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Ayalew Tefferi

Publications and source records attributed to Ayalew Tefferi.

At least 109 records · Page 6Linked to original sources
PubMed2004

Peripheral blood stem cell transplantation in 16 patients with POEMS syndrome, and a review of the literature.

POEMS syndrome is characterized by peripheral neuropathy (PN), a clonal plasma cell disorder (PCD), organomegaly, endocrinopathy, skin changes, edema, sclerotic bone lesions, and thrombocytosis. Based on the improved response rates observed with peripheral blood stem cell transplantation (PBSCT) in patients with other PCDs, autologous PBSCT may be an attractive treatment option for this syndrome. Sixteen patients with POEMS syndrome have undergone PBSCT at Mayo. Of these patients, 15 had a severe rapidly progressive sensorimotor PN (9 were wheelchair dependent) and 14 were male. Median age was 51 years (range, 19-62 years). The median number of prior therapies was 3 (range, 0-7). From first symptoms and from diagnosis of POEMS the times to transplantation were 42 months and 5 months (ranges, 8-185 months and 2-149 months), respectively. There were 15 patients who had significantly abnormal pretransplant pulmonary function tests. There was one transplant-related death. During the peritransplant period, 5 patients required intubation for respiratory compromise, including one who required intubation during his stem cell mobilization period. Another patient required noninvasive biphasic positive airway pressure throughout his course. Of the 14 evaluable patients, all have had neurologic improvement or stabilization. Other features have improved substantially. PBSCT for POEMS syndrome is effective therapy but may also be associated with significant morbidity.

Adult↗
PubMed2004

Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders.

Imatinib mesylate is a small molecule drug that in vitro inhibits the Abelson (Abl), Arg (abl-related gene), stem cell factor receptor (Kit), and platelet-derived growth factor receptor A and B (PDGFRA and PDGFRB) tyrosine kinases. The drug has acquired therapeutic relevance because of similar inhibitory activity against certain activating mutations of these molecular targets. The archetypical disease in this regard is chronic myeloid leukemia, where abl is constitutively activated by fusion with the bcr gene (bcr/abl). Similarly, the drug has now been shown to display equally impressive therapeutic activity in eosinophilia-associated chronic myeloproliferative disorders that are characterized by activating mutations of either the PDGFRB or the PDGFRA gene. The former usually results from translocations involving chromosome 5q31-33, and the latter usually results from an interstitial deletion involving chromosome 4q12 (FIP1L1-PDGFRA). In contrast, imatinib is ineffective, in vitro and in vivo, against the mastocytosis-associated c-kit D816V mutation. However, wild-type and other c-kit mutations might be vulnerable to the drug, as has been the case in gastrointestinal stomal cell tumors. Imatinib is considered investigational for the treatment of hematologic malignancies without a defined molecular drug target, such as polycythemia vera, myelofibrosis with myeloid metaplasia, and acute myeloid leukemia.

Antineoplastic Agents↗
PubMed2004

Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation.

Primary systemic amyloidosis (AL) is a fatal plasma cell disorder. Pilot data suggest survival is better in patients undergoing peripheral blood stem cell transplantation (PBSCT), but the selection process makes the apparent benefit suspect. We have reported that circulating cardiac biomarkers are the best predictors of survival outside of the transplantation setting. We now test whether cardiac troponins (cTnT and cTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) are prognostic in transplant recipients. In 98 patients with AL undergoing PBSCT, serum cardiac biomarkers were measured (cTnT, 98 patients; cTnI, 65 patients; and NT-proBNP, 63 patients). Elevated levels of cTnT, cTnI, and NT-proBNP were present in 14%, 43%, and 48% of patients, respectively. At 20 months median follow-up, median survival has not been reached for patients with values below the thresholds; in patients with values above the thresholds, median survival is 26.1 months, 66.1 months, and 66.1 months, respectively. Our previously reported risk systems incorporating these markers were also prognostic, notably the cTnT/NT-proBNP staging. Using this system, 49%, 38%, and 13% of patients were in stage I, stage II, and stage III, respectively. Determining levels of circulating biomarkers may be the most powerful tool for staging patients with AL undergoing PBSCT.

Adult↗
PubMed2004

Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study.

Primary systemic amyloidosis (AL) is a plasma cell dyscrasia resulting in multisystem failure and death. High-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) has been associated with higher response rates and seemingly higher overall survival than standard chemotherapy. Selection bias, however, confounds interpretation of these results. We performed a case-match-control study comparing overall survival of 63 AL patients undergoing transplantation with 63 patients not undergoing transplantation. Matching criteria included age, sex, time to presentation, left ventricular ejection fraction, serum creatinine, septal thickness, nerve involvement, 24-hour urine protein, and serum alkaline phosphatase. According to design, there was no difference between the groups with respect to sex (57% males), age (median, 53 years), left ventricular ejection fraction (65%), number of patients with peripheral nerve involvement (17%), cardiac interventricular septal wall thickness (12 mm), serum creatinine (1.1 mg/dL [97.24 micromol/L]), and bone marrow plasmacytosis (8%). Sixty-six patients have died (16 cases and 50 controls). For PBSCT and control groups, respectively, the 1-, 2-, and 4-year overall survival rates are 89% and 71%; 81% and 55%; and 71% and 41%. Outside a randomized clinical trial, these results present the strongest data supporting the role of PBSCT in selected patients with AL.

Adult↗
PubMed2004

Prevalence, breakpoint distribution, and clinical correlates of t(5;12).

Among 56,709 cytogenetic studies performed during a 15-year period at the Mayo Clinic, 25 cases of t(5;12) were identified. Among 11 patients with available clinical information, 4 had myelodysplastic syndrome, 2 had acute myelocytic leukemia, 2 had myelofibrosis with myeloid metaplasia (MMM), 2 had atypical chronic myelocytic disorder (ACMD), and 1 had chronic myelomonocytic leukemia (CMMoL). The 5q arm was involved in all patients and the 12p arm in only two patients [ACMD,t(5;12)(q33;p13) and MMM,t(5;12)(q11.2;p11.2)], both of whom had eosinophilia and monocytosis. These two features were present in only two other patients [CMMoL,t(5;12)(q35;q24.1) and ACMD,t(5;12)(q31;q24.1)]. The t(5;12) is a rare, myelocytic-exclusive cytogenetic abnormality with a breakpoint-specific association with eosinophilia or monocytosis.

Anemia, Refractory↗
PubMed2004

Imatinib therapy for hypereosinophilic syndrome and eosinophilia-associated myeloproliferative disorders.

A pathogenetic mutation, FIP1L1-PDGFRA, that results from an interstitial chromosome 4q12 deletion, leads to a constitutive activation of the platelet-derived growth factor receptor-alpha (PDGFRA) tyrosine kinase as well as a disease phenotype that mimics both the hypereosinophilic syndrome (HES) and systemic mast cell disease associated with eosinophilia (SMCD-eos). Complete remissions, in response to treatment with low-dose imatinib mesylate (100 mg/day or less) have now been documented in all cases of FIP1L1-PDGFRA(+) eosinophilic disorder as well as other eosinophilic disorders that carry activation mutations of the PDGFRB gene that is located on chromosome 5q33. Furthermore, response to therapy has been rapid (within days) and durable. Interestingly, imatinib mesylate treatment, at a higher dose level (400 mg/day), might induce either partial or short-lived complete remissions in HES that is not associated with the aforementioned PDGFR mutations. These observations make it necessary to re-examine current disease classification and treatment algorithms in eosinophilic disorders.

Benzamides↗
PubMed2004

Agnogenic myeloid metaplasia with pleural extramedullary leukemic transformation.

Agnogenic myeloid metaplasia (AMM) is one of the myeloproliferative disorders, and is usually accompanied by extramedullary hematopoiesis (EMH) in various organs, mainly in the liver, spleen and lymph nodes. Extramedullary hematopoiesis and/or leukemic transformation of EMH in the pleura is a rare occurrence and is usually asymptomatic. Pleural involvement is usually diagnosed on postmortem examination. Herein we describe a 71-year-old man with newly diagnosed agnogenic myeloid metaplasia who was evaluated for progressively worsening dyspnea, pulmonary hypertension and bilateral pleural effusions. EMH involving the lungs and pleura was suspected. A sulfur colloid technetium 99m bone marrow scan performed to detect extramedullary hematopoiesis was negative. The diagnostic thoracentesis yielded bloody fluid that contained a large population of myeloblasts, indicating pleural leukemic transformation. The patient received 100 cGy to the whole lung for treatment of pulmonary hypertension due to EMH. This was followed by 1500 cGy total dose of radiation to the left lung for pleural extramedullary leukemic transformation. Pleural effusions resolved and repeat echocardiography showed reduction of the pulmonary artery pressure. Three months later he had leukemic transformation involving the skin and lymph nodes. Four months after radiation therapy, he had full-blown acute myeloid leukemia. He received 2 cycles of Gemtuzumab ozogamicin (Mylotarg), allopurinol and hydroxyurea. Three months after initiation of chemotherapy, he deteriorated and received salvage chemotherapy of prednisone, VP-16 and imatinib mesylate (Gleevec). He was hospitalized for neutropenic fever and was diagnosed to have pulmonary aspergillosis. He died of multisystem failure 8 1/2 months after being diagnosed with AMM.

Aged↗
PubMed2004

Angiogenesis and anti-angiogenic therapy in myelofibrosis with myeloid metaplasia.

Myelofibrosis with myeloid metaplasia (MMM) is a clonal stem cell disorder that is characterized by florid bone marrow stromal reaction including collagen fibrosis, osteosclerosis, and angiogenesis. Almost all patients with MMM display increased bone marrow microvessel density (MVD) and the extent is among the highest in hematological malignancies. This particular information has encouraged the therapeutic use of anti-angiogenic drugs in MMM. In the current review, we summarize the general concepts regarding angiogenesis, assessment of angiogenesis in hematological malignancies and then the current literature on angiogenesis and anti-angiogenic therapy in MMM.

Angiogenesis Inhibitors↗
PubMed2004

Thromboembolism in adults with acute lymphoblastic leukemia during induction with L-asparaginase-containing multi-agent regimens: incidence, risk factors, and possible role of antithrombin.

Thromboembolism (TE) is a known complication of L-asparaginase (ASP) therapy of acute lymphoblastic leukemia (ALL), possibly attributable to reduced synthesis of natural anticoagulants, in particular antithrombin (AT). This retrospective single institution study was performed to determine the TE incidence among adults undergoing induction with contemporary, ASP-containing regimens. Ten of 54 (18.5%) consecutive adults developed symptomatic, objectively confirmed TE, at a median of 5.5 days after the first ASP dose. These were notable for CNS and upper extremity localization, varied significantly according to ALL immunophenotype (precursor B: 11% vs. T cell: 33%), without apparent effect of schedule or total dose of ASP. Median baseline AT level was 94% and fell to a nadir of 47% (P < 0.0001) during ASP therapy. Prophylactic AT had been given to 17 during ASP therapy. None of these developed TE vs. 10/37 (27%) without replacement (P = 0.021). These observations merit further study to gain insight into disease and/or therapy-specific pathogenesis of TE in this population and call for the prospective evaluation of appropriate prophylactic interventions.

Adolescent↗
PubMed2004

Hemostatic gene polymorphisms and the prevalence of thrombotic complications in polycythemia vera and essential thrombocythemia.

Patients with polycythemia vera and essential thrombocythemia are at risk for thrombotic and bleeding complications. Currently, no diagnostic test can predict thrombohemorrhagic complications. In a prospective study of 86 patients with polycythemia vera (43 patients) or essential thrombocythemia (43 patients), we examined the possible role of polymorphisms of platelet adhesion receptors [glycoprotein (GP) Ibalpha, GPIa, GPIIIa) and clotting factor II (prothrombin's G20210A mutation) and clotting factor V (Leiden mutation) in determining the risk of thrombotic or bleeding complications. Except for an association between vasomotor symptoms and prothrombin mutation (P < 0.001), no significant correlation between polymorphism of clotting factors and thrombohemorrhagic complications was identified. When the entire patient cohort was considered, the polymorphisms of platelet adhesion receptors were not associated with the risk for thrombotic or bleeding complications. However, among patients with polycythemia vera, the presence of the PlA2 allele of GPIIIa was associated with an increased risk of arterial thrombosis. In view of previous studies linking the presence of the PlA2 allele of GPIIIa to a higher risk for coronary artery thrombosis, our data have physiologic relevance. However, they need to be confirmed in a larger study.

Adult↗
PubMed2004

Clinical, genetic, and therapeutic insights into systemic mast cell disease.

PURPOSE OF REVIEW: Mast cell disease is markedly heterogeneous in its underlying molecular pathogenesis, clinical presentation, natural history, and specific treatment. Skin-only disease (cutaneous mastocytosis) is infrequent in adults and systemic mastocytosis may be broadly classified as an indolent or aggressive variant based on the absence or presence of impaired organ function. Urticaria pigmentosa and mast cell mediator release symptoms can occur in all categories of mast cell disease and may not be prognostically detrimental. The purpose of this review is to summarize current concepts and recent advances in the pathogenesis and treatment of adult mast cell disease. RECENT FINDINGS: A series of laboratory investigations has revealed that mast cell disease is a clonal stem cell disorder, and at least two genes (c-kit and PDGFRA) with pathogenetically relevant mutations have been identified. FIP1L1-PDGFRA+ mast cell disease responds completely to imatinib mesylate. Both Asp816Val c-kit+ and molecularly undefined cases have been shown to respond to 2-chlorodeoxyadenosine therapy after failing treatment with interferon-alpha. SUMMARY: A partial molecular classification of mast cell disease is now possible; Asp816Val c-kit+, FIP1L1-PDGFRA+, and molecularly undefined cases. Such molecular classification is therapeutically relevant.

Adult↗
PubMed2004

Outcome of splenectomy for thrombocytopenia associated with systemic lupus erythematosus.

OBJECTIVE: To determine the efficacy of splenectomy for treating thrombocytopenia associated with systemic lupus erythematosus (SLE). SUMMARY BACKGROUND DATA: The role of splenectomy has been controversial in this patient population. METHODS: Between 1975 and 2001, 25 consecutive adults with SLE underwent splenectomy specifically for thrombocytopenia. Surgical indications, operative mortality and morbidity, and hematological outcomes were followed in both the short-term (first 30 days) and the long-term (last recorded platelet count, last contact, or death). Response to splenectomy was rated as: complete (CR: platelets >/=150 x 10/L for at least 4 weeks), partial (PR: platelets 50-149 x 10/L for at least 4 weeks), or none (NR: platelets < 50 x 10/L at all times). Relapse occurred if platelets fell below 50 x 10/L after CR or PR. RESULTS: Indications for splenectomy included: thrombocytopenia refractory to (64%), dependent on (20%), or patient intolerance of (16%) medical treatments. Perioperative mortality was 0% and morbidity was 24%. After a median of 9.5 years, 9 patients (36%) had died, with only 1 death being secondary to bleeding. Early partial or complete response rate to splenectomy was 88%. After a median follow-up of 6.6 years, 16 (64%) patients had sustained complete or partial response without relapse. Eight (32%) of these patients required adjunctive medical therapy, whereas the other 8 (32%) did not. The remaining 9 (36%) patients relapsed, but 5 (20%) of the 9 patients were subsequently salvaged to at least partial response with further treatments. The overall PR or CR to splenectomy combined with medical therapy was 84%. CONCLUSION: Splenectomy should be considered safe and efficacious for thrombocytopenia associated with SLE.

Adolescent↗
PubMed2004

Platelet-rich plasma serotonin levels in chronic myeloproliferative disorders: evaluation of diagnostic use and comparison with the neutrophil PRV-1 assay.

In a prospective study of 109 subjects, an enzyme-linked immunosorbent assay (ELISA) was used to measure platelet-rich plasma (PRP) serotonin levels in patients with polycythaemia vera (PV; n = 27), essential thrombocythaemia (ET; n = 14), myelofibrosis with myeloid metaplasia (MMM; n = 30), secondary or spurious polycythaemia (SP; n = 22) and controls (n = 16). Nine study subjects who were taking a selective serotonin reuptake inhibitor (SSRI) all displayed a markedly decreased PRP serotonin level (median, 24.2 ng/10(9) platelets; range, 0-49.3) and were therefore excluded from further analysis. Among the remaining 100 subjects, the median and range of PRP serotonin levels, in ng/10(9) platelets, was significantly lower in MMM (89.5; 0-278.3), PV (204.8; 0-496.0) and ET (385.3; 136.8-1025.7) compared with both SP (608.8; 369.0-1780.1) and controls (567.2; 359.9-1071.1). Neutrophil polycythaemia rubra vera-1 (PRV-1) expression was concurrently assayed by real-time polymerase chain reaction in 69 patients (23 PV, 17 SP, 12 ET, seven MMM, 10 controls). PRP serotonin measurement performed as well as the PRV-1 assay in distinguishing PV from SP (93% vs. 86% test accuracy). The current study suggests that PRP serotonin concentration might be considered as one of the several biological markers that complement each other for the diagnosis of PV.

Adolescent↗
PubMed2004

Chronic myelogenous leukemia and myeloproliferative disease.

In Section I, Dr. Stephen O'Brien reviews the latest data on the clinical use of imatinib (STI571, Gleevec, Glivec) in CML. His review focuses on the use of imatinib in newly diagnosed chronic phase patients and summarizes cytogenetic and molecular response data, as well as use of the agent at high doses and in combination with other drugs. A brief summary of the prospective international Phase III studies that are currently ongoing is also provided, and the issues of resistance and definition of suboptimal therapeutic response are also covered. Finally, therapeutic decision-making and treatment strategy are considered. In Section II, Dr. Ayalew Tefferi considers the latest developments in the biology and therapy of myeloid metaplasia/myelofibrosis. Dr. Tefferi covers what is currently understood of the biology of the disease and reviews established therapies for the condition as well as novel agents that are being used in clinical trials. The development of optimal management strategies for the disease is considered. In Section III, Dr. Peter Valent reviews the classification of mast cell proliferative disorders and covers the clinical and pathological presentation of this group of neoplasms. He reviews the state-of-the-art regarding the molecular biology of mastocytosis along with diagnostic criteria and novel treatment concepts.

Antineoplastic Agents↗
PubMed2004

Imatinib therapy in clonal eosinophilic disorders, including systemic mastocytosis.

Primary (nonreactive) eosinophilia is operationally classified as either a "clonal" or an "idiopathic" process. Clonal eosinophilia stipulates the presence of cytogenetic, molecular, or bone marrow histologic evidence of acute leukemia or a chronic myeloid disorder. Idiopathic eosinophilia is a diagnosis of exclusion that is made after ruling out both "secondary" (reactive) and clonal eosinophilia. Hypereosinophilic syndrome is a subclass of idiopathic eosinophilia that requires the documentation of both sustained eosinophilia (> or = 1500/microL for at least 6 months) and target-organ damage. A series of novel observations in the last 5 years have warranted a refined approach to the diagnosis as well as the treatment of clonal eosinophilic disorders, including systemic mastocytosis. At the center of these new developments are mutations involving the platelet-derived growth factor receptor genes (PDGFRA and PDGFRB), which have been pathogenetically linked to clonal eosinophilia, and their presence predicts complete as well as durable treatment responses to imatinib mesylate. The bone marrow histologic phenotype of these imatinib-sensitive eosinophilic disorders includes systemic mastocytosis, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, and atypical chronic myeloproliferative disorder.

Antineoplastic Agents↗
PubMed2004

Anagrelide: an update on its mechanisms of action and therapeutic potential.

Thrombocytosis is an increasingly recognized clinical problem due to the widespread availability of automated cell counters. While reactive thrombocytosis does not require any therapeutic intervention, clonal thrombocytosis may require therapy to prevent thrombohemorrhagic complications. The clinician has a number of therapeutic options available when confronted with a patient having clonal thrombocytosis. One of these agents is anagrelide (Agrylin, Bristol-Myers Squibb). In this drug profile, a synopsis of the available data on this agent and its role in the control of thrombocytosis will be provided. The main side effects of the medication are discussed, as well as the potential future developments in the field.

Clinical Trials as Topic↗
PubMed2004

Myelofibrosis with myeloid metaplasia: new developments in pathogenesis and treatment.

Myeloid metaplasia with myelofibrosis (MMM) is a chronic myeloproliferative disorder (CMPD) characterized by progressive anemia, massive splenomegaly, both hepatosplenic and non-hepatosplenic extramedullary hematopoiesis (EMH), a leukoerythroblastic blood smear, circulating progenitor cells, and marked bone marrow stromal reaction including collagen fibrosis, osteosclerosis and angiogenesis. The overall median survival is 5 years although it might range from 2 to 15 years depending on the presence or absence of clinically defined prognostic factors. Death is often due to leukemic transformation, portal hypertension or infection. In addition to shortened survival, quality of life is often affected by frequent red blood cell transfusions, profound constitutional symptoms, and cachexia. Drug therapy and autologous hematopoietic stem cell transplantation (HSCT) are of only palliative value and have not been shown to improve survival. The role of allogeneic HSCT, both myeloablative and non-myeloablative, is actively being investigated. Both splenectomy and radiation therapy have defined therapeutic roles to control EMH-associated symptoms. Analysis of the molecular biology of the disease is underway with the aid of animal models leading to the identification of novel therapeutic targets. Among the novel agents tested, thalidomide seems the most promising although newer agents are on the horizon.

Aged↗