Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenström's macroglobulinemia

Irene M. Ghobrial, Aldo Roccaro, Fangxin Hong, Edie Weller, Nancy Rubin, Renee Leduc, Meghan Rourke, Stacey Chuma, Antonio Sacco, Xiaoying Jia, Feda Azab, Abdel Kareem Azab, Scott Rodig, Diane Warren, Brianna Harris, Lyuba Varticovski, Peter Sportelli, Xavier Leleu, Kenneth C. Anderson, Paul G. Richardson

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98 Scopus citations

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. Patients and 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, β2 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 κB activity. Conclusion: 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.

Original languageEnglish
Pages (from-to)1033-1041
Number of pages9
JournalClinical Cancer Research
Volume16
Issue number3
DOIs
StatePublished - Feb 1 2010
Externally publishedYes

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    Ghobrial, I. M., Roccaro, A., Hong, F., Weller, E., Rubin, N., Leduc, R., Rourke, M., Chuma, S., Sacco, A., Jia, X., Azab, F., Azab, A. K., Rodig, S., Warren, D., Harris, B., Varticovski, L., Sportelli, P., Leleu, X., Anderson, K. C., & Richardson, P. G. (2010). Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenström's macroglobulinemia. Clinical Cancer Research, 16(3), 1033-1041. https://doi.org/10.1158/1078-0432.CCR-09-1837