期刊
LEUKEMIA & LYMPHOMA
卷 55, 期 5, 页码 1067-1075出版社
TAYLOR & FRANCIS LTD
DOI: 10.3109/10428194.2013.824080
关键词
Chronic lymphocytic leukemia (CLL); AKT; phospho-flow cytometry; phase II clinical trial; perifosine
资金
- NCI Mentored Clinical Scientist Research Career Development [K08 CA134919]
Because of the importance of the phosphoinositide 3-kinase (PI3K)/AKT pathway in chronic lymphocytic leukemia (CLL), we evaluated in vitro cytotoxicity induced by perifosine, an AKT inhibitor, in CLL lymphocytes and found that the mean 50% effective dose (ED50) was 313 nM. We then performed a phase II trial of perifosine in patients with relapsed/refractory CLL to assess response, outcomes, toxicity and ex vivo correlative measures. After 3 months of treatment, six of eight patients showed stable disease, one achieved a partial response and one had progressive disease. Median event-free survival and overall survival in all patients treated were 3.9 and 9.7 months. Adverse events included hematologic, infectious/fever, pain, gastrointestinal and constitutional toxicities. Unexpectedly, AKT phosphorylation in CLL lymphocytes from treated patients was not correlated with response. Additionally, perifosine did not inhibit AKT phosphorylation in cultured CLL lymphocytes. Perifosine is cytotoxic to CLL cells in vitro, and largely induces stabilized disease in vivo, with an AKT-independent mechanism.
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