Phase II Multicenter Trial of Lenalidomide: Clinical and Immunomodulatory Effects in Patients with CTCL

Abstract 1638 Background: Lenalidomide is currently being used in various hematological malignancies and solid tumors. The mechanism of action is unknown, but appears to be immune-mediated with stimulation of T- and NK cell function, induction of Th1 cytokine production and cytotoxic activity. The biologic effects of lenalidomide in relapsed CTCL have not been defined. We performed a phase II multicenter trial in relapsed CTCL patients, and investigated the immunomodulatory effects of lenalidomide in a subset of the patients. Methods: Thirty-five heavily pretreated patients (median prior tx 7; range, 1–14) have been enrolled with 28 and 32 patients evaluable for response and toxicity, respectively. The first 18 enrolled patients received 25 mg daily for 21 days with 7 days rest of a 28-day cycle. Because of unacceptable cutaneous flare reactions, the study was amended and subsequent patients received a starting dose of 10 mg and then titrated up to 25 mg as tolerated. A subset of patients underwent immunomodulatory assessment. Blood samples of 6 patients before and 3 weeks into therapy have been analyzed by flow cytometry for various T- and NK cell subsets. Results: Clinical stages were: 7 (24%) stage IB, 2 (7%) stage IIA, 4 (14%) stage IIB; 6 (21%) stage III; 8 (28%) stage IVA, 1 (4%) stage IVB. The overall response rate was 32% (9 pts-all PR with 25 mg daily dose) with median response duration of 5 months (range, 1–12+). The stable-disease rate was 61% (17 pts), and 7% (2 pts) had PD. The median time to first response was 3 months (range, 1–5). Grade 3 adverse events were fatigue (22%), infection (9%), leukopenia (3%), and neutropenia (3%). No grade 4 toxicity occurred. Eight patients (25%) experienced grade 1 or 2 tumor flare after starting treatment with lenalidomide. There was less flare in patients dose escalated. When compared with baseline levels, 4 of 6 patients screened for immunomodulatory changes revealed a decrease in CD4+ T-cells (range, 24% – 68%) with concomitant decrease in CD4+CD25+ T regulatory cells (range, 18% to 87%). When compared to clinical response 2 of these patients achieved PR and 2 patients remained stable during therapy. The remaining 2 patients (2× SD) experienced an increase of CD4+ T-cells (2%, 43%) with increase of CD4+CD25+ T regulatory cells (50%, 73%). Conclusions: In our study oral lenalidomide demonstrates activity in patients with relapsed/advanced CTCL consistent with activity of other currently available agents, with a manageable toxicity profile. Our data suggest that the immunomodulatory cutaneous effects of lenalidomide could be associated with decreased Treg and correlates with blood CD4+ T-cell number. Skin biopsies from 6 patients are being investigated for cytokine expression before and during therapy. Use as maintenance therapy or in combination with other biologic agents is worth investigating. Disclosures: Off Label Use: Lenalidomide. Rosen: Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Kim: kyowa: Consultancy, Research Funding; Merck: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Allos: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Millenium: Consultancy. Kuzel: Celgene: Research Funding, Speakers Bureau.