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Ayalew Tefferi - One of the best experts on this subject based on the ideXlab platform.
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Myelofibrosis with Myeloid metaplasia
2016Co-Authors: Ayalew TefferiAbstract:The primary disease process in myelofibrosis with Myeloid metaplasia (MMM) is clonal myeloproliferation with varying degrees of phenotypic differentiation. This is characteristically accompanied by secondary intramedullary collagen fibrosis, osteosclerosis, angiogenesis, and extramedullary hematopoiesis. Modern clonality studies have confirmed the multipotent stem-cell origin of the neoplastic process in MMM. The nature of the specific oncogenic mutation(s) is currently being unraveled with the recent discovery of an association between a somatic point mutation of JAK2 tyrosine kinase (V617F) and bcr/abl-negative myeloproliferative disorders, including MMM. The pathogenetic mechanisms that underlie the secondary bone marrow stromal changes in MMM are also incompletely understood. Mouse models of this latter disease aspect have been constructed by either in vivo overexpression of thrombopoietin (TPOhigh mice) or megakaryocyte lineage restricted underexpression of the transcription factor GATA-1 (GATA-1low mice). Gene knockout experiments using such animal models have suggested the essential role of hematopoietic cell-derived transforming growth factor beta1 in inducing bone marrow fibrosis and stromal cell–derived osteoprotegerin in promoting osteosclerosis. However, experimental myelofibrosis in mice does not recapitulate clonal myeloproliferation that is fundamental to human MMM. Other cytokines that are implicated in mediating myelofibrosis and angiogenesis in MMM include basic fibroblast, platelet-derived, and vascular endothelial growth factors. It is currently assumed that such cytokines are abnormally released from clonal megakaryocytes as a result of a pathologic interaction with neutrophils (eg, emperipolesis). This latter phenomenon, through neutrophil-derived elastase, could also underlie the abnormal peripheral-blood egress of Myeloid progenitors in MMM. J Clin Oncol 23:8520-8530. © 2005 by American Society of Clinical Oncolog
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Myelofibrosis with Myeloid metaplasia
2013Co-Authors: Ayalew TefferiAbstract:Myelofibrosis with Myeloid metaplasia (MMM) represents both agnogenic Myeloid metaplasia (AMM) and the fibrotic stages of polycythemia vera (PV) and essential thrombocythemia (ET). The latter two conditions are also referre
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concurrent mpl515 and jak2v617f mutations in myelofibrosis chronology of clonal emergence and changes in mutant allele burden over time
British Journal of Haematology, 2006Co-Authors: Terra L Lasho, Ruben A Mesa, Gary D Gilliland, Ross L Levine, Rebecca F Mcclure, Animesh Pardanani, Ayalew TefferiAbstract:MPLW515L/K and JAK2V617F can co-exist in myelofibrosis with Myeloid metaplasia (MMM). The chronology of clonal emergence was studied in three such cases using serially stored bone marrow. At diagnosis, a major MPL515 mutant clone was accompanied by a minor JAK2V617F clone in all three instances. At 25 time points over a period of 4-8 years, allele burden fluctuated but remained high for MPLW515L/K and low for JAK2V617F. We conclude that MPLW515L/K and JAK2V617F are both early events in MMM and allele burden, rather than the mere presence of these mutations, might be relevant to phenotypic variation in myeloproliferative disorders.
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jak2v617f and leukemic transformation in myelofibrosis with Myeloid metaplasia
Leukemia Research, 2006Co-Authors: Ruben A Mesa, Terra L Lasho, Heather Powell, Gordon W Dewald, Rebecca F Mcclure, Ayalew TefferiAbstract:Amongst 42 consecutive patients with leukemic transformation (LT) from myelofibrosis with Myeloid metaplasia (MMM) 72% carried the JAK2(V617F) mutation. The mutation was observed at expected frequencies in all subtypes of MMM and acute Myeloid leukemia. Although the patients with the mutation were younger and had a shorter interval to LT there was no difference in survival. Additionally, both the lack of mutation status progression in serial analysis (available in nine patients) and the low frequency of patients with high mutated allele burden suggest that LT arising from MMM is probably not dependent on changes in JAK2(V617F) mutation status.
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international working group iwg consensus criteria for treatment response in myelofibrosis with Myeloid metaplasia for the iwg for myelofibrosis research and treatment iwg mrt
Blood, 2006Co-Authors: Ayalew Tefferi, Ruben A Mesa, Giovanni Barosi, Francisco Cervantes, Joachim H Deeg, John T Reilly, Srdan Verstovsek, Brigitte Dupriez, Richard T Silver, Olatoyosi OdenikeAbstract:Myelofibrosis with Myeloid metaplasia (MMM) is a clinicopathologic entity characterized by stem cell-derived clonal myeloproliferation, ineffective erythropoiesis, extramedullary hematopoiesis, and bone marrow fibrosis and osteosclerosis. Patients with MMM have shortened survival and their quality of life is compromised by progressive anemia, marked hepatosplenomegaly, and severe constitutional symptoms including cachexia. After decades of frustration with ineffective therapy, patients are now being served by promising treatment approaches that include allogeneic hematopoietic stem cell transplantation and immunomodulatory drugs. Recent information regarding disease pathogenesis, including a contribution to the myeloproliferative disorder phenotype by a gain-of-function JAK2 mutation (JAK2(V617F)), has revived the prospect of targeted therapeutics as well as molecular monitoring of treatment response. Such progress calls for standardization of response criteria to accurately assess the value of new treatment modalities, to allow accurate comparison between studies, and to ensure that the definition of response reflects meaningful health outcome. Accordingly, an international panel of experts recently convened and delineated 3 response categories: complete remission (CR), partial remission (PR), and clinical improvement (CI). Bone marrow histologic and hematologic remissions characterize CR and CR/PR, respectively. The panel agreed that the CI response category is applicable only to patients with moderate to severe cytopenia or splenomegaly.
Giovanni Barosi - One of the best experts on this subject based on the ideXlab platform.
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primary myelofibrosis pmf post polycythemia vera myelofibrosis post pv mf post essential thrombocythemia myelofibrosis post et mf blast phase pmf pmf bp consensus on terminology by the international working group for myelofibrosis research and treatm
Leukemia Research, 2007Co-Authors: Srdan Verstovsek, Martha Wadleigh, Giovanni Barosi, Francisco Cervantes, John T Reilly, Brigitte Dupriez, Ross L Levine, Mariecaroline Le Boussekerdiles, Peter J CampbellAbstract:Abstract The International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) is comprised of hematologists, hematopathologists, and laboratory scientists and its main goal is to provide a forum for scientific exchange and collaboration. During its first general meeting in April 2006, the IWG-MRT established uniform treatment response criteria for chronic idiopathic myelofibrosis (CIMF); also known as agnogenic Myeloid metaplasia (AMM), myelofibrosis with Myeloid metaplasia (MMM), and many other names in the hematologic literature. This document summarizes the proceedings from the second meeting of the IWG-MRT, in November 2006, where the group discussed and agreed to standardize the nomenclature referring to CIMF: (i) the term primary myelofibrosis (PMF) was chosen over several other designations including CIMF, AMM, and MMM, (ii) myelofibrosis that develops in the setting of either polycythemia vera (PV) or essential thrombocythemia (ET) will be referred to as post-PV MF and post-ET MF, respectively, and (iii) “leukemic” transformation will be recognized as blast phase disease (PMF-BP, post-PV/ET MF in blast phase).
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international working group iwg consensus criteria for treatment response in myelofibrosis with Myeloid metaplasia for the iwg for myelofibrosis research and treatment iwg mrt
Blood, 2006Co-Authors: Ayalew Tefferi, Ruben A Mesa, Giovanni Barosi, Francisco Cervantes, Joachim H Deeg, John T Reilly, Srdan Verstovsek, Brigitte Dupriez, Richard T Silver, Olatoyosi OdenikeAbstract:Myelofibrosis with Myeloid metaplasia (MMM) is a clinicopathologic entity characterized by stem cell-derived clonal myeloproliferation, ineffective erythropoiesis, extramedullary hematopoiesis, and bone marrow fibrosis and osteosclerosis. Patients with MMM have shortened survival and their quality of life is compromised by progressive anemia, marked hepatosplenomegaly, and severe constitutional symptoms including cachexia. After decades of frustration with ineffective therapy, patients are now being served by promising treatment approaches that include allogeneic hematopoietic stem cell transplantation and immunomodulatory drugs. Recent information regarding disease pathogenesis, including a contribution to the myeloproliferative disorder phenotype by a gain-of-function JAK2 mutation (JAK2(V617F)), has revived the prospect of targeted therapeutics as well as molecular monitoring of treatment response. Such progress calls for standardization of response criteria to accurately assess the value of new treatment modalities, to allow accurate comparison between studies, and to ensure that the definition of response reflects meaningful health outcome. Accordingly, an international panel of experts recently convened and delineated 3 response categories: complete remission (CR), partial remission (PR), and clinical improvement (CI). Bone marrow histologic and hematologic remissions characterize CR and CR/PR, respectively. The panel agreed that the CI response category is applicable only to patients with moderate to severe cytopenia or splenomegaly.
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99mtc bw250 183 bone marrow immunoscintigraphy is correlated to clinical and biologic features of myelofibrosis with Myeloid metaplasia
Blood, 2005Co-Authors: Monia Marchetti, Carlo Aprile, Carla Greco, Giovanni BarosiAbstract:BACKGROUND: Myelofibrosis with Myeloid metaplasia (MMM) is a rare chronic myeloproliferative disease characterized by both myeloproliferative and myelodepletive features: myeloproliferation typically includes enhanced spontaneous mobilization of hematopoietic progenitor cells (HPC) from the bone marrow (BM) and their homing into extramedullary sites (mainly spleen); myelodepletion results from exhaustion of both BM and extramedullary hemopoiesis. AIMS: To investigate the extent and distribution of hematopoiesis in MMM patients and to capture its relationship with BM fibrosis, HPC mobilization and clinical severity. METHODS: Immunoscintigraphy employing a dual-head camera was performed 120–260 minutes (median 180 minutes) after administration of 553–830 MBq (median 700 MBq) 99mTc-BW250/183, corresponding to 0.3–0.5 mg. Hematopoietic function in the central compartment (sacrum) was described by “subtypes” (normal, increased or decreased) and by the sacrum-to-soft tissue uptake ratio (UR) (Huic at el, J Nucl Med 1997). The degree of peripheral BM displacement (limbs) was described through 5 “types” (I to V) (Huic at el, J Nucl Med 1997). RESULTS: Twenty-three MMM patients (13 males, median age 55 years) were studied. Eleven patients showed a reduced uptake by the central BM compartment: they had a higher WHO fibrosis grade (p=0.008), lower hemoglobin values (p=0.012) and lower platelet counts (p=0.007) than patients with a preserved central compartment. Patients with an exhausted central compartment at immunoscintigraphy also showed a significantly higher mobilization of HPC into peripheral blood, as documented by higher values of the following parameters: CD34+ count (0.86% vs 0.12%; p=0.029), immature Myeloid cells or blasts (9.5% versus 0.3%; p=0.005), spleen size (9.3 vs 2.4 centimeters from costal arc; p=0.007). Among the patients with a depressed central compartment, those who also lost peripheral BM function (type V) showed a more severe myelodepletion and more intense HPC mobilization. On the opposite side, among the 12 patients with a preserved central compartment, the 8 ones with a mild peripheral BM displacement (type I–II) showed absent or mild fibrosis (WHO 0-1), elevated platelet counts, normal to high hemoglobin values, minimally enlarged spleens and no hints of increased HPC mobilization (CD34+ CONCLUSIONS: BM immunoscintigraphy accurately tracks MMM clinical features and may help staging MMM patients, understanding MMM biology and targeting therapies
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response criteria for myelofibrosis with Myeloid metaplasia results of an initiative of the european myelofibrosis network eumnet
Blood, 2005Co-Authors: Giovanni Barosi, Francisco Cervantes, Brigitte Dupriez, Jean Loup Demory, Dominique Bordessoule, Jean Briere, Heinz Gisslinger, Martin Griesshammer, Hans Carl Hasselbalch, Rajko KusecAbstract:The European Myelofibrosis Network (EUMNET), a European research network on myelofibrosis with Myeloid metaplasia (MMM), has developed a definition of response for the disease by using clinicohematologic, histologic, and cytogenetic criteria. A core set of 5 clinicohematologic criteria was selected out of 9 candidates on the basis of their sensitivity to change measured in 196 patients treated either during clinical trials or routine clinical practice. A consensus panel of 16 international experts was convened and asked to score the level of response in 104 patient profiles as major, moderate, minor, or no response according to changes of the clinicohematologic criteria. Using the experts' consensus as the gold standard, the performance of 100 possible definitions of response was evaluated. Criteria for major or moderate clinicohematologic response were determined to be changes in hemoglobin (Hb) and spleen size and the presence of constitutional symptoms, while changes in platelet count and white blood cell (WBC) count served as complementary criteria and were of value for defining minor responses. A histologic response was defined by changes in bone marrow fibrosis and cellularity grades. The combined use of these response definitions should help standardize the design and reporting of future clinical studies in MMM.
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allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in intermediate or high risk patients with myelofibrosis with Myeloid metaplasia
Blood, 2005Co-Authors: Damiano Rondelli, Giovanni Barosi, Uday R Popat, Josef T Prchal, Andrea Bacigalupo, Emilio P Alessandrino, Jerry L Spivak, Douglas B Smith, Hans Klingemann, Steven FruchtmanAbstract:A total of 21 patients with myelofibrosis with Myeloid metaplasia (MMM), with a median age of 54 years (range, 27-68 years), were prepared with a reduced-intensity conditioning (RIC) regimen. The patients received an allogeneic marrow (n = 3) or peripheral blood stem-cell (n = 18) transplant from HLA-matched related (n = 18) or unrelated (n = 2), or 1 Ag-mismatched related (n = 1), donors. RIC regimens included fludarabine/total body irradiation 200 cGy (n = 5) or 450 cGy (n = 1), fludarabine/melphalan (n = 7), thiotepa/cyclophosphamide (n = 7), and thiotepa/fludarabine (n = 1). At the time of transplantation, all of the patients were at intermediate (n = 13) or high (n = 8) risk, according to the Dupriez classification. Of the patients, 19 had grade III or IV marrow fibrosis. All of the patients achieved full engraftment but one. Posttransplantation chimerism analysis showed more than 95% donor cells in 18 patients, while 2 patients achieved complete donor chimerism after donor leukocyte infusion (DLI). Acute graft-versus-host disease (GVHD) grades II to IV was observed in 7 patients, grades III to IV in 2, and extensive chronic GVHD in 8 of 18 evaluable patients. There were 3 patients who died from acute GVHD, infection, and relapse. There are 18 patients alive 12 to 122 months (median, 31 months) after transplantation, and 17 are in remission (1 after a second transplantation). The use of RIC regimens in allogeneic stem cell transplantation results in prolonged survival in intermediate/high-risk MMM patients.
Francisco Cervantes - One of the best experts on this subject based on the ideXlab platform.
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primary myelofibrosis pmf post polycythemia vera myelofibrosis post pv mf post essential thrombocythemia myelofibrosis post et mf blast phase pmf pmf bp consensus on terminology by the international working group for myelofibrosis research and treatm
Leukemia Research, 2007Co-Authors: Srdan Verstovsek, Martha Wadleigh, Giovanni Barosi, Francisco Cervantes, John T Reilly, Brigitte Dupriez, Ross L Levine, Mariecaroline Le Boussekerdiles, Peter J CampbellAbstract:Abstract The International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) is comprised of hematologists, hematopathologists, and laboratory scientists and its main goal is to provide a forum for scientific exchange and collaboration. During its first general meeting in April 2006, the IWG-MRT established uniform treatment response criteria for chronic idiopathic myelofibrosis (CIMF); also known as agnogenic Myeloid metaplasia (AMM), myelofibrosis with Myeloid metaplasia (MMM), and many other names in the hematologic literature. This document summarizes the proceedings from the second meeting of the IWG-MRT, in November 2006, where the group discussed and agreed to standardize the nomenclature referring to CIMF: (i) the term primary myelofibrosis (PMF) was chosen over several other designations including CIMF, AMM, and MMM, (ii) myelofibrosis that develops in the setting of either polycythemia vera (PV) or essential thrombocythemia (ET) will be referred to as post-PV MF and post-ET MF, respectively, and (iii) “leukemic” transformation will be recognized as blast phase disease (PMF-BP, post-PV/ET MF in blast phase).
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international working group iwg consensus criteria for treatment response in myelofibrosis with Myeloid metaplasia for the iwg for myelofibrosis research and treatment iwg mrt
Blood, 2006Co-Authors: Ayalew Tefferi, Ruben A Mesa, Giovanni Barosi, Francisco Cervantes, Joachim H Deeg, John T Reilly, Srdan Verstovsek, Brigitte Dupriez, Richard T Silver, Olatoyosi OdenikeAbstract:Myelofibrosis with Myeloid metaplasia (MMM) is a clinicopathologic entity characterized by stem cell-derived clonal myeloproliferation, ineffective erythropoiesis, extramedullary hematopoiesis, and bone marrow fibrosis and osteosclerosis. Patients with MMM have shortened survival and their quality of life is compromised by progressive anemia, marked hepatosplenomegaly, and severe constitutional symptoms including cachexia. After decades of frustration with ineffective therapy, patients are now being served by promising treatment approaches that include allogeneic hematopoietic stem cell transplantation and immunomodulatory drugs. Recent information regarding disease pathogenesis, including a contribution to the myeloproliferative disorder phenotype by a gain-of-function JAK2 mutation (JAK2(V617F)), has revived the prospect of targeted therapeutics as well as molecular monitoring of treatment response. Such progress calls for standardization of response criteria to accurately assess the value of new treatment modalities, to allow accurate comparison between studies, and to ensure that the definition of response reflects meaningful health outcome. Accordingly, an international panel of experts recently convened and delineated 3 response categories: complete remission (CR), partial remission (PR), and clinical improvement (CI). Bone marrow histologic and hematologic remissions characterize CR and CR/PR, respectively. The panel agreed that the CI response category is applicable only to patients with moderate to severe cytopenia or splenomegaly.
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response criteria for myelofibrosis with Myeloid metaplasia results of an initiative of the european myelofibrosis network eumnet
Blood, 2005Co-Authors: Giovanni Barosi, Francisco Cervantes, Brigitte Dupriez, Jean Loup Demory, Dominique Bordessoule, Jean Briere, Heinz Gisslinger, Martin Griesshammer, Hans Carl Hasselbalch, Rajko KusecAbstract:The European Myelofibrosis Network (EUMNET), a European research network on myelofibrosis with Myeloid metaplasia (MMM), has developed a definition of response for the disease by using clinicohematologic, histologic, and cytogenetic criteria. A core set of 5 clinicohematologic criteria was selected out of 9 candidates on the basis of their sensitivity to change measured in 196 patients treated either during clinical trials or routine clinical practice. A consensus panel of 16 international experts was convened and asked to score the level of response in 104 patient profiles as major, moderate, minor, or no response according to changes of the clinicohematologic criteria. Using the experts' consensus as the gold standard, the performance of 100 possible definitions of response was evaluated. Criteria for major or moderate clinicohematologic response were determined to be changes in hemoglobin (Hb) and spleen size and the presence of constitutional symptoms, while changes in platelet count and white blood cell (WBC) count served as complementary criteria and were of value for defining minor responses. A histologic response was defined by changes in bone marrow fibrosis and cellularity grades. The combined use of these response definitions should help standardize the design and reporting of future clinical studies in MMM.
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efficacy and tolerability of danazol as a treatment for the anaemia of myelofibrosis with Myeloid metaplasia long term results in 30 patients
British Journal of Haematology, 2005Co-Authors: Francisco Cervantes, Alberto Alvarezlarran, Abel Domingo, Eduardo Arellanorodrigo, Emili MontserratAbstract:Summary Androgens are considered the treatment of choice for the anaemia of myelofibrosis with Myeloid metaplasia (MMM). Good results have been reported in a few patients treated with danazol, a synthetic attenuated androgen. The long-term efficacy and tolerability of danazol as treatment for the anaemia of MMM was evaluated in 30 patients, who received 600 mg/d, with progressive tapering to the minimum effective dose in the responders after 6 months. Complete response (CR) was defined as transfusion cessation with normal Hb and partial response (PR) as an Hb increase ≥1·5 g/dl with transfusion-independent Hb values >10 g/dl maintained for at least 8 weeks. Median follow-up was 20·5 months (range: 3·5–58 months). Response was achieved in 11 patients (37%), including eight CRs and three PRs. Median time to response was 5 months (range: 1–9 months). Four patients stopped responding at 6–24 months, two responders discontinued treatment because of toxicity, and five maintained response at 3·5–42 months. Pretreatment variables associated with response were lack of transfusion requirement (P= 0·001) and higher Hb at treatment start (P= 0·02). Toxicity was usually moderate, leading to treatment withdrawal in only two cases. Danazol is effective and well tolerated in a substantial proportion of MMM patients with anaemia.
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myelofibrosis with Myeloid metaplasia following essential thrombocythaemia actuarial probability presenting characteristics and evolution in a series of 195 patients
British Journal of Haematology, 2002Co-Authors: Francisco Cervantes, Alberto Alvarezlarran, Carme Talarn, Marta Gomez, Emili MontserratAbstract:Myelofibrotic transformation is a known complication of essential thrombocythaemia (ET), but information on its incidence, presenting features and evolution is scarce. In a series of 195 patients with ET followed for a median of 7.2 years (range: 1.9-24), evolution into myelofibrosis with Myeloid metaplasia (MMM) occurred in 13 cases, a median of 8 years (range: 3.6-20.2) from diagnosis. The actuarial probability of this complication was 2.7% (95% CI: 2.4-2.9) at 5 years, 8.3% (95% CI: 7.8-8.9) at 10 years, and 15.3% (95% CI: 6.1-24.5) at 15 years. Four patients had not been treated before developing MMM. The main features indicating this condition were the appearance of immature Myeloid precursors in the peripheral blood, a decrease in the Hb value not related to treatment and increased serum lactate dehydrogenase levels, followed by a progressive decrease in the platelet count, increasing leucocytosis and progressive splenomegaly. No patient had constitutional symptoms, and none of five evaluable cases showed chromosome abnormalities in bone marrow or unstimulated blood. After a median the myelofibrotic transformation, three patients have died and four have not required treatment for MMM as yet.
Ruben A Mesa - One of the best experts on this subject based on the ideXlab platform.
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CHING-LIANG HO
2015Co-Authors: James D. Hoyer, Ruben A MesaAbstract:Bone marrow angiogenesis and its clinical correlates in myelofibrosis with Myeloid metaplasia The term myelofibrosis with Myeloidmetaplasia (MMM) describes a clonalstem cell disorder that is characterized by bone marrow myeloproliferation associ-ated with a polymorphic stromal reaction including myelofibrosis, osteosclerosis, and angiogenesis.1 The median survival ranges from 2 to more than 15 years depending on the presence or absence of well-defined prognostic factors including age, hemoglobin level, leukocyte count, hypercatabolic symp-toms, and circulating myeloblast percent-age.2,3 Interestingly, neither the degree of bone marrow fibrosis nor spleen size ha
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concurrent mpl515 and jak2v617f mutations in myelofibrosis chronology of clonal emergence and changes in mutant allele burden over time
British Journal of Haematology, 2006Co-Authors: Terra L Lasho, Ruben A Mesa, Gary D Gilliland, Ross L Levine, Rebecca F Mcclure, Animesh Pardanani, Ayalew TefferiAbstract:MPLW515L/K and JAK2V617F can co-exist in myelofibrosis with Myeloid metaplasia (MMM). The chronology of clonal emergence was studied in three such cases using serially stored bone marrow. At diagnosis, a major MPL515 mutant clone was accompanied by a minor JAK2V617F clone in all three instances. At 25 time points over a period of 4-8 years, allele burden fluctuated but remained high for MPLW515L/K and low for JAK2V617F. We conclude that MPLW515L/K and JAK2V617F are both early events in MMM and allele burden, rather than the mere presence of these mutations, might be relevant to phenotypic variation in myeloproliferative disorders.
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jak2v617f and leukemic transformation in myelofibrosis with Myeloid metaplasia
Leukemia Research, 2006Co-Authors: Ruben A Mesa, Terra L Lasho, Heather Powell, Gordon W Dewald, Rebecca F Mcclure, Ayalew TefferiAbstract:Amongst 42 consecutive patients with leukemic transformation (LT) from myelofibrosis with Myeloid metaplasia (MMM) 72% carried the JAK2(V617F) mutation. The mutation was observed at expected frequencies in all subtypes of MMM and acute Myeloid leukemia. Although the patients with the mutation were younger and had a shorter interval to LT there was no difference in survival. Additionally, both the lack of mutation status progression in serial analysis (available in nine patients) and the low frequency of patients with high mutated allele burden suggest that LT arising from MMM is probably not dependent on changes in JAK2(V617F) mutation status.
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international working group iwg consensus criteria for treatment response in myelofibrosis with Myeloid metaplasia for the iwg for myelofibrosis research and treatment iwg mrt
Blood, 2006Co-Authors: Ayalew Tefferi, Ruben A Mesa, Giovanni Barosi, Francisco Cervantes, Joachim H Deeg, John T Reilly, Srdan Verstovsek, Brigitte Dupriez, Richard T Silver, Olatoyosi OdenikeAbstract:Myelofibrosis with Myeloid metaplasia (MMM) is a clinicopathologic entity characterized by stem cell-derived clonal myeloproliferation, ineffective erythropoiesis, extramedullary hematopoiesis, and bone marrow fibrosis and osteosclerosis. Patients with MMM have shortened survival and their quality of life is compromised by progressive anemia, marked hepatosplenomegaly, and severe constitutional symptoms including cachexia. After decades of frustration with ineffective therapy, patients are now being served by promising treatment approaches that include allogeneic hematopoietic stem cell transplantation and immunomodulatory drugs. Recent information regarding disease pathogenesis, including a contribution to the myeloproliferative disorder phenotype by a gain-of-function JAK2 mutation (JAK2(V617F)), has revived the prospect of targeted therapeutics as well as molecular monitoring of treatment response. Such progress calls for standardization of response criteria to accurately assess the value of new treatment modalities, to allow accurate comparison between studies, and to ensure that the definition of response reflects meaningful health outcome. Accordingly, an international panel of experts recently convened and delineated 3 response categories: complete remission (CR), partial remission (PR), and clinical improvement (CI). Bone marrow histologic and hematologic remissions characterize CR and CR/PR, respectively. The panel agreed that the CI response category is applicable only to patients with moderate to severe cytopenia or splenomegaly.
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lenalidomide therapy in myelofibrosis with Myeloid metaplasia
Blood, 2006Co-Authors: Ayalew Tefferi, Terra L Lasho, Ruben A Mesa, Srdan Verstovsek, Jorge E Cortes, Deborah A Thomas, William J Hogan, Mark R Litzow, Jacob B Allred, Dan JonesAbstract:We present results of 2 similarly designed but separate phase 2 studies involving single-agent lenalidomide (CC-5013, Revlimid) in a total of 68 patients with symptomatic myelofibrosis with Myeloid metaplasia (MMM). Protocol treatment consisted of oral lenalidomide at 10 mg/d (5 mg/d if baseline platelet count < 100 x 10(9)/L) for 3 to 4 months with a plan to continue treatment for either 3 or 24 additional months, in case of response. Overall response rates were 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia. Response in anemia was deemed impressive in 8 patients whose hemoglobin level normalized from a baseline of either transfusion dependency or hemoglobin level lower than 100 g/L. Additional treatment effects in these patients included resolution of leukoerythroblastosis (4 patients), a decrease in medullary fibrosis and angiogenesis (2 patients), and del(5)(q13q33) cytogenetic remission accompanied by a reduction in JAK2(V617F) mutation burden (1 patient). Grade 3 or 4 adverse events included neutropenia (31%) and thrombocytopenia (19%). We conclude that lenalidomide engenders an intriguing treatment activity in a subset of patients with MMM that includes an unprecedented effect on peripheral blood and bone marrow abnormalities.
Benjamin L Ebert - One of the best experts on this subject based on the ideXlab platform.
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mplw515l is a novel somatic activating mutation in myelofibrosis with Myeloid metaplasia
PLOS Medicine, 2006Co-Authors: Yana Pikman, Benjamin H Lee, Thomas Mercher, Elizabeth Mcdowell, Benjamin L Ebert, Maricel Gozo, Adam Cuker, Gerlinde Wernig, Sandra A MooreAbstract:Background The JAK2V617F allele has recently been identified in patients with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis with Myeloid metaplasia (MF). Subsequent analysis has shown that constitutive activation of the JAK-STAT signal transduction pathway is an important pathogenetic event in these patients, and that enzymatic inhibition of JAK2V617F may be of therapeutic benefit in this context. However, a significant proportion of patients with ET or MF are JAK2V617F-negative. We hypothesized that activation of the JAK-STAT pathway might also occur as a consequence of activating mutations in certain hematopoietic-specific cytokine receptors, including the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte-colony stimulating factor receptor (GCSFR).
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MPLW515L is a novel somatic activating mutation in myelofibrosis with Myeloid metaplasia.
Public Library of Science (PLoS), 2006Co-Authors: Yana Pikman, Benjamin H Lee, Thomas Mercher, Elizabeth Mcdowell, Benjamin L Ebert, Maricel Gozo, Adam Cuker, Gerlinde Wernig, Sandra Moore, Ilene GalinskyAbstract:The JAK2V617F allele has recently been identified in patients with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis with Myeloid metaplasia (MF). Subsequent analysis has shown that constitutive activation of the JAK-STAT signal transduction pathway is an important pathogenetic event in these patients, and that enzymatic inhibition of JAK2V617F may be of therapeutic benefit in this context. However, a significant proportion of patients with ET or MF are JAK2V617F-negative. We hypothesized that activation of the JAK-STAT pathway might also occur as a consequence of activating mutations in certain hematopoietic-specific cytokine receptors, including the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte-colony stimulating factor receptor (GCSFR).DNA sequence analysis of the exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR, and comparison with germline DNA derived from buccal swabs, identified a somatic activating mutation in the transmembrane domain of MPL (W515L) in 9% (4/45) of JAKV617F-negative MF. Expression of MPLW515L in 32D, UT7, or Ba/F3 cells conferred cytokine-independent growth and thrombopoietin hypersensitivity, and resulted in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK. Furthermore, a small molecule JAK kinase inhibitor inhibited MPLW515L-mediated proliferation and JAK-STAT signaling in vitro. In a murine bone marrow transplant assay, expression of MPLW515L, but not wild-type MPL, resulted in a fully penetrant myeloproliferative disorder characterized by marked thrombocytosis (Plt count 1.9-4.0 x 10(12)/L), marked splenomegaly due to extramedullary hematopoiesis, and increased reticulin fibrosis.Activation of JAK-STAT signaling via MPLW515L is an important pathogenetic event in patients with JAK2V617F-negative MF. The bone marrow transplant model of MPLW515L-mediated myeloproliferative disorders (MPD) exhibits certain features of human MF, including extramedullary hematopoiesis, splenomegaly, and megakaryocytic proliferation. Further analysis of positive and negative regulators of the JAK-STAT pathway is warranted in JAK2V617F-negative MPD
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activating mutation in the tyrosine kinase jak2 in polycythemia vera essential thrombocythemia and Myeloid metaplasia with myelofibrosis
Cancer Cell, 2005Co-Authors: Martha Wadleigh, Ross L Levine, Benjamin L Ebert, Gerlinde Wernig, Jan Cools, Brian J P Huntly, Titus J Boggon, Iwona WlodarskaAbstract:Polycythemia vera (PV), essential thrombocythemia (ET), and Myeloid metaplasia with myelofibrosis (MMM) are clonal disorders arising from hematopoietic progenitors. An internet-based protocol was used to collect clinical information and biological specimens from patients with these diseases. High-throughput DNA resequencing identified a recurrent somatic missense mutation JAK2V617F in granulocyte DNA samples of 121 of 164 PV patients, of which 41 had homozygous and 80 had heterozygous mutations. Molecular and cytogenetic analyses demonstrated that homozygous mutations were due to duplication of the mutant allele. JAK2V617F was also identified in granulocyte DNA samples from 37 of 115 ET and 16 of 46 MMM patients, but was not observed in 269 normal individuals. In vitro analysis demonstrated that JAK2V617F is a constitutively active tyrosine kinase.
