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Ayalew Tefferi

Publications and source records attributed to Ayalew Tefferi.

At least 163 records · Page 9Linked to original sources
PubMed2003

The forgotten myeloproliferative disorder: myeloid metaplasia.

Myelofibrosis with myeloid metaplasia is a hematologic disorder currently classified with polycythemia vera and essential thrombocythemia as a chronic myeloproliferative disease. The median age at diagnosis is 60 years, and more than 90% of patients are diagnosed after age 40 years. Clinical manifestations include massive splenomegaly, progressive anemia, profound constitutional symptoms, and extramedullary hematopoiesis. The diagnosis is confirmed by bone marrow examination after other causes of myelofibrosis are ruled out. Median survival is 5 years and causes of death include leukemic transformation. Prognosis is adversely affected by the presence of anemia (hemoglobin <10 g/dl), leukopenia or leukocytosis (white blood cells >30,000/ micro l), circulating blasts, and hypercatabolic symptoms. Conventional treatment is palliative and does not improve survival. In this regard, androgen preparations, corticosteroids, and erythropoietin are useful for the treatment of disease-associated anemia. Symptomatic splenomegaly is best managed by cytoreductive therapy or surgical removal. Radiation therapy is most useful in the treatment of nonhepatosplenic extramedullary hematopoiesis. New treatment approaches include the use of thalidomide alone or in combination with prednisone and hematopoietic stem cell transplantation.

Humans↗
PubMed2003

Nonhepatosplenic extramedullary hematopoiesis: associated diseases, pathology, clinical course, and treatment.

OBJECTIVE: To define associated clinical conditions, pathology, natural history, and treatment outcome of nonhepatosplenic extramedullary hematopoiesis (NHS-EMH). PATIENTS AND METHODS: We retrospectively reviewed the medical charts of all patients identified as having NHS-EMH from 1975 to 2002. Diagnosis was made by tissue biopsy, fine-needle aspiration biopsy, or radionuclide bone marrow scanning. RESULTS: We identified 27 patients with antemortem diagnosis of NHS-EMH. The most common associated condition and disease site were myelofibrosis with myeloid metaplasia (MMM) (in 18 patients [67%]) and the vertebral column (in 7 patients [26%]; all involving the thoracic region), respectively. At the time of diagnosis of NHS-EMH, concurrent splenic EMH (in 22 patients [82%]; 15 [56%] had undergone splenectomy) and red blood cell transfusion dependency (in 12 patients [44%]) were prevalent. Of the 27 patients, 9 (33%) required no specific therapy. Specific therapy was radiation (in 7 patients with a 71% response rate) and surgical excision (in 6 patients with a 67% response). Treatment-associated complications were limited to surgery. Radiation therapy was not used in the non-MMM group, but low-dose radiation therapy was used in the MMM group for paraspinal or intraspinal EMH (median dose, 1 Gy; range, 1-10 Gy), pleural or pulmonary disease (median dose, 1.25 Gy; range, 1.00-1.50 Gy), and abdominal or pelvic disease (median dose, 2.02 Gy; range, 150-4.50 Gy). Median survival after the diagnosis of NHS-EMH was 13 months in the MMM group and 21 months in the non-MMM group. CONCLUSIONS: This retrospective study suggests that NHS-EMH is rare, is often associated with MMM, and preferentially affects the thoracic spinal region. Asymptomatic disease may require no specific treatment, whereas symptomatic disease is best managed with low-dose radiation therapy.

Adult↗
PubMed2003

Anemia in adults: a contemporary approach to diagnosis.

There are numerous ways of classifying the causes of anemia, and no one way is necessarily superior to another. It is equally important to appreciate the differences in the approaches to diagnosis between children and adults, men and women, and persons of different ethnic backgrounds. Regardless of the specific algorithm followed in evaluating anemia, it is essential that easily remediable causes such as nutritional deficiencies, hemolysis, and anemia of renal insufficiency are identified early and treated appropriately. In general, the differential diagnosis of anemia can be substantially narrowed by subcategorization into "microcytic," "normocytic," and "macrocytic" subtypes on the basis of mean corpuscular volume. However, such classification is a starting point and not infallible. Each category then can be deciphered using a stepwise approach that utilizes readily accessible laboratory tests.

Adult↗
PubMed2003

Rituximab for immune cytopenia in adults: idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and Evans syndrome.

OBJECTIVE: To evaluate the efficacy of rituximab for the treatment of adult patients with immune cytopenia, including idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, and Evans syndrome. PATIENTS AND METHODS: We retrospectively reviewed the medical charts of all patients treated with rituximab for immune cytopenia at the Mayo Clinic in Rochester, Minn, through January 1, 2003. Fourteen patients (median age at first diagnosis, 51 years; range, 21-79 years) were identified who received 1 or more treatment courses of rituximab for treatment of refractory ITP (12 patients), autoimmune hemolytic anemia (AIHA) (5 patients), or both ITP and AIHA (classified as Evans syndrome) (4 patients). Data regarding age, diagnosis, date of diagnosis, previous treatments, comorbid conditions, blood cell counts before taking rituximab, number of rituximab treatments, and response to treatment were extracted and analyzed. RESULTS: Of 12 patients treated for ITP, 6 were receiving corticosteroid-based treatment either alone or combined with other immunosuppressive therapy at the time they received rituximab. Complete remission occurred in 5 (42%) of 12 patients with ITP and in 2 (40%) of 5 patients with AIHA. Response to rituximab in patients with Evans syndrome was seen in either ITP or AIHA, but not both. Complete response was often durable in ITP. Responses were seen in both splenectomized and nonsplenectomized patients. CONCLUSIONS: Our findings, considered with the results of other studies, suggest that rituximab deserves early consideration as salvage therapy for immune cytopenias that are refractory to both corticosteroid treatment and splenectomy. This series represents the largest series of adult patients with AIHA and Evans syndrome.

Adult↗
PubMed2003

Polycythemia vera: a comprehensive review and clinical recommendations.

More than a century has elapsed since the appearance of the modern descriptions of polycythemia vera (PV). During this time, much has been learned regarding disease pathogenesis and PV-associated molecular aberrations. New information has allowed amendments to traditional diagnostic criteria. Phlebotomy remains the cornerstone treatment of PV, whereas myelosuppressive agents may augment the benefit of using phlebotomy for thrombosis prevention in high-risk patients. Excessive aspirin use is contraindicated in PV, although the use of lower-dose aspirin has been shown to be safe and effective in alleviating microvascular symptoms including erythromelalgia and headaches. Recent studies have shown the utility of selective serotonin receptor antagonists for treating PV-associated pruritus. Nevertheless, many questions remain unanswered. What is the specific genetic mutation or altered molecular pathway that is causally related to the disease? In the absence of a specific molecular marker, how is a working diagnosis of PV made? What evidence supports current practice in the management of PV? This article summarizes both old and new information on PV; proposes a modern diagnostic algorithm to formulate a working diagnosis; and provides recommendations for patient management, relying whenever possible on an evidence-based approach.

Algorithms↗
PubMed2003

2-Chlorodeoxyadenosine therapy for disseminated Langerhans cell histiocytosis.

OBJECTIVE: To evaluate the efficacy of 2-chlorodeoxyadenosine (2-CDA), a purine nucleoside analogue, in treating disseminated Langerhans cell histiocytosis (LCH). PATIENTS AND METHODS: We retrospectively reviewed the clinical records of 5 patients who were seen at our institution for histologically confirmed disseminated LCH, including 1 patient with central nervous system parenchymal involvement. These patients were treated consecutively with 2-CDA chemotherapy between December 1994 and January 2001. The patients ranged in age from 19 to 81 years, and the median pretreatment duration of disease was 23 months. Median follow-up after initiation of 2-CDA treatment was 33 months. 2-Chlorodeoxyadenosine was used as frontline therapy for 1 patient and as salvage therapy for the other patients. Patients generally received 0.7 mg/kg over 5 or 7 days; the median number of courses was 4. RESULTS: Complete responses were achieved in 3 patients, including the patient with central nervous system disease, which, to our knowledge, has not been described previously. Two other patients achieved partial responses. The overall response rate was 100%. Toxic effects consisted mainly of myelosuppression; 1 patient developed dermatomal herpes zoster infection. CONCLUSION: Our experience confirms the reported efficacy of 2-CDA in the treatment of LCH; however, the optimal timing and schedule of therapy remain to be determined.

Adult↗
PubMed2003

Primer on medical genomics. Part VI: Genomics and molecular genetics in clinical practice.

An important milestone in medical science is the recent completion of a "working draft" of the human genome sequence. The identification of all human genes and their regulatory regions provides the framework to expedite our understanding of the molecular basis of disease. This advance has also formed the foundation for a broad range of genomic tools that can be applied to medical science. These developments in global gene and gene product analysis as well as targeted molecular genetic testing are destined to change the practice of modern medicine. Despite these exciting advances, many practicing clinicians perceive that the role of molecular genetics, especially that of genomics, is confined primarily to the research arena with little current clinical applicability. The aim of this article is to highlight advances in DNA/RNA-based methods of susceptibility screening, disease diagnosis and prognostication, and prediction of treatment outcome in regard to both drug toxicity and response as they apply to various areas of clinical medicine.

Cardiovascular Diseases↗
PubMed2003

Posttransplantation thrombotic thrombocytopenic purpura: a single-center experience and a contemporary review.

OBJECTIVE: To assess the activity of von Willebrand factor-cleaving protease (vWF-CP) in patients with thrombotic thrombocytopenic purpura (TTP) complicating bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT). PATIENTS AND METHODS: From March 1, 1999, to June 30, 2001, allogeneic and autologous hematopoietic stem cell transplantation was performed in 118 and 400 patients, respectively. We reviewed risk factors for development of posttransplantation TTP and measured vWF-CP activity during active TTP in 10 recipients. RESULTS: The incidence of TTP after allogeneic and autologous transplantation was 6.8% (8/118) and 0.25% (1/400), respectively. Among the allogeneic transplant recipients, the incidence of TTP after nonmyeloablative (NMA) PBSCT, matched unrelated donor BMT, and sibling BMT or PBSCT was 15.4% (2/13), 11.8% (2/17), and 4.5% (4/88), respectively. Of the 10 patients with TTP, 9 (90%) had received extensive prior therapy, including autologous transplantation in both NMA recipients. Acute graft-vs-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate in most affected patients. The vWF antigen level was elevated in all patients, and no patients showed evidence of vWF-CP deficiency. During active TTP, 6 patients had grade II-IV acute GVHD, 1 had extensive chronic GVHD, and 4 had cytomegalovirus viremia. Risk factor analysis for development of TTP showed that transplant type (NMA and matched unrelated donor) and source of stem cells (bone marrow vs peripheral blood stem cell) were significant. CONCLUSIONS: Posttransplantation TTP was not found to be associated with severe vWF-CP deficiency. The elevated levels of vWF antigen are consistent with diffuse endothelial injury likely because of multiple interacting factors such as extensive prior therapy, GVHD, cyclosporine, and reactivation of cytomegalovirus. The disorder appears to be more frequent among patients with, or at risk for, acute GVHD, suggesting a possible role in the pathogenesis. Nonmyeloablative transplantation does not appear to confer a lesser risk, possibly for these reasons.

ADAM Proteins↗
PubMed2003

Hepatic veno-occlusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation.

Hepatic veno-occlusive disease (VOD), increasingly referred to as sinusoidal obstruction syndrome, is a well-recognized complication of hematopoietic stem cell transplantation and contributes to considerable morbidity and mortality. In the Western Hemisphere, VOD, classified as a conditioning-related toxicity, is most commonly caused by stem cell transplantation. VOD has been described after all types of stem cell transplantation, irrespective of the stem cell source, type of conditioning therapy, or underlying disease. Recognition of this disease in the posttransplantation setting remains a challenge in the absence of specific diagnostic features because many other more common conditions can mimic it. Limited therapeutic or preventive strategies are currently available for the management of VOD. In this review, we provide a comprehensive account of the pathophysiology of this disease as we understand it today, risk factors for its development, and the current state of knowledge regarding preventive and therapeutic options.

Diagnosis, Differential↗
PubMed2003

Primer on medical genomics. Part VIII: Essentials of medical genetics for the practicing physician.

After the mapping and sequencing of the human genome, medical professionals from essentially all specialties turned their attention to investigating the role genes play in health and disease. Until recently, medical genetics was considered a specialty of minor practical relevance. This view has changed with the development of new diagnostic and therapeutic possibilities. It is now realized that genetic disease represents an important part of medical practice. Achievements in cancer genetics, in the field of prenatal diagnostics (including carrier testing for common recessive disorders), and in newborn screening for treatable metabolic disorders reinforce the rapidly expanding role of genetics in medicine. Diagnosing a genetic disorder not only allows for disease-specific management options but also has implications for the affected individual's entire family. A working understanding of the underlying concepts of genetic disease with regard to chromosome, single gene, mitochondrial, and multifactorial disorders is necessary for today's practicing physician. Routine clinical practice in virtually all medical specialties will soon require integration of these fundamental concepts for use in accurate diagnosis and ensuring appropriate referrals for patients with genetic disease and their families.

Chromosome Disorders↗
PubMed2003

A contemporary approach to the diagnosis and management of polycythemia vera.

The natural history of polycythemia vera (PV) includes an increased lifetime risk of thrombohemorrhagic complications and disease transformation into myelofibrosis with myeloid metaplasia and acute myeloid leukemia. The latter is the primary reason for the shortening of survival that becomes significant after the first decade of disease. Historic nonrandomized studies have suggested that aggressive phlebotomy improves survival in PV. However, prospective randomized studies have failed to demonstrate a better treatment than phlebotomy alone, in terms of survival. However, the addition of cytoreductive therapy to phlebotomy in high-risk patients with PV may reduce the risk of recurrent thrombosis. Other disease features of PV include aquagenic pruritus and microvascular disturbances such as erythromelalgia. This review outlines a practical approach to diagnosis, in addition to treatment of life-threatening and non-life-threatening complications of PV.

Algorithms↗
PubMed2002

Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders.

Imatinib mesylate (Gleevec), a small molecule inhibitor of abl, kit, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, has been reported to be effective in the treatment of hypereosinophilic syndrome (HES) and a rare eosinophilia-associated chronic myeloid disorder (eos-CMD) characterized by the t(5;12)(q33;p13) cytogenetic abnormality. In the current study, we sought to confirm the preliminary observations in HES as well as evaluate the therapeutic value of imatinib in eos-CMD that is not associated with t(5;12)(q33;p13). Five patients with HES (all men, median age = 46 years) and 2 with eos-CMD (both men, aged 45 and 58 years) were treated with imatinib at a starting dose of 100 to 400 mg/day. Cytogenetic studies showed no evidence of either the bcr-abl translocation or t(5;12)(q33;p13) in any patient. Screening of exons encoding the intracellular catalytic domains and extracellular ligand binding domains of PDGFR beta (exons 2-23) and c-kit (exons 1-21) in 6 patients demonstrated mostly previously known polymorphisms. At a median follow-up of 17 weeks (range, 10-33 weeks), 2 patients with HES and 1 with eos-CMD have achieved complete clinical remission and 1 additional patient with HES has achieved a partial remission. In contrast to previous observations, all 4 responding patients had elevated serum interleukin-5 levels. Although the drug was well tolerated in most patients, a previously unrecognized treatment toxicity of acute left ventricular dysfunction occurred in a responding patient with HES within the first week of treatment. Myocardial biopsy revealed eosinophilic infiltration and degranulation, and the cardiogenic shock was reversed with the prompt institution of corticosteroid therapy.

Adult↗
PubMed2002

A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia.

Single-agent thalidomide (THAL) at "conventional" doses (> 100 mg/d) has been evaluated in myelofibrosis with myeloid metaplasia (MMM) based on its antiangiogenic properties and the prominent neoangiogenesis that occurs in MMM. THAL monotherapy at such doses produces approximately a 20% response rate in anemia but is poorly tolerated (an adverse dropout rate of > 50% in 3 months). To improve efficacy and tolerability, we prospectively treated 21 symptomatic patients (hemoglobin level < 10 g/dL or symptomatic splenomegaly) with MMM with low-dose THAL (50 mg/d) along with a 3-month oral prednisone (PRED) taper (beginning at 0.5 mg/kg/d). THAL-PRED was well tolerated in all enrolled patients, with 20 patients (95%) able to complete 3 months of treatment. An objective clinical response was demonstrated in 13 (62%) patients, all improvements in anemia. Among 10 patients who were dependent on erythrocyte transfusions, 7 (70%) improved and 4 (40%) became transfusion independent. Among 8 patients with thrombocytopenia (platelet count < 100 x 10(9)/L), 6 (75%) experienced a 50% or higher increase in their platelet count. In 4 of 21 patients (19%), spleen size decreased by more than 50%. Responses observed were mostly durable after discontinuation of the PRED. The dose of THAL in this study (50 mg/d) was better tolerated than the higher doses used in previous studies. Adverse events associated with corticosteroid therapy were mild and transient. Clinical responses did not correlate with improvements in either intramedullary fibrosis or angiogenesis. THAL-PRED is well tolerated and preliminarily appears to be a promising drug regimen for treating cytopenias in patients with MMM.

Adrenal Cortex Hormones↗
PubMed2002

Antithymocyte globulin has limited efficacy and substantial toxicity in unselected anemic patients with myelodysplastic syndrome.

Antithymocyte globulin (ATG) has recently been popularized as an effective treatment in myelodysplastic syndrome (MDS). We treated 8 anemic MDS patients (refractory anemia [RA] and refractory anemia with excess blasts [RAEB-1]) with ATG (40 mg/kg/d for 4 days) and prednisone in a phase 2 trial. The study was stopped early according to a preset termination rule because of lack of efficacy. There were no salutary responses. Toxicities included serum sickness (in all patients), transient neutropenia and thrombocytopenia, diarrhea, vomiting, and syncope with a generalized seizure. At least 3 patients had the HLA-DR15 (DR2) allele. We conclude that the risk-benefit ratio of ATG in an unselected population of MDS patients may be unfavorable, and more work is needed to define the subset of patients who will respond to ATG before its widespread use can be recommended.

Aged↗
PubMed2002

Both B and T lymphocytes may be clonally involved in myelofibrosis with myeloid metaplasia.

A combination of magnetic cell sorting (MACS) and fluorescent in situ hybridization (FISH) techniques was used to detect clonal cytogenetic markers in different myeloid and lymphoid cell types of the peripheral blood from 4 patients with myelofibrosis with myeloid metaplasia (MMM) that was associated with either a 13q- or a 20q- karyotypic abnormality. Interphase cytogenetics studies demonstrated abnormal clonal FISH signal patterns in neutrophil, myeloid, erythroid, megakaryocyte, and B- and T-cell preparations in 3 of the 4 patients. In one patient, FISH results were within normal limits in T cells and slightly abnormal in B cells. In general, the percentage of abnormal nuclei was variable in both lymphocyte populations but always higher in B lymphocytes compared with T lymphocytes. The current study provides direct evidence for the clonal involvement of both B and T lymphocytes in MMM. A larger study is needed to clarify the relevance of the observed interpatient heterogeneity in clonal constitution.

Antigens, CD↗
PubMed2002

Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients.

Previous studies have reported mortality rates of about 80% in hematopoietic stem cell transplant recipients with diffuse alveolar hemorrhage. This retrospective study describes the clinical course of 48 such patients: mean age 47.7 years, 52% autologous transplant and 67% peripheral stem cell source. The hemorrhage occurred within one month of transplant in 28 patients. Symptoms included dyspnea in 92%, fever in 67%, cough in 56%, and hemoptysis in 15%. Intensive care unit admission was required in 85% and mechanical ventilation in 77%. Most of the patients were treated with intravenous methylprednisolone 1 g daily for 3 days and then tapered off after a median of 22 days. The hospital mortality was 48%. The cause of death was respiratory failure in 15 of the 23 deaths. Mortality was 28% in autologous compared with 70% in allogeneic transplant recipients (p = 0.0040). The mortality rate of patients whose hemorrhage occurred within the first 30 days of transplant was 32% compared with 70% of those with late hemorrhage (p = 0.0096). This study shows that survival rate of hematopoietic stem cell transplant recipients with diffuse alveolar hemorrhage is better than previously reported, and that early onset and autologous transplant are favorable prognostic indicators.

Adrenal Cortex Hormones↗