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Ayalew Tefferi

Publications and source records attributed to Ayalew Tefferi.

At least 19 recordsLinked to original sources
PubMed2007

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 treatment (IWG-MRT).

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).

Blast Crisis↗
PubMed2007

The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): an international Internet-based survey of 1179 MPD patients.

BACKGROUND: Few objective data exist on the burden of fatigue and other constitutional symptoms in patients with myeloproliferative disorders (MPD). METHODS: The authors used validated instruments of fatigue and physical activity assessment during an Internet-based symptom survey of 1179 MPD patients (median age, 56 years; 41.4% men). RESULTS: The frequency of self-reporting was 80.7% for fatigue, which was substantially higher than that of pruritus (52.2%), night sweats (49.2%), bone pain (43.9%), fever (13.7%), and weight loss (13.1%). In the majority of patients, these symptoms restricted participation in both social functions and physical activity. In addition, 34.5% of patients needed assistance with activities of daily living, and 11.2% reported MPD-associated medical disability. As expected, the presence of myelofibrosis, anemia, splenomegaly, or other features associated with advanced disease favored a higher degree of fatigue. However, fatigue remained the major complaint also in polycythemia vera (84.9%) and essential thrombocythemia (72.4%); these figures were significantly higher than those of published controls (P < .0001). CONCLUSIONS: The current study identifies fatigue as the major contributor to poor quality of life in MPD, provides baseline information on constitutional symptoms, and underscores the need for the incorporation of quality of life assessment in clinical trials.

Activities of Daily Living↗
PubMed2006

Efficacy of conventional cytogenetics and FISH for EGR1 to detect deletion 5q in hematological disorders and to assess response to treatment with Lenalidomide.

In clinical practice, whether FISH for EGR1 in interphase nuclei has similar efficacy to detect deletion 5q anomalies as conventional cytogenetic studies is unknown. We compared conventional cytogenetics and FISH for 145 patients with deletion 5q and detected this anomaly by both methods in 144. Nine patients with myelodysplasia were studied before and after treatment with Lenalidomide and results were concordant for 28 of 29 specimens. FISH did not detect anomalies other than deletion 5q in 31 patients. This study suggests FISH is useful to detect deletion 5q, but is not a substitute for conventional cytogenetics.

Adult↗
PubMed2006

Thalidomide therapy in adult patients with myelodysplastic syndrome. A North Central Cancer Treatment Group phase II trial.

BACKGROUND: Thalidomide has shown promise for the treatment of patients with myelodysplastic syndrome. The current prospective multicenter study examined the efficacy and toxicity of thalidomide in adult patients with myelodysplastic syndrome. METHODS: Using the International Prognostic Scoring System (IPSS), patients were stratified into 2 groups: favorable (IPSS score, 0-1.0) or unfavorable (IPSS score, 1.5-3.5). Seventy-two patients (42 of whom were favorable and 30 of whom were unfavorable) received a starting dose of oral thalidomide of 200 mg daily. The dose was increased by 50 mg per week to a targeted maximum daily dose of 1000 mg. RESULTS: According to the International Working Group response criteria for myelodysplastic syndrome, 1 patient in the unfavorable group achieved a partial remission with a complete cytogenetic response. Overall, 2 patients (5%) in the favorable group and 4 patients (14%) in the unfavorable group experienced either a hematologic improvement or a partial response. The most frequent Grade 3 or 4 (grading was based on the National Cancer Institute's Common Toxicity Criteria [version 2.0]) nonhematologic adverse events were fatigue (24%), infection (19%), neuropathy (13%), dyspnea (8%), and constipation (7%). CONCLUSIONS: Thalidomide alone, at the schedule and dose levels used in the current study, is not a safe and viable therapeutic option for patients with myelodysplastic syndrome. Limited efficacy and increased toxicity were observed in the current Phase II trial.

Aged↗
PubMed2006

EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation.

Gain-of-function mutations of the receptor tyrosine kinase KIT play a key role in the pathogenesis of systemic mastocytosis (SM), gastrointestinal stromal tumors (GISTs), and some cases of acute myeloid leukemia (AML). Whereas KIT juxtamembrane domain mutations seen in most patients with GIST are highly sensitive to imatinib, the kinase activation loop mutant D816V, frequently encountered in SM, hampers the binding ability of imatinib. We investigated the inhibitory activity of the novel tyrosine kinase inhibitor EXEL-0862 against 2 subclones of human mast cell line-1 (HMC-1)-HMC-1.1, harboring the juxtamembrane domain mutation V560G, and HMC-1.2, carrying V560G and the activation loop mutation D816V, found in more than 80% of patients with SM. EXEL-0862 inhibited the phosphorylation of KIT in a dose-dependent manner and decreased cell proliferation in both mast cell lines with higher activity against HMC-1.2 cells. The phosphorylation of KIT-dependent signal transducer and activator of transcription-3 (STAT3) and STAT5 was abrogated upon exposure to nanomolar concentrations of EXEL-0862. In addition, EXEL-0862 induced a time- and dose-dependent proapoptotic effect in both mast cell lines and caused a significant reduction in mast-cell content in bone marrow samples from patients with SM harboring D816V and from those without the D816V mutation. We conclude that EXEL-0862 is active against KIT activation loop mutants and is a promising candidate for the treatment of patients with SM and other KIT-driven malignancies harboring active site mutations.

Aged↗
PubMed2006

MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients.

Recently, a gain-of-function MPL mutation, MPLW515L, was described in patients with JAK2V617F-negative myelofibrosis with myeloid metaplasia (MMM). To gain more information on mutational frequency, disease specificity, and clinical correlates, genomic DNA from 1182 patients with myeloproliferative and other myeloid disorders and 64 healthy controls was screened for MPL515 mutations, regardless of JAK2V617F mutational status: 290 with MMM, 242 with polycythemia vera, 318 with essential thrombocythemia (ET), 88 with myelodysplastic syndrome, 118 with chronic myelomonocytic leukemia, and 126 with acute myeloid leukemia (AML). MPL515 mutations, either MPLW515L (n = 17) or a previously undescribed MPLW515K (n = 5), were detected in 20 patients. The diagnosis of patients with mutant MPL alleles at the time of molecular testing was de novo MMM in 12 patients, ET in 4, post-ET MMM in 1, and MMM in blast crisis in 3. Six patients carried the MPLW515L and JAK2V617F alleles concurrently. We conclude that MPLW515L or MPLW515K mutations are present in patients with MMM or ET at a frequency of approximately 5% and 1%, respectively, but are not observed in patients with polycythemia vera (PV) or other myeloid disorders. Furthermore, MPL mutations may occur concurrently with the JAK2V617F mutation, suggesting that these alleles may have functional complementation in myeloproliferative disease.

Adult↗
PubMed2006

Abdominal vein thrombosis in essential thrombocythemia: prevalence, clinical correlates, and prognostic implications.

Among 460 consecutive patients with essential thrombocythemia (ET) seen at our institution, 19 cases (4%) of abdominal vein thrombosis (AVT) were documented either at (n = 9) or after (n = 10) diagnosis. Women (P = 0.03) and the young (P = 0.002) were preferentially affected. Accordingly, clinical comparisons were performed among three groups of female patients: those with AVT (group A; n = 17), a control group without AVT but closely matched to group A in terms of age and year of diagnosis (group B; n = 34), and all female patients without AVT (group C; n = 288). As expected from the consequences of AVT-associated portal hypertension and anticoagulant therapy, patients in group A experienced significantly higher rates of hemorrhage, palpable splenomegaly, and anemia. Unexpectedly, however, compared with group B, group A displayed both a higher conversion rate into myelofibrosis/acute leukemia (P = 0.0008) and a shorter median survival (116 vs. 156 months; P = 0.0012). Multivariable analysis including all female patients with ET identified AVT, along with advanced age, leukocytosis, and tobacco use, as an independent risk factor for inferior survival. Groups A, B, and C did not differ in either JAK2(V617F) mutational frequency or incidence of non-abdominal thrombosis. We conclude that AVT in ET is a marker of aggressive disease biology.

Abdomen↗
PubMed2006

Palliative goals, patient selection, and perioperative platelet management: outcomes and lessons from 3 decades of splenectomy for myelofibrosis with myeloid metaplasia at the Mayo Clinic.

BACKGROUND: Although splenectomy may palliate massive splenomegaly in patients with myelofibrosis with myeloid metaplasia, this procedure carries significant risks. The authors retrospectively analyzed their experience with splenectomy over the course of 30 years to analyze the impact of improved techniques, antimicrobials, and aggressive postoperative control of platelet counts on outcome. METHODS: A total of 314 patients underwent splenectomy between 1976 and 2004 for mechanical symptoms (= 156 patients [49%]), anemia (= 78 patients [25%]), portal hypertension (= 47 patients [15%]), or thrombocytopenia (= 33 patients [11%]). Of a total of 91 patients studied during the last decade, 69 patients (76%) experienced a palliative benefit for their primary surgical indication for a median of 12 months (range, 1-91 months). RESULTS: Perioperative complications occurred in 87 patients (27.7%) including infection (= 31 patients [9.9%]), thrombosis (= 31 patients [9.9%]), or bleeding (= 44 patients [14%]), 21 of which (6.7% of all patients) were fatal. Perioperative thrombohemorrhagic complications decreased in the last decade through the use of platelet apheresis and the prompt use of cytoreductive agents to counteract postsplenectomy thrombocytosis. Survival after splenectomy was found to be decreased in patients with preoperative thrombocytopenia (<100 x 10(9)/L [P = 0.006]) but not by indication, myelofibrosis with myeloid metaplasia (MMM) prognostic score, or the decade in which splenectomy was performed. CONCLUSIONS: The lack of improvement in overall postsplenectomy survival over time may be a reflection on the failure of medical therapy to improve survival in patients with MMM.

Adolescent↗
PubMed2006

Effects of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, on human mast cells bearing wild-type or mutated codon 816 c-kit.

Most adults with systemic mastocytosis (SM) carry an activating mutation in the codon 816 of c-kit. We investigated the activity of the new tyrosine kinase inhibitor AMN107 on c-kit mutated mast cell lines and bone marrow samples from patients with SM and compared it to that of imatinib mesylate, a tyrosine kinase inhibitor effective in some patients with SM. In HMC-1(560) mast cells carrying wild-type codon 816 c-kit, AMN107 was very effective and as potent as imatinib in inhibiting cellular proliferation and inducing apoptosis (P<0.0823). By contrast, in HMC-1(560,816) cells bearing a c-kit mutation in codon 816, neither drug exerted a significant effect (P<0.0015). AMN107 was also as effective as imatinib in inhibiting phosphorylation of c-kit in HMC-1(560) cells. However, AMN107 had little effect on ex vivo survival of bone marrow mast cells with 816 c-kit mutation obtained from patients with SM. Based upon our results, AMN107 and imatinib are equipotent against mast cells with wild-type c-kit and those harboring the juxtamembrane D560G c-kit mutant but have no significant activity over the dose range tested against cells expressing the c-kit D816V mutant tyrosine kinase.

Benzamides↗
PubMed2006

Estrogen-based hormone therapy and thrombosis risk in women with essential thrombocythemia.

BACKGROUND: There is currently insufficient evidence to either support or refute an association between estrogen-based hormone treatment (EBHT) and thrombosis risk in essential thrombocythemia (ET). METHODS: A retrospective review of thrombotic events, which occurred both at diagnosis of ET and during subsequent follow-up, was performed in a consecutive cohort of women with WHO-defined ET seen at the Mayo Clinic. Details of EBHT were concomitantly obtained. RESULTS: A total of 305 women were seen during the study period and followed for a median of 133 months. EBHT at diagnosis was documented in 59 women and such therapy was instituted at a variable time after diagnosis in 34 additional patients. At diagnosis, major thrombosis occurred in 73 patients (24%), including 11 of 59 (19%) on EBHT and 62 of 246 (25%) not on EBHT (P=.28). Thrombosis after diagnosis occurred in 94 patients (31%), including 64 of 212 (30%) not on EBHT, 5 of 17 (29%) in whom EBHT was discontinued at diagnosis, 13 of 42 (31%) in whom EBHT was continued despite the diagnosis of ET, and 12 of 34 (35%) in whom EBHT was started after diagnosis (P=.95). The overall results were the same when arterial and venous events were analyzed separately. However, EBHT in the form of oral contraceptives (OCP) was associated with an increased risk of venous thrombosis (P=.03). CONCLUSIONS: EBHT is safe in ET outside the setting of OCP use, which might be associated with an increased risk of deep vein thrombosis.

Adolescent↗
PubMed2006

Activity of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, against human FIP1L1-PDGFR-alpha-expressing cells.

Idiopathic hypereosinophilic syndrome (HES) is a myeloproliferative disorder characterized by tissue involvement and organ dysfunction due to abnormal eosinophil proliferation. In a subset of patients, this is caused by the FIP1L1-PDGFR-alpha fusion tyrosine kinase. Cumulative evidence indicates that the Bcr-Abl tyrosine kinase inhibitor imatinib mesylate (Gleevec) is active for the treatment of patients with HES, particularly those expressing the FIP1L1-PDGFR-alpha oncoprotein. The novel tyrosine kinase inhibitor AMN107 was initially developed as a potent Bcr-Abl inhibitor based on the molecular structure of imatinib. We tested the in vitro efficacy of imatinib and AMN107 in the EOL-1 cell line and in cells from a patient with HES harboring the FIP1L1-PDGFR-alpha fusion kinase. AMN107 was as potent as imatinib in inducing apoptosis and inhibiting proliferation of EOL-1 cells, with IC(50) values of 0.54 and 0.20 nM, respectively. In addition, both drugs inhibited the phosphorylation of PDGFR-alpha tyrosine kinase with equivalent efficacy. We conclude that AMN107 and imatinib are active and equipotent against cells expressing the FIP1L1-PDGFR-alpha fusion gene.

Antineoplastic Agents↗
PubMed2006

International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT).

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.

Disease Progression↗
PubMed2006

Presence of unfavorable cytogenetic abnormalities is the strongest predictor of poor survival in secondary myelofibrosis.

BACKGROUND: Postpolycythemic (PV) and postthrombocythemic (ET) myeloid metaplasia are consensually referred to as secondary myelofibrosis (sMF). Prognostic variables in sMF are not as well defined as they are for de novo myelofibrosis with myeloid metaplasia (MMM), which is also known as agnogenic myeloid metaplasia (AMM). Such information is particularly crucial for management decisions in transplant-eligible patients. METHODS: Diagnoses of PV and ET required fulfillment of the World Health Organization criteria for the diagnosis of MMM as well as an antecedent history of either polycythemia vera or essential thrombocythemia that was supported by bone marrow examination. Cytogenetic findings were classified as being either favorable (normal or isolated 13q- or 20q- clones) or unfavorable (presence of abnormalities other than 13q- and 20q-). RESULTS: The study population was comprised of 66 young patients (age <60 yrs) with sMF, including 37 patients with PV and 29 patients with ET. Multivariate analysis of parameters other than cytogenetics identified older age (P = .02), anemia (hemoglobin level <10 g/dL [P = .007]), and PV (P = .009) to be independent risk factors for shortened survival. However, when such analysis was restricted to patients in whom cytogenetic studies were performed (n = 31 patients), the presence of unfavorable cytogenetic abnormalities (i.e., clones other than 20q- and 13q-) became the only adverse prognostic factor for survival (P = .001). A similar analysis in a temporal cohort of 50 age-matched patients with AMM also identified unfavorable cytogenetics as an independent predictor of poor survival, along with thrombocytopenia and anemia. CONCLUSIONS: The results of the current study suggest that cytogenetic findings might supersede AMM-derived prognostic scoring systems for predicting survival in patients with sMF.

Adult↗
PubMed2006

Respective clustering of unfavorable and favorable cytogenetic clones in myelofibrosis with myeloid metaplasia with homozygosity for JAK2(V617F) and response to erythropoietin therapy.

BACKGROUND: Patients who have myelofibrosis with myeloid metaplasia (MMM) display recurrent, albeit nonspecific cytogenetic abnormalities that are diverse prognostically. For the current study, the authors explored the relation between specific cytogenetic clones and JAK2(V617F) mutational status in patients with MMM and the effects on treatment response to erythropoietin (Epo). METHODS: Concomitantly collected blood granulocytes and bone marrow were processed for JAK2(V617F) mutation analysis and cytogenetic studies, respectively. Genomic DNA was amplified by polymerase chain reaction, and fluorescent dye chemistry sequencing was performed by using the same primers that were used for amplification. RESULTS: Among 105 study patients, cytogenetic abnormalities were detected in 47 patients (45%), and the JAK2(V617F) mutation was detected in 52 patients (50%). Comparison of mutational frequencies between favorable (normal, sole 13q-, or 20q- clones; n = 70 patients) and unfavorable (all other abnormalities; n = 35 patients) cytogenetic categories revealed a significantly different incidence of homozygous JAK2(V617F) between them (9% vs. 23%, respectively; P = .04). Furthermore, the mutant allele coexisted with several recurrent cytogenetic lesions. Among 25 patients who received Epo either alone (n = 17 patients) or in combination with hydroxyurea (n = 8 patients), 4 patients (16%) achieved a response, and none of them were homozygous for JAK2(V617F). Conversely, a response was more likely (P = .0001) in the presence of favorable cytogenetic abnormalities (i.e., 3 of 4 responders carried sole 13q- or 20q- clones). CONCLUSIONS: Unfavorable and favorable cytogenetic clones in MMM clustered with homozygosity for JAK2(V617F) and treatment response to Epo-based therapy, respectively.

Clone Cells↗