bl-4162a and Leukemia--Myeloid

The last four years have seen an explosion in our understanding of the myeloproliferative neoplasms. Important and often unexpected insights into the molecular mechanisms responsible for these disorders have been accompanied by the development of new diagnostic tests and by an improved understanding of the relationship between the different disease entities. This review will focus on recent developments in the pathogenesis and management of essential thrombocythemia with a particular emphasis on its phenotypic overlap with polycythemia vera and primary myelofibrosis.

Topics: Acute Disease; Aged; Aspirin; Clone Cells; Disease Management; Disease Progression; Humans; Hydroxyurea; Interferon-alpha; Janus Kinase 2; Leukemia, Myeloid; Middle Aged; Models, Biological; Mutation, Missense; Polycythemia Vera; Primary Myelofibrosis; Prognosis; Protein Kinase Inhibitors; Quinazolines; Thrombocythemia, Essential; Thrombophilia

The conventional management of patients with high-risk Philadelphia chromosome-negative (Ph-negative) myeloproliferative disorders (MPDs) revolves around the administration of cytoreductive agents such as hydroxyurea, anagrelide, and recombinant human interferon alpha (IFN-alpha). IFN-alpha has shown significant activity in the treatment of chronic myelogenous leukemia (CML) and Ph-negative MDPs. However, the response rates of IFN-alpha therapy frequently have been hampered by high dropout rates due to side effects and inconvenient dosing schedules. Pegylated (PEG) IFN-alpha is formulated by covalently attaching polymers of ethylene glycol of large molecular weight to the native IFN-alpha molecule. Such chemical modification increases serum half-life, decreases renal excretion, and results in prolonged patient exposure to PEG-IFN-alpha, thus allowing for weekly administration while maintaining acceptable toxicity, tolerability, and activity profiles. The lack of adequate therapies for patients with MPDs and the superior pharmacokinetic and pharmacodynamic profile of PEG-IFN-alpha relative to standard IFN-alpha has prompted the investigation of the activity and safety of PEG-IFN-alpha in patients with essential thrombocythemia, polycythemia vera, and idiopathic myelofibrosis. We summarize the available data on the use of PEG-IFN-alpha in patients with Ph-negative MPDs.

Topics: Antineoplastic Agents; Humans; Hydroxyurea; Interferon-alpha; Leukemia, Myeloid; Myeloproliferative Disorders; Philadelphia Chromosome; Quinazolines

Topics: Acute Disease; Alkylating Agents; Aspirin; Cardiovascular Diseases; Clone Cells; Gene Expression; Hemorrhage; Humans; Hydroxyurea; Leukemia, Myeloid; Megakaryocytes; Platelet Aggregation Inhibitors; Quinazolines; Risk; Thrombocythemia, Essential; Thrombophilia

The clinical course in both polycythaemia vera (PV) and essential thrombocythaemia (ET) is characterized by significant thrombohaemorrhagic complications and variable risk of disease transformation into myeloid metaplasia with myelofibrosis or acute myeloid leukaemia. Randomized studies have shown that the risk of thrombosis was significantly reduced in ET with the use of hydroxyurea (HU) and in PV with the use of chlorambucil or 32P. However, the use of chlorambucil or 32P has been associated with an increased risk of leukaemic transformation. Subsequently, other studies have suggested that both HU and pipobroman may be less leukaemogenic and as effective as chlorambucil and 32P for preventing thrombosis in PV. However, the results from these prospective studies have raised concern that even HU and pipobroman may be associated with excess leukaemic events in both ET and PV. The recent introduction of anagrelide as a specific platelet-lowering agent, the demonstration of treatment efficacy with interferon-alpha, and the revived interest in using low-dose acetylsalicylic acid provide the opportunity to initiate prospective randomized studies incorporating these treatments.

Topics: Adult; Aged; Aspirin; Chlorambucil; Disease Progression; Female; Hemorrhage; Humans; Hydroxyurea; Interferon-alpha; Leukemia, Myeloid; Leukemia, Radiation-Induced; Male; Middle Aged; Phlebotomy; Phosphorus Radioisotopes; Pipobroman; Polycythemia Vera; Primary Myelofibrosis; Prospective Studies; Quinazolines; Thrombocythemia, Essential; Thrombosis

The chronic myeloproliferative syndromes are bone marrow stem cell disorders. An increase of cell counts of one or rather all three blood cell types is characteristic for these disorders. The most important diseases in this group are: chronic myelogenous/granulocytic leukemia, polycythemia rubra vera, osteomyelosclerosis or agnogenic myeloid metaplasia and essential thrombocythemia. The cells are normally differentiating in these diseases, while the control of cell dividing is abnormal and therefore the cells are produced and accumulated in excess. Splenomegaly is a common and characteristic clinical finding. The fibrotic or sclerotic transformation of the bone marrow can take place in all forms of the syndrome. Extramedullary haematopoiesis can occur in all of the above diseases, but it is most common in myelofibrosis/agnogenic myeloid metaplasia. In the last phase of the disease a terminal blastic crisis may terminate the course of chronic myeloproliferative diseases. The myeloproliferative disorders can be transformed in each other--the most common transformation is that of the polycythemia rubra vera into myelofibrosis. The greatest progress in the therapy of chronic myeloproliferative diseases is achieved in chronic myelogenous leukemia: bone marrow transplantation and interferon treatment (the latter also in essential thrombocythemia and polycythemia rubra vera) are routine modalities worldwide. A new drug, anagrelide is effective in the treatment of myeloproliferative thrombocytosis and thrombocythemia.

Topics: Chronic Disease; Female; Fibrinolytic Agents; Humans; Interferons; Leukemia, Myeloid; Male; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis; Quinazolines; Thrombocythemia, Essential