SAN DIEGO, CA—Oral lenalidomide demonstrated activity in patients with relapsed/advanced cutaneous T-cell lymphoma (CTCL) consistent with that of other currently available agents, according to results of a Phase 2 multicenter trial presented at the 53rd American Society of Hematology Annual Meeting and Exposition. These results suggest lenalidomide may have utility as maintenance therapy or in combination with other biologic agents.

Although the mechanism of action of lenalidomide is unknown, it appears to be immune-mediated, with stimulation of T-cell and NK cell function, induction of Th1 cytokine production, and cytotoxic activity. The biologic effects of lenalidomide, currently being used in various hematological malignancies and solid tumors, have yet to be defined in patients with relapsed CTCL.

To investigate the immunomodulatory effects of lenalidomide in a subset of patients with relapsed CTCL, Christiane Querfeld, MD, PhD, of Memorial Sloan-Kettering Cancer Center, New York, and colleagues enrolled 35 heavily pretreated patients who had a median number of seven prior therapies (range 1–14). The first 18 patients received lenalidomide 25mg/day orally for 21 days, followed by a seven-day rest period (28-day cycle). Due to unacceptable cutaneous flare reactions, the study was amended and 13 subsequent patients received a starting dose of lenalidomide 10mg, titrated to 25mg as tolerated. One patient was initiated at 5mg/day.

Immunomodulatory assessment was conducted in a subset of patients after every cycle using Composite Assessment of Index Lesion Disease Severity for skin lesions, absolute Sézary cell count for quantification of circulating malignancy lymphocytes and or CT scans for evidence of adenopathy or visceral disease. Blood samples collected from six patients prior to initiation of therapy and three weeks into therapy were analyzed by flow cytometry for various T-cell and NK cell subsets. A total of 29 patients were evaluable for response and 32 for toxicity.

Of those evaluable for response, seven patients (24%) had clinical stage IB, two (7%) stage IIA, four (14%) stage IIB, six (21%) stage III, eight (28%) stage IVA, and one (4%) stage IVB. Overall response rate (ORR) was 31%, which was observed in nine patients, all of whom had partial responses (PR) at the lenalidomide 25mg daily dose. Median duration of response was five months (range 1–12+). Seventeen patients (59%) had stable disease (SD) and three patients (10%) had disease progression. Median time to first response was three months (range 1–5). In 15 patients, partial or near complete clearance of skin patches, plaques, tumors, or erythroderma was seen.

Frequently occurring adverse events included fatigue, pruritus, lower leg edema, GI symptoms, and hematologic events. The most commonly occurring 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; flare occurred less frequently in patients who were dose escalated.

Compared with baseline levels, four of six patients screened for immunomodulatory changes demonstrated a decrease in CD4+ T-cells (range 24–68%) with a concomitant decrease in CD4+CD25+ T regulatory (Treg) cells (range 18–87%). Two of the patients achieved a PR and two remained stable during therapy. The remaining two patients, both of whom had SD, experienced an increase of CD4+ T-cells (2%, 43%), with an increase of CD4+CD25+ Treg cells (50%, 73%).

In this study, oral lenalidomide had a manageable toxicity profile. The data suggest the immunomodulatory cutaneous effects of lenalidomide could be associated with decreased Treg and correlate with blood CD4+ T-cell number. Dr. Querfeld noted that skin biopsies from six patients are being investigated for cytokine expression before and during therapy.