Treatment with lenalidomide modulates T-cell immunophenotype and cytokine production in patients with chronic lymphocytic leukemia

Abstract

Background: Lenalidomide, an immunomodulatory agent, has activity in lymphoproliferative disorders. The authors, therefore, evaluated its effects on T-cell immunophenotype and cytokine production in patients with chronic lymphocytic leukemia (CLL).

Methods: To study the immunomodulatory effects of lenalidomide in CLL, the authors recruited 24 patients with untreated CLL enrolled in a phase 2 clinical trial of lenalidomide and obtained peripheral blood specimens for immunologic studies consisting of enumeration of T cells and assessing their ability to synthesize cytokines after activation through T-cell receptor (TCR).

Results: After 3 cycles of therapy, patients had a significant reduction in percentage (%) and absolute lymphocyte count (ALC) and an increase in percentage of T cells, percentage of activated CD8(+) T cells producing IFN-γ, and percentage of regulatory T (T(R) ) cells when compared with their respective levels before treatment. After 15 cycles of treatment, responder patients had significant reduction in percentage of lymphocytes and ALC, percentage of activated CD4(+) T cells producing IL-2, IFN-γ, or TNF-α, and percentage of T(R) cells when compared with their perspective levels after 3 cycles of treatment. Furthermore, the numbers of activated CD4(+) T cells producing IL-2, IFN-γ, or TNF-α, activated CD8(+) T cells producing IFN-γ, and T(R) cells normalized to the range of healthy subjects.

Conclusions: Treatment with lenalidomide resulted in the normalization of functional T-cell subsets in responders, suggesting that lenalidomide may modulate cell-mediated immunity in patients with CLL.

Figure 1

Decreases in (a) percentages and (b) numbers of lymphocytes and increases (c) in percentage and (d) number of T cells with lenalidomide are shown. Data obtained from healthy subjects (HS) are shown on the right side of each figure. Asterisks represent significant differences between healthy subjects and those of CLL patients at the designated time points during treatment. Solid line represents significant differences between pretreatment versus after 3 cycles of therapy; dashed line represents significant differences between after 3 cycles versus after 15 cycles of therapy.

Figure 2

Lenalidomide modulates the absolute numbers of TCR-activated CD4⁺ T cells that synthesized (a) IL-2, (b) IFN-γ, (c) TNF-α, and (d) IL-10. Data obtained from healthy subjects are shown on the right side of each figure. Asterisks represent significant differences between responses of healthy subjects (HS) and those of CLL patients at the designated time points during treatment. Solid line represents significant differences in activated CD4⁺ T cells synthesizing cytokines between pretreatment versus after 3 cycles of therapy; dashed line represents significant differences between after 3 cycles versus after 15 cycles of therapy.

Figure 3

Lenalidomide modulates the absolute number of TCR-activated CD8⁺ T cells that synthesized (a) IL-2, (b) IFN-γ, (c) TNF-α, and (d) IL-10. Data obtained from healthy subjects are shown on the right side of each figure. Asterisks represent significant differences between responses of healthy subjects (HS) and those of CLL patients at the designated time points during treatment. Solid line represents significant differences between pretreatment versus after 3 cycles of therapy; dashed line represents significant differences between after 3 cycles versus after 15 cycles of therapy.

Figure 4

(a) Percentage and (b) number of regulatory T cells (T_R) of pretreatment CLL patients are shown after 3 cycles and after 15 cycles of lenalidomide therapy. Data obtained from healthy subjects (HS) are shown on the right side of each figure. Asterisks represent significant differences in T_R cells between healthy subjects and CLL patients at the designated time points during treatment. Solid line represents significant differences in T_R cells between pretreatment versus after 3 cycles of therapy; dashed line represents significant differences in T_R cells after 3 cycles versus after 15 cycles of therapy.