Denileukin diftitox in combination with rituximab for previously untreated follicular B-cell non-Hodgkin's lymphoma

S M Ansell, H Tang, P J Kurtin, P A Koenig, G S Nowakowski, D A Nikcevich, G D Nelson, Z Yang, D M Grote, S C Ziesmer, P T Silberstein, C Erlichman, T E Witzig, S M Ansell, H Tang, P J Kurtin, P A Koenig, G S Nowakowski, D A Nikcevich, G D Nelson, Z Yang, D M Grote, S C Ziesmer, P T Silberstein, C Erlichman, T E Witzig

Abstract

Follicular lymphoma exhibits intratumoral infiltration by non-malignant T lymphocytes, including CD4+CD25+ regulatory T (T(reg)) cells. We combined denileukin diftitox with rituximab in previously untreated, advanced-stage follicular lymphoma patients anticipating that denileukin diftitox would deplete CD25+ T(reg) cells while rituximab would deplete malignant B cells. Patients received rituximab 375 mg/m(2) weekly for 4 weeks and denileukin diftitox 18 mcg/kg/day for 5 days every 3 weeks for 4 cycles; neither agent was given as maintenance therapy. Between August 2008 and March 2010, 24 patients were enrolled. One patient died before treatment was given and was not included in the analysis. Eleven of 23 patients (48%; 95% confidence interval (CI): 27-69%) responded; 2 (9%) had complete responses and 9 (39%) had partial responses. The progression-free rate at 2 years was 55% (95%CI: 37-82%). Thirteen patients (57%) experienced grade ≥3 adverse events and one patient (4%) died. In correlative studies, soluble CD25 and the number of CD25+ T cells decreased after treatment; however, there was a compensatory increase in IL-15 and IP-10. We conclude that although the addition of denileukin diftitox to rituximab decreased the number of CD25+ T cells, denileukin diftitox contributed to the toxicity of the combination without an improvement in response rate or time to progression.

Conflict of interest statement

Conflict of Interest Disclosures

SMA received research funding from Eisai Inc. for this study. The remaining authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Time to Progression (TTP) for patients with follicular grade 1 and 2 non-Hodgkin lymphoma treated with rituximab and denileukin diftitox
Figure 2. Percentage of CD4+CD25+ T-cells in…
Figure 2. Percentage of CD4+CD25+ T-cells in the peripheral blood after treatment with rituximab and denileukin diftitox
A) Flow cytometry on peripheral blood mononuclear cells from a representative patient showing a decrease in CD4+ T-cells expressing CD25. B) CD4+CD25+ T-cells as a percent of all CD4+ cells in the perpheral blood during treatment with rituximab and denileukin difitox (n=13).
Figure 3. Serum cytokines and soluble receptors…
Figure 3. Serum cytokines and soluble receptors after treatment with rituximab and denileukin diftitox
Serum levels of A) IL-2R (soluble CD25), B) IL-2, C) IL-15, and D) IP-10 measured by multiplex ELISA after treatment with rituximab and denileukin diftitox (n=13). While IL-2R decreased with therapy, serum levels of IL-2 remained essentially unchanged and a compensatory increase in IL-15 and IP-10 was seen.

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