title: Perifosine treatment in chronic lymphocytic leukemia: results of a phase II clinical trial and in vitro studies.
abstract: Abstract 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.
authors.affiliation: Department of Medicine, Duke University Medical Center , Durham, NC , USA.
authors.forename: Daphne R
authors.initials: DR
authors.lastname: Friedman
authors.forename: Mark C
authors.initials: MC
authors.lastname: Lanasa
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Davis
authors.forename: Sallie D
authors.initials: SD
authors.lastname: Allgood
authors.forename: Karen M
authors.initials: KM
authors.lastname: Matta
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Brander
authors.forename: Youwei
authors.initials: Y
authors.lastname: Chen
authors.forename: Evan D
authors.initials: ED
authors.lastname: Davis
authors.forename: Alicia D
authors.initials: AD
authors.lastname: Volkheimer
authors.forename: Joseph O
authors.initials: JO
authors.lastname: Moore
authors.forename: Jon P
authors.initials: JP
authors.lastname: Gockerman
authors.forename: Peter
authors.initials: P
authors.lastname: Sportelli
authors.forename: J Brice
authors.initials: JB
authors.lastname: Weinberg
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010766:Phosphorylation / Q000187:drug effects; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D010767:Phosphorylcholine; C105905:perifosine; D051057:Proto-Oncogene Proteins c-akt