title: Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom's macroglobulinemia.
abstract: BACKGROUND
  Waldenström's macroglobulinemia (WM) is a rare, low-grade lymphoproliferative disorder. Based on preclinical studies, we conducted a phase II clinical trial testing the efficacy and safety of the Akt inhibitor perifosine in patients with relapsed/refractory WM.
  
  
  METHODS
  Thirty-seven patients were treated with oral perifosine (150 mg daily) for six cycles. Stable or responding patients were allowed to continue therapy until progression.
  
  
  RESULTS
  The median age was 65 years (range, 44-82). The median number of prior therapy lines was two (range, one to five). Of the 37 patients, 4 achieved partial response (11%), 9 minimal response (24%), and 20 showed stable disease (54%). The median progression-free survival was 12.6 months. Additionally, beta2 microglobulin of >3.5 mg/dL was associated with poor event-free survival (P = 0.002). Perifosine was generally well tolerated; adverse events related to therapy were cytopenias (grade 3-4, 13%), gastrointestinal symptoms (grade 1-2, 81%), and arthritis flare (all grades, 11%). Translational studies using gene expression profiling and immunohistochemistry showed that perifosine inhibited pGSK activity downstream of Akt, and inhibited nuclear factor kappaB activity.
  
  
  CONCLUSIONS
  Perifosine resulted in at least a minimal response in 35% of patients and a median progression-free survival of 12.6 months in patients with relapsed or relapsed/refractory WM, as well as in vivo inhibition of pGSK activity. The results of this study warrant further evaluation of perifosine in combination with rituximab or other active agents in patients with WM.
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA. irene_ghobrial@dfci.harvard.edu
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
authors.forename: Aldo
authors.initials: A
authors.lastname: Roccaro
authors.forename: Fangxin
authors.initials: F
authors.lastname: Hong
authors.forename: Edie
authors.initials: E
authors.lastname: Weller
authors.forename: Nancy
authors.initials: N
authors.lastname: Rubin
authors.forename: Renee
authors.initials: R
authors.lastname: Leduc
authors.forename: Meghan
authors.initials: M
authors.lastname: Rourke
authors.forename: Stacey
authors.initials: S
authors.lastname: Chuma
authors.forename: Antonio
authors.initials: A
authors.lastname: Sacco
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Jia
authors.forename: Feda
authors.initials: F
authors.lastname: Azab
authors.forename: Abdel Kareem
authors.initials: AK
authors.lastname: Azab
authors.forename: Scott
authors.initials: S
authors.lastname: Rodig
authors.forename: Diane
authors.initials: D
authors.lastname: Warren
authors.forename: Brianna
authors.initials: B
authors.lastname: Harris
authors.forename: Lyuba
authors.initials: L
authors.lastname: Varticovski
authors.forename: Peter
authors.initials: P
authors.lastname: Sportelli
authors.forename: Xavier
authors.initials: X
authors.lastname: Leleu
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D012008:Recurrence; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D010767:Phosphorylcholine; C105905:perifosine; C056289:GSK peptide; D051057:Proto-Oncogene Proteins c-akt