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April 5, 2001
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An Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia
BCR-ABL, a chimeric protein with tyrosine kinase activity, results from the formation of the Philadelphia chromosome and causes chronic myeloid leukemia. STI571, a specific inhibitor of the enzymatic activity of BCR-ABL, was tested in patients with chronic myeloid leukemia in whom conventional therapy had failed. The drug was well tolerated, and virtually all patients receiving daily doses of 300 mg or more had a response to treatment.
A BCR-ABL Tyrosine Kinase Inhibitor in the Blast Crisis of Chronic Myeloid Leukemia
This paper, a companion to the study of STI571 in chronic myeloid leukemia in this issue of the Journal, reports a trial of STI571 in patients with the blast crisis of chronic myeloid leukemia or Philadelphia-chromosomeŠpositive acute lymphoblastic leukemia. All patients had no response to standard chemotherapy or had relapsed and as a result had a poor prognosis. STI571 induced hematologic responses in the myeloid and lymphoid forms of the blast crisis and in acute lymphoblastic leukemia; however, all but 1 of the latter 20 patients relapsed. By contrast, 7 of 38 patients with a myeloid blast crisis are in remission up to one year after treatment began.
STI571 is a new treatment for both the chronic and blast phases of chronic myeloid leukemia. The development of the drug arose from research showing that the BCR-ABL fusion protein is a constitutively activated tyrosine kinase. This enzyme is central to the signaling machinery that controls the proliferation of cells, and its incessant activity causes chronic myeloid leukemia. The results of treating chronic myeloid leukemia with STI571 were dramatic, but in the blast crisis of chronic myeloid leukemia the results were not nearly as striking. As the BCR-ABL tyrosine kinase occurs in both the chronic and accelerated phases of chronic myeloid leukemia, STI571 may be a useful probe of the differences between these two aspects of chronic myeloid leukemia.
Related Editorial
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Effect of STI571 on a Metastatic Gastrointestinal Stromal Tumor
Gastrointestinal stromal tumors arise from primitive connective-tissue cells in which a mutation causes unremitting expression of c-kit, a growth factor receptor with tyrosine kinase activity. A patient with a gastrointestinal stromal tumor that had resisted numerous forms of therapy had a rapid response to treatment with STI571, an inhibitor of this type of kinase.
This case report suggests that, in addition to its effects in chronic myeloid leukemia, STI571 can be effective in solid tumors that constitutively express active tyrosine kinases.
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Long-Term Survival after Atrioventricular-Node Ablation and Implantation of a Permanent Pacemaker in Patients with Atrial Fibrillation
In some patients with atrial fibrillation, the arrhythmia is refractory to medical therapy because sinus rhythm cannot be maintained and the ventricular rate cannot be controlled. An alternative therapeutic approach is to ablate the atrioventricular node (resulting in complete heart block) and implant a permanent pacemaker, but there is concern about the long-term consequences of the procedure. This study shows that the approach has no adverse effect on long-term survival.
Refractory, chronic atrial fibrillation can be a serious, debilitating problem. In some patients, ablation of the atrioventricular node and implantation of a pacemaker can alleviate symptoms and improve the quality of life. The current study provides reassurance that this procedure, which entails the creation of permanent, complete heart block, does not adversely affect survival.
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Advances in Immunology: Complement
Complement, a multicomponent system of proteins, is best known for its ability to lyse cells coated with antibodies. During the past few years, it has become apparent that the complement system has additional activities, especially in the regulation of the immune system and in the disposal of dead cells. This is the first of a two-part review of the complement system. The review centers around diseases associated with abnormalities of the system.
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Medical Progress: Atrial Fibrillation
Atrial fibrillation is one of the most common rhythm disorders encountered in clinical practice. Recently, there have been substantial advances in our understanding of the pathophysiology of atrial fibrillation; in drug therapy, including anticoagulation; and in such nonpharmacologic interventions as ablation of the atrioventricular node with the implantation of a pacemaker. This review article covers these topics comprehensively.
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Clinical Problem-Solving: Less Is More
This case study involves a 63-year-old woman with type 2 diabetes mellitus and a remote history of a positive skin test for tuberculosis with purified protein derivative who presents with fatigue, anorexia, and unintentional weight loss. Her serum aminotransferase and alkaline phosphatase levels are elevated. Ptosis and conjunctival injection of the left eye subsequently develop.
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