Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom's macroglobulinemia.
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.
Ghobrial
Irene M
IM
Dana-Farber Cancer Institute, Boston, MA, USA. irene_ghobrial@dfci.harvard.edu
Roccaro
Aldo
A
Hong
Fangxin
F
Weller
Edie
E
Rubin
Nancy
N
Leduc
Renee
R
Rourke
Meghan
M
Chuma
Stacey
S
Sacco
Antonio
A
Jia
Xiaoying
X
Azab
Feda
F
Azab
Abdel Kareem
AK
Rodig
Scott
S
Warren
Diane
D
Harris
Brianna
B
Varticovski
Lyuba
L
Sportelli
Peter
P
Leleu
Xavier
X
Anderson
Kenneth C
KC
Richardson
Paul G
PG
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*
D000970:Antineoplastic Agents; D009842:Oligopeptides; D010767:Phosphorylcholine; C105905:perifosine; C056289:GSK peptide; D051057:Proto-Oncogene Proteins c-akt