-
Annual Review of Medicine 2009Primary myelofibrosis (PMF) is a clonal stem cell disorder that manifests clinically as anemia, splenomegaly due to extramedullary hematopoiesis, leukoerythroblastosis,... (Review)
Review
Primary myelofibrosis (PMF) is a clonal stem cell disorder that manifests clinically as anemia, splenomegaly due to extramedullary hematopoiesis, leukoerythroblastosis, and constitutional symptoms, which are the clinical hallmarks of PMF. Within the past three years it has been determined that a single, recurrent, somatic mutation in the gene encoding the cytoplasmic tyrosine kinase Janus kinase 2 (JAK2) occurs in the majority of patients with PMF, and more recently, activating mutations in the gene encoding the thrombopoietin receptor MPL have also been identified in a subset of PMF patients. These discoveries have yielded important insights into the pathogenesis of PMF and have brought about the first opportunity for rationally targeted therapy for this disorder. Here we present an updated review of the pathogenesis, definition, and treatment of PMF in light of the discovery of JAK2 and MPL mutations, as well as other recent work in the myeloproliferative neoplasm field.
Topics: Humans; Primary Myelofibrosis
PubMed: 18947294
DOI: 10.1146/annurev.med.60.041707.160528 -
American Journal of Hematology Dec 2011Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by stem cell-derived clonal myeloproliferation, abnormal cytokine expression, bone marrow... (Review)
Review
DISEASE OVERVIEW
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by stem cell-derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival.
DIAGNOSIS
Diagnosis is based on bone marrow morphology. The presence of fibrosis, JAK2/MPL mutation or +9/13q- cytogenetic abnormality is supportive but not essential for diagnosis. Prefibrotic PMF mimics essential thrombocythemia in its presentation and the distinction is prognostically relevant. Differential diagnosis of myelofibrosis should include chronic myelogenous leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia.
RISK STRATIFICATION
The Dynamic International Prognostic Scoring System-plus (DIPSS-plus) prognostic model for PMF can be applied at any point during the disease course and uses eight independent predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocytes >25 × 10(9) /L, circulating blasts ≥1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 × 10(9) /L, and unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p- or 11q23 rearrangement). The presence of 0, 1, "2 or 3," and ≥4 adverse factors defines low, intermediate-1, intermediate-2, and high-risk disease with median survivals of ~15.4, 6.5, 2.9, and 1.3 years, respectively. A >80% two-year mortality is predicted by monosomal karyotype, inv(3)/i(17q) abnormalities, or any two of circulating blasts >9%, leukocytes ≥40 × 10(9) /L or other unfavorable karyotype.
RISK-ADAPTED THERAPY
Observation alone is adequate for asymptomatic low/intermediate-1 risk disease. Allogeneic stem cell transplantation or experimental drug therapy is considered for intermediate-2/ high risk disease. Conventional or experimental drug therapy is reasonable for symptomatic intermediate-1 risk disease. Splenectomy and low-dose radiotherapy are used for drug-refractory splenomegaly. Radiotherapy is also used for the treatment of non-hepatosplenic EMH, PMF-associated pulmonary hypertension, and extremity bone pain.
Topics: Abnormal Karyotype; Bone Marrow; Decision Trees; Diagnosis, Differential; Humans; Practice Guidelines as Topic; Primary Myelofibrosis; Prognosis; Risk Assessment; Severity of Illness Index
PubMed: 22086865
DOI: 10.1002/ajh.22210 -
Asian Pacific Journal of Cancer... Jun 2019Primary Myelofibrosis is a BCR-ABL negative myeloproliferative neoplasm with a variety of hematological presentations, including thrombosis, bleeding diathesis and... (Review)
Review
Primary Myelofibrosis is a BCR-ABL negative myeloproliferative neoplasm with a variety of hematological presentations, including thrombosis, bleeding diathesis and marrow fibrosis. It is estimated to have an incidence of 1.5 per 100,000 people each year. Although JAK2 or MPL mutations are seen in PMF, several other mutations have recently been documented, including mutations in CALR, epigenetic regulators like TET, ASXL1, and 13q deletions. The identification of these mutations has improved the ability to develop novel treatment options. These include JAK inhibitors like ruxolitinib, heat shock protein-90 inhibitors like ganetespib, histone deacetylase inhibitors including panobinostat, pracinostat, vorinostat and givinostat, hypomethylating agents like decitabine, hedgehog inhibitors like glasdegib, PI3K, AKT and mTOR inhibitors like everolimus as well as telomerase inhibitors like imtelstat. Research on novel therapeutic options is being actively pursued in order to expand treatment options for primary myelofibrosis however currently, there is no curative therapy other than allogenic hematopoietic stem cell transplantation (ASCT) which is possible in select patients.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Humans; Mutation; Primary Myelofibrosis; Prognosis; Protein Kinase Inhibitors
PubMed: 31244289
DOI: 10.31557/APJCP.2019.20.6.1691 -
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 -
Cardiovascular & Hematological... Sep 2012Primary myelofibrosis is a clonal hematopoietic disorder characterized by ineffective hematopoiesis and progressive bone marrow fibrosis. Patients with high risk... (Review)
Review
Primary myelofibrosis is a clonal hematopoietic disorder characterized by ineffective hematopoiesis and progressive bone marrow fibrosis. Patients with high risk myelofibrosis as determined by their advanced age, degree of anemia, leukocytosis, constitutional symptoms and high percentage of circulating blasts have a very short median survival of 2 years. In addition quality of life is significantly compromised due to cytokine induced constitutional symptoms, frequent transfusion for cytopenias and bulky splenomegaly. Progression to myelogenous leukemia occurs in about 20% of patients within 10 years of diagnosis and is often fatal. Allogeneic hematopoietic transplantation is the only curative therapy but is limited by patient eligibility, transplant related mortality and graft versus host disease. Androgens, erythropoietin analogues, hydroxyurea, alkylators and spleen directed therapies have all been used with limited efficacy and no curative potential. The discovery of mutations in the hematopoietic progenitors of patients with myelofibrosis, including the JAK2 V617F mutation and others has greatly improved our understanding of the disease and facilitated development of newer targeted therapies. Our article will review new discoveries in the pathogenesis of myelofibrosis and focus on emerging targeted treatments. These novel therapies including oral JAK2 inhibitors, immunomodulators, as well as inhibitors of HDAC and mTOR, in isolation and in combination are likely to improve outcomes in management of this disease.
Topics: Humans; Primary Myelofibrosis
PubMed: 22746348
DOI: 10.2174/187152912801823174 -
International Journal of Laboratory... Jul 2021Philadelphia (BCR-ABL)-negative myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). MPN... (Meta-Analysis)
Meta-Analysis Review
Philadelphia (BCR-ABL)-negative myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). MPN can transform into an accelerated or a blast phase, which is associated with poor response to standard therapy and low overall median survival. We present an interesting case of a patient with a history of PMF and progression and summarize the current studies on genetic features of myeloproliferative neoplasms in blast phase (MPN-BP) with an emphasis on PMF. Although MPN-BP show ≥20% blasts in peripheral blood or bone marrow, it is not considered as acute myeloid leukemia (AML) according to the WHO classification. While MPNs-BP typically lack genetic mutations seen in de novo AML, they commonly harbor IDH1/2, SRSF2, ASXL1, and TP53 mutations, similar to the genetic profiles of acute myeloid leukemia with myelodysplasia-related changes (AML-MRC).
Topics: Biomarkers; Bone Marrow; Cytogenetic Analysis; Disease Progression; Disease Susceptibility; Erythrocyte Indices; Genetic Predisposition to Disease; Humans; Immunophenotyping; Middle Aged; Primary Myelofibrosis
PubMed: 34288445
DOI: 10.1111/ijlh.13565 -
Hematology. American Society of... 2007Primary myelofibrosis (PMF) is a chronic myeloproliferative disorder associated with an average survival of less than 5 years. Therapy for PMF has used chemotherapeutic... (Review)
Review
Primary myelofibrosis (PMF) is a chronic myeloproliferative disorder associated with an average survival of less than 5 years. Therapy for PMF has used chemotherapeutic agents, immunomodulatory drugs, or biological-response modifiers that have not always been directed at the biological processes that underlie the origins of PMF. Such strategies are palliative and have an uncertain effect on survival. At present, allogeneic stem cell transplantation (ASCT) is the only means of altering the natural history of patients with PMF and provides the only hope for cure of this disorder. Enthusiasm for ASCT in PMF has been muted due to an unacceptable transplantation-related morbidity and mortality in patients receiving fully myeloablative conditioning regimens. Recently, a variety of reduced-intensity conditioning regimens have been utilized in older patients with PMF with significant comorbidities with promising results. Greater understanding of the cellular and molecular events that lead to the development of PMF have provided the opportunity for targeted therapies for PMF. Such therapies must be first evaluated in phase 1/2 trials using a variety of endpoints to assess their efficacy and their potential associated toxicities. The performance of randomized clinical trials comparing these agents to the present standard of care would permit for the first time evidence-based therapeutic decisions to be made for patients with PMF.
Topics: Antineoplastic Agents; Humans; Myeloablative Agonists; Primary Myelofibrosis; Prognosis; Stem Cell Transplantation; Transplantation Conditioning
PubMed: 18024650
DOI: 10.1182/asheducation-2007.1.346 -
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 -
Hematology. American Society of... 2011Myelofibrosis (MF), either primary or arising from previous polycythemia vera (PV) or essential thrombocythemia (ET), is the worst among the chronic myeloproliferative... (Review)
Review
Myelofibrosis (MF), either primary or arising from previous polycythemia vera (PV) or essential thrombocythemia (ET), is the worst among the chronic myeloproliferative neoplasms in terms of survival and quality of life. Patients with MF have to face several clinical issues that, because of the poor effectiveness of medical therapy, surgery or radiotherapy, represent largely unmet clinical needs. Powerful risk stratification systems, applicable either at diagnosis using the International Prognostic Scoring System (IPSS) or during the variable course of illness using the Dynamic International Prognostic Scoring System (DIPSS) and DIPSS Plus, allow recognition of categories of patients with survival times ranging from decades to < 2 years. These scores are especially important for therapeutic decisions that include allogeneic stem cell transplantation (allogeneic SCT), the only curative approach that still carries a nonnegligible risk of morbidity and mortality even with newest reduced intensity conditioning (RIC) regimens. Discovery of JAK2V617F mutation prompted the development of clinical trials using JAK2 inhibitors; these agents overall have resulted in meaningful symptomatic improvement and reduction of splenomegaly that were otherwise not achievable with conventional therapy. Intriguing differences in the efficacy and tolerability of JAK2 inhibitors are being recognized, which could lead to a nonoverlapping spectrum of activity/safety. Other agents that do not directly target JAK2 and have shown symptomatic efficacy in MF are represented by inhibitors of the mammalian target of rapamycin (mTOR) and histone deacetylases (HDACs). Pomalidomide appears to be particularly active against MF-associated anemia. However, because these agents are all poorly effective in reducing the burden of mutated cells, further advancements are needed to move from enhancing our ability to palliate the disease to arriving at an actual cure for MF.
Topics: Humans; Primary Myelofibrosis; Risk Factors; Stem Cell Transplantation; Transplantation, Homologous
PubMed: 22160038
DOI: 10.1182/asheducation-2011.1.222 -
European Journal of Haematology Nov 1988
Topics: Humans; Methylprednisolone; Primary Myelofibrosis
PubMed: 3208874
DOI: No ID Found