Treatment with Lenalidomide Has a Positive Immunomodulatory Effect in Patients with Chronic Lymphocytic Leukemia.

Lenalidomide (Revlimid) is known to downregulate TNF-a, IL-6, IL-8, and VEGF, impair bone marrow microenviroment-neoplastic cell interaction, activate NK cells, and stimulate T-cell activity. Based on these properties, we sought to further evaluate the immumodulatory activity of treatment with lenalidomide in patients with previously untreated chronic lymphocytic leukemia age 65 and older. Nineteen patients enrolled in a phase II clinical trial were treated with lenalidomide, given orally at the dose of 5mg daily for 28 days followed by individual titration up of 5mg increments every 28 days to reach a maximum dose of 25mg daily. Patients were evaluated for response after 3 months and if an objective response or disease stability was obtained, the treatment was continued until obvious disease progression. Peripheral blood (15ml) was collected at baseline, after three months and every six months thereafter while on treatment in patients that agreed to optional correlative studies. Data at baseline and after three months of treatment are presented. Plasma cytokine levels were determined by Luminex Multiplex assay system. Percentages of CD3, CD4, and CD8 T cells and natural regulatory T cells (T_R, CD4+CD25^hiFoxP3+) cells, and the ability of anti-CD3 activated T cells to synthesize of IL-2, IFN-g, TNF-a, and IL-10 were measured by multi-color flow cytometry. Eleven patients had a partial response (responder, R) and 8 patients failed to respond (non-responder, NR) after 3 months of therapy. All patients had significantly higher percentages of CD3+ and CD4+ T-cells (P = 0.012) after three months of treatment respect to baseline, but only R patients had a significantly higher percentage of T_R cells (P = 0.041). Both R (P = 0.016) and NR (P = 0.025) patients had higher percentages of IFN-g-producing CD8+ T cells after three months of therapy. Moreover in NR patients, the percentage of T_R cells negatively correlated with the percentages of CD4+ T cells that produced IL-2 and TNF-a, and of CD8+ T cells that produced IFN-g and TNF-a. Following 3 months of therapy, plasma levels of IL-10 were significantly increased in both R (P =0.012) and NR (P = 0.05); IL-1b plasma level was elevated in NR (P = 0.012) but not in R; IL-17 plasma level was decreased in R (P = 0.006); neither R nor NR had changes in plasma levels of IL-1RA, IL-2, IL-6, TNF-a, TNF-R1, VEGF, and VEGF-R (R1, R2, R3). In conclusion treatment with lenalidomide increased the percentages of T-helper cells in both R and NR patients and of T_R cells in R patients. Treatment with lenalidomide also increased the function of CD8+ T cells as exhibited by the synthesis of IFN-g in both R and NR patients. These preliminary data suggest that lenalidomide has a favorable immunomodulatory effect on patients with B-CLL. Sample collection is ongoing for further analyses.