bl-4162a and Leukemia--Myeloid--Acute

Essential thrombocythemia is a chronic myeloproliferative neoplasm characterized by sustained thrombocytosis, bone marrow megakaryocytic hyperplasia and an increased risk of thrombosis and hemorrhage. The goal of treatment is to prevent the development of vascular complications without increasing the risk of transformation. Patients aged>60 years or a history of thrombosis have a high risk of thrombosis while those with a platelet count>1,500 x 10(9)/l have a higher risk of hemorrhage. Patients with low-risk essential thrombocythemia can be managed appropriately with low-dose of acetylsalicylic acid or even observation only, while patients with a high-risk disease are candidates to receive cytoreductive treatment, hydroxyurea being the first choice therapy. Anagrelide is the most suitable option for patients with resistance or intolerance to hydroxyurea. All patients must be submitted to a rigorous control of cardiovascular risk factors.

Topics: Adult; Age Factors; Aged; Anticoagulants; Aspirin; Cell Transformation, Neoplastic; Disease Progression; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Hydroxyurea; Intraoperative Complications; Janus Kinase 2; Leukemia, Myeloid, Acute; Life Expectancy; Male; Middle Aged; Mutation, Missense; Platelet Aggregation Inhibitors; Point Mutation; Pregnancy; Pregnancy Complications, Hematologic; Primary Myelofibrosis; Quinazolines; Risk Factors; Thrombocythemia, Essential; Thrombophilia

The incidence of essential thrombocythaemia (ET) in children (age ≤18 years) is extremely low. The natural course of the disorder in children has not been clarified. The rarity of patients and the variability of tested parameters make it difficult to draw any definitive conclusion in pathogenesis and diagnosis of paediatric ET. What makes the onset of thrombocytosis earlier in children is still uncertain. A diagnostic algorithm for paediatric ET has not been established, and current risk stratification used to guide therapeutic decisions in adults has not been validated in children. Vascular complications and transformation to myelofibrosis and leukaemia in this special entity have been reported, suggesting that ET in children is not an entirely benign disease. The crucial question is how to identify patients who are at high risk of complications and need treatment. There are insufficient data to recommend a specific agent in children. The purpose of this review is to outline the most recent progress in paediatric ET and to help with understanding the clinical course, molecular features, diagnosis and treatment strategies in this special group.

Topics: Adolescent; Age of Onset; Anticoagulants; Child; Child, Preschool; Clone Cells; Disease Progression; GPI-Linked Proteins; Hemorrhage; Humans; Hydroxyurea; Incidence; Infant; Isoantigens; Janus Kinase 2; Leukemia, Myeloid, Acute; Platelet Aggregation Inhibitors; Point Mutation; Primary Myelofibrosis; Quinazolines; Receptors, Cell Surface; Risk Assessment; Symptom Assessment; Thrombocythemia, Essential; Thrombophilia

EXELS, a post-marketing observational study, is the largest prospective study of high-risk essential thrombocythemia (ET) patients, with an observation time of 5 years. EXELS found higher event rates of acute leukemia transformation in patients treated with hydroxycarbamide (HC). In the current analysis, we report age-adjusted rates of malignant transformation from 3460 EXELS patients exposed to HC, anagrelide (ANA), or both. At registration, 481 patients had ANA treatment without HC exposure, 2305 had HC without ANA exposure, and 674 had been exposed to both. Standard incidence ratios (SIRs) were calculated using data from the Cancer Incidence in Five Continents database to account for differences in age-, gender-, and country-specific background rates. SIRs for acute myelogenous leukemia (AML) were high in ET patients. SIRs for AML were high in HC-treated patients, but AML was rare in ANA-treated patients; no cases of AML were found in patients only treated with ANA. No statistically significant difference was seen between SIRs for ANA and HC treatment for AML or skin cancer. SIRs for other cancers were similar in the HC and ANA groups and close to 1, indicating little difference in risk. Although statistically inconclusive, this study strengthens concerns regarding possible leukemogenic risk with HC treatment. (NCT00202644).

Topics: Adult; Aged; Aged, 80 and over; Cell Transformation, Neoplastic; Female; Humans; Hydroxyurea; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasms, Second Primary; Quinazolines; Thrombocythemia, Essential

We conducted a randomized comparison of hydroxyurea with anagrelide in the treatment of essential thrombocythemia.. A total of 809 patients with essential thrombocythemia who were at high risk for vascular events received low-dose aspirin plus either anagrelide or hydroxyurea. The composite primary end point was the actuarial risk of arterial thrombosis (myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, or peripheral arterial thrombosis), venous thrombosis (deep-vein thrombosis, splanchnic-vein thrombosis, or pulmonary embolism), serious hemorrhage, or death from thrombotic or hemorrhagic causes.. After a median follow-up of 39 months, patients in the anagrelide group were significantly more likely than those in the hydroxyurea group to have reached the primary end point (odds ratio, 1.57; 95 percent confidence interval, 1.04 to 2.37; P=0.03). As compared with hydroxyurea plus aspirin, anagrelide plus aspirin was associated with increased rates of arterial thrombosis (P=0.004), serious hemorrhage (P=0.008), and transformation to myelofibrosis (P=0.01) but with a decreased rate of venous thromboembolism (P=0.006). Patients receiving anagrelide were more likely to withdraw from their assigned treatment (P<0.001). Equivalent long-term control of the platelet count was achieved in both groups.. Hydroxyurea plus low-dose aspirin is superior to anagrelide plus low-dose aspirin for patients with essential thrombocythemia at high risk for vascular events.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Aspirin; Drug Therapy, Combination; Female; Follow-Up Studies; Hemorrhage; Humans; Hydroxyurea; Leukemia, Myeloid, Acute; Male; Middle Aged; Platelet Aggregation Inhibitors; Platelet Count; Primary Myelofibrosis; Quinazolines; Thrombocythemia, Essential; Thrombosis

We hereby report a case of acute myeloid leukemia with translocation t(2;3) and involvement of the ectopic virus integration site-1 (EVI1) gene. Like most other 3q26-related disorders reported thus far, we describe a phenotype with elevated platelet counts and dysmegakaryopoesis. The clinical course of our patient was complicated by symptomatic thrombophilia and chemoresistance. In addition, our case exhibited FLT3 (Fms-related tyrosine kinase 3) internal tandem duplication. Although anagrelide was successful in controlling elevated platelet counts, allogeneic stem cell transplantation failed to overcome chemoresistance due to simultaneous graft-versus-host-disease and relapse of acute myeloid leukemia. Given the dismal outcome of our case and previously reported cases, we propagate the implementation of targeted therapies to newly diagnosed patients with acute myeloid leukemia t(2;3). Preclinical models indicate drugs that plausibly target the EVI1-related molecular vulnerability as candidates for basket trials. Anagrelide exhibited a hopeful signal of activity in 3q26-related thrombocytosis and should be evaluated for implementation as supportive care.

Topics: Blood Platelets; DNA-Binding Proteins; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Male; MDS1 and EVI1 Complex Locus Protein; Middle Aged; Platelet Aggregation Inhibitors; Platelet Count; Proto-Oncogenes; Quinazolines; Stem Cell Transplantation; Thrombophilia; Transcription Factors; Translocation, Genetic

Topics: Antineoplastic Agents; Aspirin; Drug Therapy, Combination; Hemorrhage; Humans; Hydroxyurea; Leukemia, Myeloid, Acute; Platelet Aggregation Inhibitors; Primary Myelofibrosis; Quinazolines; Risk Factors; Thrombocythemia, Essential; Thrombosis