Combination of the AKT inhibitor Perifosine (Æterna Zentaris GmbH, Germany) with the multikinase inhibitor Sorafenib (Nexavar, Bayer) induces gene expression profiling and signaling changes resulting in a synergistic cytotoxic activity against lymphoma cell lines. Based on this preclinical rationale, we performed a phase II study aimed at determining safety and activity of the Perifosine/Sorafenib combination therapy in relapsed/refractory lymphomas, and at evaluating predictive and prognostic biomarkers.
Between July 2008 and November 2011, 40 patients (26 males and 14 females; median age, 42 years; range, 17–77 years) with relapsed/refractory diffuse large B-cell lymphoma (DLBCL, n = 3), follicular lymphoma (FL, n = 3), Waldenstrom macroglobulinemia (WM, n = 1), chronic lymphocytic leukemia (CLL, n = 8), and classical Hodgkin Lymphoma (cHL, n = 25) who have failed second- or subsequent-line salvage chemo-radiotherapy were enrolled in this trial. Prior to study entry, patients received a median of 5 (range 2 – 11) lines of treatment with autologous stem cell transplant (SCT) performed in 27 (67%) and an additional allogeneic SCT in 17 (42%) patients. At study entry, 12 patients (30%) had relapsed and 28 (70%) refractory disease. Treatment plan included an initial 4-week treatment with Perifosine alone (50 mg BID, per os) to assess tolerability and tumor response. Subsequently, patients achieving less than partial remission (PR) were given the combination therapy, i.e., Perifosine (50 mg BID, per os) plus Sorafenib (400 mg BID, per os) until disease progression (PD) or clinical significant toxicity, whereas patients achieving more than PR went off-study and continued with Perifosine alone (50 mg BID, per os) until PD or clinical significant toxicity. Phosphorylation levels of ERK (pERK) and AKT (pAKT) were investigated by flow cytometry on peripheral blood lymphocytes (PBL) collected prior to therapy initiation and monthly thereafter. Tumor response was assessed according to the revised response criteria for malignant lymphoma of the International Working Group. The study was approved by the Institutional Review Board and Ethical Committee.
Based on tumor response to the initial 4-week Perifosine therapy, 36 of 40 patients who achieved less than PR were subsequently administered with the combination therapy and are reported herein. In contrast, 4 CLL patients who achieved more than PR with Perifosine alone went off-study and continued with single agent therapy. Median duration of combination therapy was 4 months (range, 2 – 18). The most common drug-related toxicities were grade 1–2 anemia (17%), thrombocytopenia (9%), diarrhea (25%) and joint pain (22%). Hand-foot skin reaction was of grade 2 in 25% and of grade 3 in 14% of patients. Grade 4 neutropenia was observed in one patient. Definitive treatment discontinuation was required in 2 patients experiencing grade 3 pneumonitis. Best response to combination therapy included 8 (22%) PR, 15 (42%) stable disease (SD) and 13 (36%) PD. Median time to achieve PR was 4 months (range, 1–8) and median duration of response (DoR) was 4 months (range, 1 – 12). Patients achieving PR included 7 cHL and 1 CLL patients, resulting in an overall response rate (ORR) of 28% in the cHL subgroup. After a median follow-up of 14 months (range, 2 – 45), the median overall survival (OS) and progression free survival (PFS) for all study patients were 16 and 5 months, respectively; for responding cHL patients median OS was not reached and median PFS was 12 months. A significant correlation between pERK and pAKT reduction during the first two months of therapy and clinical response was demonstrated by logistic regression model. The reduction of pERK and pAKT values (i.e., the difference between baseline values vs 60-day values) was related to a highly significant probability to observe a clinical response (P = 0.003 and P = 0.005 for pERK and pAKT, respectively).
Combination therapy with Perifosine and Sorafenib is well tolerated by heavily pretreated lymphoma patients. Promising activity in term of clinical response is observed in relapsed/refractory cHL patients, suggesting this subgroup could represent the target population for future studies. Early reduction of pERK and pAKT during the first two months of therapy has a significant predictive value of clinical response and needs to be confirmed in a larger cohort of patients.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.