Phase II Clinical Trial of Denileukin Diftitox In Combination with Rituximab In Previously Untreated Follicular B-Cell Non-Hodgkin's Lymphoma

Abstract 2862

Follicular lymphoma (FL) is a B-cell malignancy that exhibits significant intratumoral infiltration by non-malignant T lymphocytes. The pathophysiological significance of infiltrating T cells is poorly understood but recent studies have suggested that CD4+CD25+ regulatory T (T_reg) cells are highly represented in lymph nodes involved by FL. These T_reg cells display the ability to suppress the proliferation and cytokine production of other tumor-infiltrating T cells and migrate to areas of B-cell lymphoma in response to chemotactic signals provided by the malignant B-cells. Denileukin diftitox, a chimeric immunotoxin composed of the modified cytotoxic domain of diphtheria toxin and human interleukin-2 (IL-2) protein, targets cells expressing CD25 and has proven efficacy in patients with relapsed B-cell lymphoma. In this study, we combined denileukin diftitox with rituximab in a cohort of previously untreated, advanced-stage follicular lymphoma patients. Our hypothesis was that denileukin diftitox would deplete the T_reg cells, thereby removing the inhibition of the immune response, and rituximab would deplete the B-cells thereby preventing further recruitment of T_reg cells to the areas of lymphoma.

Between August 2008 and March 2010, twenty-four patients with stage III and IV follicular grade 1 or 2 non-Hodgkin lymphoma were accrued to the study. One patient died before treatment was given and is not included in the analysis. The median age was 60 years (range: 27 – 79), 12 (52%) of the patients were male, 19 (83%) had a PS of 0 and 4 (17%) had a PS of 1. Based on the Follicular Lymphoma International Prognostic Index (FLIPI), 3 (13%) were low risk, 14 (61%) were intermediate risk and 6 (26%) were high risk. Patients received rituximab 375 mg/m2 on days 1, 8, 15 and 22 and denileukin diftitox 18 mcg/kg/day on days 1–5 every 3 weeks for 4 cycles. A median of 4 cycles of therapy was given (range: 1 – 4). Thirteen patients completed treatment per protocol (57%), however 5 patients discontinued treatment due to adverse events (22%), 2 refused further treatment (9%) and 1 discontinued due to disease progression (4%). Nine of the 23 patients (39%; 95% CI: 21–61%) responded to treatment, 3 (13%) had a complete response and 6 (26%) had a partial response. Twenty-one patients (91%) are alive with a median follow-up of 8.7 months (range: 3.4–19.5). Seven (30%) patients have progressed and two (8.7%) has died. The median time to progression is 13.4 months (95% CI: 10.4 – NA). The combination, however, was associated with significant toxicity. Thirteen patients (57%) experienced grade 3 or greater adverse events. Six patients (26%) had symptoms of capillary leak syndrome, 1 of whom died. In correlative studies performed on the peripheral blood, the number of CD25+ T-cells decreased after treatment when compared to pretreatment numbers (median 24%; range: 8–44%).

We conclude that while the addition of denileukin diftitox to rituximab decreased the numbers of CD25+ T-cells, denileukin diftitox contributed significantly to the toxicity of the combination. Furthermore, the overall response rate and time to progression in this study were no better than what would be expected in follicular lymphoma patients treated with rituximab alone.