Denileukin diftitox (ONTAK, Ligand Pharmaceuticals) is a genetically engineered fusion protein comprising the enzymatically active domain of diphtheria toxin and the full length sequence of interleukin-2 (IL-2) that targets malignancies expressing the IL-2 receptor. The drug has established efficacy in cutaneous T-cell lymphoma and we have previously reported its clinical activity in patients with recurrent B-cell Non-Hodgkin’s Lymphomas (B-NHL) (

Dang et al.
J Clin Oncol
). Given the significant activity of rituximab and the non-cross-resistant mechanism of action, we initiated a phase II study at MD Anderson Cancer Center to evaluate the efficacy of the combination of denileukin diftitox and rituximab in relapsed/refractory B-NHL. Patients were required to have prior exposure to rituximab, absolute neutrophil count ≥ 1000/uL, platelets ≥ 40,000/uL, serum creatinine ≤ 1.5 mg/dL, serum albumin ≥ 3.0 g/dL. Rituximab was given as an IV infusion at a dose of 375 mg/m2 on day one of each cycle. Denileukin diftitox was given at a dose schedule of 18 mcg/kg/day by IV infusion once daily for 5 days on days 2–6 of each cycle. Cycles were repeated every 3 weeks. Restaging evaluation of response was performed after every 2 cycles. Patients with stable disease or objective response were allowed to continue until a maximum of 8 cycles. Premedications (corticosteroids, antihistamines and fluids) were given prior to each drug infusion to decrease the risk and severity of acute hypersensitivity reactions. Thirty-three patients have been entered to date, with 30 being evaluable for toxicity and 28 for response. Median age was 67 (range 47–82), and median number of previous treatment was 4 (range 1–9). Among patients evaluable for response, there were 10 cases of diffuse large cell lymphoma (DLCL), 9 cases of follicular lymphoma (FL), 3 cases of transformed lymphoma from FL (T-FL), 3 cases of mantle cell lymphoma (MCL), 2 cases of small lymphocytic lymphoma (SLL), and 1 case of marginal zone lymphoma (MZL). Twenty patients (71%) were refractory to prior treatment with rituximab. The overall response rate was 32% with 3 CR (11%, 2 FL, 1 T-FL) and 6 PR (21%, 3 FL, 1 T-FL, 1 MCL, 1 SLL). Eight patients (29%) had stable disease. All responders but one had disease refractory to previous rituximab treatment and one CR occurred in a patient who had failed 4 prior treatments that included autologous transplantation. Five of the 9 responders had CD25 + histologies. Median time to progression for responders was 6 months, with the 3 CRs still ongoing at 14+, 10+ and 8+ months. Grade 3–4 toxicities were uncommon and included fatigue 9%, fever 6% and infection 6%. Two patients experienced visual changes; one patient had transient changes and has fully recovered, and the other has residual effects. The patient left with residual effects completed 8 cycles and obtained a CR The etiology of these visual changes is unknown. We conclude that the novel combination of denileukin diftitox and rituximab has significant clinical activity in this heavily pretreated population, with toxicities that can be managed with premedications and close monitoring. Accrual is ongoing.

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