primary Myelofibrosis; Splenomegaly
PubMed: 34903489
DOI: 10.1016/j.clml.2021.11.007 -
Leukemia & Lymphoma May 2022Myelofibrosis is a myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells, bone marrow fibrosis and cytopenias, extramedullary hematopoiesis... (Review)
Review
Myelofibrosis is a myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells, bone marrow fibrosis and cytopenias, extramedullary hematopoiesis and hepatosplenomegaly, increased pro-inflammatory cytokine production, and systemic symptoms. Patients with MF also have a propensity toward leukemic transformation. Allogeneic hematopoietic stem cell transplantation (aHCT) is the only curative therapy for patients with MF; however, transplant-related morbidity and mortality precludes this option for the majority of patients. In the last decade, two targeted therapies have been approved for the treatment of MF, both JAK2 inhibitors, ruxolitinib and fedratinib. Despite the clinical efficacy of these two compounds in terms of splenomegaly and symptom burden reduction, there remain many areas of unmet need in the treatment of myelofibrosis. In this review, we discuss the limitations of currently approved treatment options and novel therapeutic targets with drug candidates in late-stage (phase II or III) clinical development for the treatment of MF. We delve into the mechanism of action and scientific rational of each candidate agent as well as the available clinical data, and ongoing trials that could lead to the approval of some of these novel therapies.
Topics: Humans; Janus Kinase Inhibitors; Myeloproliferative Disorders; Primary Myelofibrosis; Splenomegaly; Treatment Outcome
PubMed: 34852713
DOI: 10.1080/10428194.2021.2010068 -
Journal of Clinical Oncology : Official... Jun 2018
Topics: DNA Mutational Analysis; Humans; Karyotype; Mutation; Primary Myelofibrosis; Prognosis
PubMed: 29708808
DOI: 10.1200/JCO.2018.78.9867 -
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