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Ayalew Tefferi

Publications and source records attributed to Ayalew Tefferi.

At least 37 records · Page 2Linked to original sources
PubMed2006

Lenalidomide therapy in myelofibrosis with myeloid metaplasia.

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.

Administration, Oral↗
PubMed2006

JAK2(V617F) and leukemic transformation in myelofibrosis with myeloid metaplasia.

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.

Adult↗
PubMed2006

Mutation screening for JAK2V617F: when to order the test and how to interpret the results.

With the application of adequately sensitive tests, it is now becoming evident that more than 90% of patients with conventionally-defined polycythemia vera (PV) carry the somatic JAK2V617F mutation in their granulocytes. However, the specific mutation is also found in other classic and atypical myeloproliferative disorders (MPD), albeit at a lesser frequency. In contrast, JAK2V617F has not been reported in patients with either reactive myeloproliferation or lymphoid disorders. Therefore, mutation screening for JAK2V617F can be considered as a myeloid-specific clonality assay and it is diagnostically most useful in the evaluation of "polycythemia".

Amino Acid Substitution↗
PubMed2006

Prognosis in transplant-eligible patients with agnogenic myeloid metaplasia: a simple CBC-based scoring system.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation is potentially curative in agnogenic myeloid metaplasia (AMM) but is associated with substantial mortality and morbidity that necessitates accurate identification of patients in whom benefit outweighs risk. The current study describes the natural history of AMM in transplant-eligible patients and proposes a new prognostic scoring system that favorably compares with other established models. METHODS: Patients diagnosed with AMM before the age of 60 years and seen at Mayo Clinic were identified and the diagnosis confirmed. Relevant demographic, clinical, and laboratory characteristics were abstracted, and the impact of various parameters on overall survival (OS) was evaluated with univariate and multivariate analyses. RESULTS: A cohort of 160 patients with AMM is described. OS was 78 months. Multivariate analysis identified a hemoglobin level of <10 g/dL, white blood cell count of either <4 or >30x10(9)/L, platelet count of <100x10(9)/L, presence of constitutional symptoms, and hepatomegaly as independent predictors of inferior survival. The first 3 complete blood count-based parameters were combined into a new scoring system that resulted in median survivals of 155, 69, and 24 months in the presence of 0, 1, or >or=2 adverse features. The chi-square value for the new model was 80.6 compared with 51.4, 48.4, and 43.7 for the models by Dupriez, Cervantes, and Visani, respectively. CONCLUSIONS: A new scoring system based on blood count at the time of diagnosis can adequately stratify by risk transplant-eligible patients with AMM and can accurately identify high-risk as well as intermediate-risk disease. The new system displayed a stronger discriminative value, between risk categories, compared with currently existing prognostic models.

Adolescent↗
PubMed2006

The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera.

BACKGROUND: Several studies have recently reported on the occurrence of a JAK2(V617F) mutation in myeloid cells from the majority of patients with polycythemia vera (PV). The clinical relevance of this novel observation currently is under study. METHODS: In a single institutional study, mutation screening for JAK2(V617F) was performed in DNA derived from archived blood granulocytes from 63 consecutive patients with PV in whom current diagnostic criteria were strictly applied and the diagnosis confirmed by bone marrow histology. RESULTS: The JAK2(V617F) mutant allele was detected in 58 of the 63 patients (92%) with 21% homozygosity. The clinical phenotype of the five patients with the wild-type allele was otherwise typical for the disease. A statistical comparison between JAK2(V617F) heterozygotes (n=45 patients) and homozygotes (n=13 patients) did not reveal any significant associations with regard to age, gender, leukocyte or platelet count at the time of diagnosis, duration of disease, or the incidences of thrombosis or bleeding. However, compared with their heterozygote counterparts, JAK2(V617F) homozygote patients displayed a significantly higher hemoglobin level at the time of diagnosis (P=0.001), an increased incidence of pruritus (69% vs. 38%; P=0.04), a higher rate of fibrotic transformation (23% vs. 2%; P=0.009), and higher PRV-1 transcript levels in their blood granulocytes (P=0.07). CONCLUSIONS: The results of the current clinical study support previous laboratory observations that link JAK2(V617F) with the PV phenotype by demonstrating a mutant allele dose effect on erythrocytosis and clinical and laboratory features characteristic of PV.

Adolescent↗
PubMed2006

Classification of chronic myeloid disorders: from Dameshek towards a semi-molecular system.

Hematological malignancies are phenotypically organized into lymphoid and myeloid disorders, although such a distinction might not be precise from the standpoint of lineage clonality. In turn, myeloid malignancies are broadly categorized into either acute myeloid leukemia (AML) or chronic myeloid disorder (CMD), depending on the presence or absence, respectively, of AML-defining cytomorphologic and cytogenetic features. The CMD are traditionally classified by their morphologic appearances into discrete clinicopathologic entities based primarily on subjective technologies. It has now become evident that most CMD represent clonal stem cell processes where the primary oncogenic event has been characterized in certain instances; Bcr/Abl in chronic myeloid leukemia, FIP1L1-PDGFRA or c-kit(D816V) in systemic mastocytosis, rearrangements of PDGFRB in chronic eosinophilic leukemia, and rearrangements of FGFR1 in stem cell leukemia/lymphoma syndrome. In addition, Bcr/Abl-negative classic myeloproliferative disorders are characterized by recurrent JAK2(V617F) mutations, whereas other mutations affecting the RAS signaling pathway molecules have been associated with juvenile myelomonocytic leukemia. Such progress is paving the way for a transition from a histologic to a semi-molecular classification system that preserves conventional terminology, while incorporating new information on molecular pathogenesis.

Fusion Proteins, bcr-abl↗
PubMed2006

The diagnosis of polycythemia vera: new tests and old dictums.

Pathogenetically fundamental observations have identified polycythemia vera (PV) as a clonal stem cell disease with bone marrow histological and other biological features that distinctly differentiate it from other causes of 'increased' hematocrit. However, relatively little attention has been given to the effective utilization of pathology and laboratory markers of clonal myeloproliferation as diagnostic tools in PV. In contrast, the diagnostic use of red cell mass (RCM) measurement in PV stemmed from the accidental endorsement, as 'diagnostic criteria', of 'study eligibility criteria' that were formulated for clinical trials. It has since become evident that RCM measurement is a tedious procedure that is fraught with multiple-level imprecision, as well as suboptimal diagnostic accuracy. Therefore, it is reasonable to consider dispensing with RCM measurement as a diagnostic test for PV and instead utilize a diagnostic algorithm that combines clinical information with easily accessible laboratory data, including serum erythropoietin level and bone marrow histology. Recent discoveries of myeloproliferative-disease-specific molecular markers, including the JAK2 V617F tyrosine kinase mutation that is found in the majority of patients with PV, provide further support for such a measure.

Algorithms↗
PubMed2006

Myelofibrosis with myeloid metaplasia: disease overview and non-transplant treatment options.

Myelofibrosis with myeloid metaplasia (MMM) is currently classified as a classic (i.e. not yet molecularly defined) myeloproliferative disorder (MPD), along with essential thrombocythemia (ET) and polycythemia vera (PV). All three MPDs represent stem-cell-derived clonal myeloproliferation that, in the case of MMM, is accompanied by an intense bone marrow stromal reaction that includes collagen fibrosis, osteosclerosis, and angiogenesis. To date, both the molecular basis of the primary clonal process and the pathogenetic mechanisms that underlie the secondary histological changes remain elusive. Clinically, MMM is characterized by anemia, multi-organ extramedullary hematopoiesis that often involves the spleen and liver, constitutional symptoms, and premature death from either leukemic transformation or other disease complications. Current diagnosis is based on characteristic but not diagnostic bone marrow histological features. Modern therapy remains palliative but allogeneic stem cell transplantation might be curative to a selected group of patients. This chapter reviews both the old and the new therapy with regard to non-transplant treatment options for MMM.

Combined Modality Therapy↗
PubMed2006

Fluorescent in situ hybridization in the diagnosis, prognosis, and treatment monitoring of chronic myeloid leukemia.

The unique molecular characteristic of chronic myeloid leukemia (CML), the disease-causing ABL (9q34) to BCR (22q11) translocation, has provided an invaluable tool for disease diagnosis and monitoring of treatment response. The traditional standard in this regard is bone marrow karyotype, also known as conventional cytogenetics (CC), which reveals a shortened chromosome 22, the Philadelphia chromosome, t(9;22)(q34;q11). CC in CML has also been effectively used for monitoring the response to drug therapy. However, this particular laboratory test misses submicroscopic BCR/ABL translocations and is suboptimal for minimal residual disease (MRD) assessment. Both fluorescence in situ hybridization (FISH) and reverse-transcriptase polymerase chain reaction (RT-PCR) feature higher sensitivity in terms of both diagnosis and MRD assessment in CML, compared to CC. Another advantage of these alternative tests is their effective applicability to peripheral blood specimens. The current review highlights the practical literature with respect to the use of FISH for CML whereas the use of RT-PCR has been extensively covered in recent communications.

Humans↗
PubMed2006

Utility of peripheral blood dual color, double fusion fluorescent in situ hybridization for BCR/ABL fusion to assess cytogenetic remission status in chronic myeloid leukemia.

The molecular signature of BCR-ABL fusion in chronic myeloid leukemia (CML) provides a unique tool for diagnosis and monitoring of tumor burden during therapy. The gold standard in this regard is conventional bone marrow cytogenetics. Peripheral blood fluorescent in situ hybridization (FISH) offers the possibility of a less invasive, more practical alternative method in terms of both cost and turnaround time. In the present study, we examined 296 paired samples from 65 patients with CML and demonstrate a tight correlation, in quantifying BCR-ABL burden between bone marrow cytogenetics, bone marrow dual color, double fusion (D-FISH), and peripheral blood D-FISH (P < 0.0001 for each). Furthermore, we demonstrate that peripheral blood D-FISH can be used as a surrogate for cytogenetic studies in monitoring cytogenetic remission status.

Adult↗
PubMed2006

New insights into the pathogenesis and drug treatment of myelofibrosis.

PURPOSE OF REVIEW: Myelofibrosis with myeloid metaplasia was first described in 1879, classified as a myeloproliferative disorder in 1951, and characterized as a clonal stem cell disorder in 1978. Despite the passing of time, the molecular basis of the disease has remained elusive although substantial progress has been made regarding the pathogenesis of the associated bone marrow stromal reaction. Advances have also been meager in terms of treatment for disease complications, including anemia, splenomegaly, and leukemic transformation. RECENT FINDINGS: At the molecular level, a JAK2 tyrosine kinase mutation (JAK2) has recently been described in a spectrum of myeloproliferative disorders including myelofibrosis with myeloid metaplasia with the reported mutational frequency ranging from 35% to 57% with 9-29% homozygosity. To date, the presence of JAK2 in myelofibrosis with myeloid metaplasia has not been shown to have prognostic relevance. Other recent observations of potential pathogenetic relevance in this disease include the description of a highly specific chromosomal translocation {der(6)t(1;6)(q23;p21)}, the demonstration of an epigenetic downregulation of the retinoic acid receptor-beta2 expression in CD34 cells, and the direct implication of transforming growth factor-beta1 in thrombopoietin-driven experimental myelofibrosis in mice. From a therapeutic standpoint, benefit to a subset of patients has been demonstrated for both allogeneic stem cell transplantation and novel drugs, including thalidomide and lenalidomide. SUMMARY: Recent advances in the pathogenesis of myelofibrosis with myeloid metaplasia are expected to facilitate the development of molecularly targeted therapy. In the mean time, current management strategies include observation, participation in experimental drug therapy, and allogeneic stem cell transplantation for low-risk, intermediate-risk, and high-risk disease, respectively.

Anemia↗
PubMed2006

Essential thrombocythemia: scientific advances and current practice.

PURPOSE OF REVIEW: Median survival in essential thrombocythemia exceeds 20 years and clinical course is usually indolent with a minority of patients experiencing thrombohemorrhagic complications. Leukemic, polycythemic, or fibrotic disease transformation in essential thrombocythemia is an infrequent occurrence with a 15-year cumulative risk of approximately 5% or less in each instance. The major incentives for this review have been the recent description of an activating JAK2 tyrosine kinase mutation (JAK2 (V617F)) in essential thrombocythemia, related myeloproliferative disorders, and the impact on clinical practice from the publication of a major treatment trial. RECENT FINDINGS: Several studies have reported on the occurrence of JAK2(V617F) in approximately 50% of patients with essential thrombocythemia and its presence has been associated with advanced age at diagnosis, higher hemoglobin and leukocyte levels, and increased rate of polycythemic transformation. In contrast, the mutation did not appear to affect the incidence of thrombotic, leukemic, or fibrotic events. There is increasing evidence regarding the thrombogenic role of neutrophils in essential thrombocythemia and this might partly explain the superior overall performance by hydroxyurea, compared with anagrelide, in a recent randomized study. SUMMARY: Although it is in vogue to consider essential thrombocythemia as more than one disease in terms of both molecular phenotype (presence or absence of JAK2(V617F)) and putative pattern of myelopoiesis (monoclonal versus polyclonal), it is yet to be shown that such differences influence either the natural history of the disease or current therapy. From a treatment standpoint, hydroxyurea is now confirmed to be the drug of choice for high-risk patients with essential thrombocythemia.

Antineoplastic Agents↗
PubMed2006

Eosinophilia: secondary, clonal and idiopathic.

Blood eosinophilia signifies either a cytokine-mediated reactive phenomenon (secondary) or an integral phenotype of an underlying haematological neoplasm (primary). Secondary eosinophilia is usually associated with parasitosis in Third World countries and allergic conditions in the West. Primary eosinophilia is operationally classified as being clonal or idiopathic, depending on the respective presence or absence of a molecular, cytogenetic or histological evidence for a myeloid malignancy. The current communication features a comprehensive clinical summary of both secondary and primary eosinophilic disorders with emphasis on recent developments in molecular pathogenesis and treatment.

Benzamides↗
PubMed2006

C-terminal nucleophosmin mutations are uncommon in chronic myeloid disorders.

C-terminal somatic mutations in nucleophosmin (NPM), a nucleolar shuttling protein that binds p53 and p19(Arf), were recently described in karyotypically normal acute myeloid leukaemia (AML). We analysed primary marrow samples from 150 patients with various chronic myeloid disorders for mutations in the NPM1 gene encoding NPM. NPM1 mutations (tetranucleotide duplication) were detected in three patients, all of whom had chronic myelomonocytic leukaemia (CMML) and a short (<1 year) survival, with rapid progression to overt AML. All other patients were NPM1-wild type in the region analysed. In conclusion, C-terminal NPM mutations are uncommon in chronic myeloid neoplasia, but if present may represent an evolving leukaemic clone.

Base Sequence↗