STI571: Targeting BCR-ABL as therapy for CML

被引:150
作者
Mauro, MJ [1 ]
Druker, BJ [1 ]
机构
[1] Oregon Hlth & Sci Univ, Div Hematol & Med Oncol, Leukemia Program, Portland, OR 97201 USA
关键词
chronic myelogenous leukemia; tyrosine kinase; Philadelphia chromosome; STI571;
D O I
10.1634/theoncologist.6-3-233
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Therapeutic agent ST1571 (signal transduction inhibitor number 571) is a rationally developed, potent, and selective inhibitor for abl tyrosine kinases, including bcr-abl, as well c-kit and the platelet-derived growth factor receptor tyrosine kinases. Results of clinical trials to date have demonstrated the crucial role of the bcr-abl tyrosine kinase in chronic myelogenous leukemia (CIVIL) pathogenesis and the potential of anticancer agents designed to target specific molecular abnormalities in human cancer. An initial phase I study of ST1571 included 83 Ph+ CML patients who had failed interferon-based therapy. Patients were required to be in chronic phase, defined liberally as less than 15% blasts in blood or bone marrow. Patients were treated with once-daily oral doses of ST1571 in 14 successive dose cohorts ranging from 25-1,000 mg. In this phase I study, no dose-limiting toxicity was encountered and toxicity at all dose levels was minimal. The threshold for a maximally effective dose was found at 300 mg; for patients treated at or above this level, complete hematologic response was seen in 98% of patients, with complete cytogenetic responses in 13 % and major cytogenetic responses in 31 %. With a median duration of follow-up of 310 days, ongoing responses are evident in 96% of patients. In the phase 11 study of the accelerated phase of CIVIL, 233 patients were treated with either 400 or 600 mg of ST1571. With similar follow-up to the chronic phase trial, 91% of patients showed a hematological response; 63% of patients achieved a complete hematological response but not all patients had recovery of peripheral blood counts. In addition to the phase 11 clinical trials with ST1571, a phase III trial randomizing newly diagnosed patients to either interferon with low-dose s.c. cytosine arabinoside versus ST1571 is ongoing; this trial accrued rapidly and data collection is ongoing. Integration of ST1571 into CIVIL treatment algorithms will require long-term follow-up data from the ongoing phase 11 and III clinical studies.
引用
收藏
页码:233 / 238
页数:6
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