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.

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, 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.

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.

Figure 1A. Percent decrease in IgM frombaseline in all 37 patients

The median decrease in IgM from baseline among all 37 patients was 650 mg/dl (range, 0-3370) and the median percent decrease in IgM in all 37 patients was 22 %(range, 0-60%).

Figure 1B. Percent change in hemoglobinfrom baseline in all 37 patients

The median improvement in hemoglobin from baseline was 0.6 gm/dL (range, −1 to 2.4 gm/dL) and the median percent change in hemoglobin among all 37 patients was 5% (range, −11 to 29%).

Figure 2A. Progression Free Survival

Progression free survival. The median time to progression and progression free survival were similar among all 37 patients and were at 12.6 months, 90% C.I. (10.2 – 22.7 months).

Figure 2B. Event free survival

Event free survival. The median time to event free survival was 8.3 months, 90% C.I. (6.7 – 12.0 months)

Figure 2C. Overall survival

Overall survival. Kaplan Meier curve for overall survival. The median overall survival was 26 months, 90% C.I. (26.0 – months, no estimate for upper limit). Death occurred in 7 patients.

Figure 2D. Theeffect of beta-2 microglobulin > 3.5 mg/dL on event free survival

The effect of Beta-2 microglobulin >3.5mg/dL on event free survival. Beta-2 microglobulin of >3.5 mg/dL was associated with a worse event free survival in these patients (p=0.002, hazard ratio n=2.42).

Figure 3A. Supervised clustering of gene expression profiling of pre-treatment versus post-treatment samples

Supervised clustering of gene expression profiling of pre-treatment vs. post-treatment samples. Purified cRNA (15 mg) isolated from primary WM cells was hybridized to HG-U133Plus2.0 GeneChip (Affymetrix). Supervised clustering analysis in 6 pre- and 5 post-treatment patients. Fold change is shown by the intensity of induction (red) or suppression (blue) (p<0.05). Samples 1, 2, 3 and 4 have matching pre- and post-treatment samples, while samples a and b were available for pre-treatment only and sample c was available in post-treatment only.

Figure 3B. Immunohistochemistry of phospho-GSK (pGSK) in pre - and post-treatment samples

Immunohistochemistry of phospho-GSK in pre- and post-treatment samples. Scoring was performed by an independent pathologist, who was blinded to the clinical results. Each sample was given a score of 0 (no staining), 1 (weak staining), 2 (moderate staining) or 3 (strong staining of tumor cells) depending on the intensity of pGSK staining in the lymphoplasmacytic cells. For each sample, a table was placed with the score given for the pre-and post-treatment samples and the corresponding clinical response observed by monoclonal protein in these patients. Samples at cycle 3 were also obtained and showed similar results to the EOS samples and therefore, were not included in the figure.