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

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.

Off Label Use: Lenalidomide. Rosen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:kyowa: Consultancy, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Consultancy. Kuzel:Celgene: Research Funding, Speakers Bureau.