Efficacy of Denileukin Diftitox Retreatment In Patients with Cutaneous T-Cell Lymphoma Who Relapsed After Initial Response

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin's lymphomas typically characterized by skin patches, plaques, and tumors. Although CTCL primarily develops in the skin, it may progress to involve lymph nodes, blood, and visceral organs. Denileukin diftitox (DD) is a recombinant fusion protein that targets the interleukin-2 receptor found on malignant T lymphocytes. In a Phase III trial in DD-naïve patients with CD25 assay-positive CTCL (the approved indication for DD), patients treated with DD 9 and 18 μg/kg/day had overall response rates (ORR) of 37% and 46%, respectively, compared with 15% in the placebo arm. Here we analyze results from a multicenter, international, open-label phase 3 study that included a cohort of patients previously treated with DD to determine the benefit of DD retreatment following disease progression.

Study L4389-14 was designed to ascertain the efficacy and safety of DD in patients with stage IA-III CTCL, receipt of ≤3 previous therapies, and life expectancy ≥12 months. The current analysis focuses on the subgroup of CD25-positive patients who experienced response to DD 9 or 18 μg/kg/day in previous clinical trials but who then relapsed. Retreatment consisted of DD 18 μg/kg/day intravenously on Days 1–5 of a 21-day cycle for up to 8 courses. Response assessment was based on the percentage change in tumor burden at each study visit based on a global, weighted score of skin, lymph node, and blood involvement, and responses were confirmed in 3 consecutive DD courses. The primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS), time to treatment failure (TTF), and safety.

Twenty patients with CD25-positive CTCL received DD retreatment (4 had complete response to the prior DD treatment, 13 had partial response to prior treatment, 1 had stable disease as prior response, and 2 had unrecorded prior response). At baseline, these patients had a median age of 59.5 years, 70% were male, 80% were white, and 80% had early-stage disease (stage ≤IIA). The 20 patients received a median of 8 courses of DD retreatment. Overall, 40% (8/20) of patients had a secondary response, the majority of which were partial responses (30%; 6/20). Secondary response rates for patients with baseline CTCL stages ≤IIA and ≥IIB were 38% (6/16) and 50% (2/4), respectively. Kaplan-Meier estimated median time to response for the intent-to-treat population was 102 days, and the median duration of response was 274 days. Progression events were observed for 9 patients, all of whom had stage ≤IIA disease at baseline. Kaplan-Meier estimated median PFS for the intent-to-treat population was 205 days (95% CI: 170–429 days), and the median TTF was 189 days (95% CI: 72–429 days). In total, 85% of patients had a treatment-related adverse event (AE), 55% had a treatment-related grade 3/4 AE, and 5% had a treatment-related serious AE. The most common treatment-related AEs were nausea (35%), fatigue (25%), headache (15%), rigors (20%), and pyrexia (10%). The 1 treatment-related serious AE involved pleural effusion.

Patients with CD25-positive CTCL who had been treated previously with DD and subsequently relapsed were able to show durable responses upon retreatment. The observed ORR of 40% was similar to that seen with primary treatment with an estimated median duration of response of 9.8 months.

Duvic:Eisai: Consultancy, Research Funding, Speakers Bureau. Olsen:Eisai: Research Funding; Merck: Consultancy, Research Funding; Gloucester: Consultancy; Yaupon: Research Funding; Biocryst: Research Funding; Johnson & Johnson : Consultancy, Research Funding. Fivenson:Amgen: Honoraria, Research Funding, Speakers Bureau; Dermik: Research Funding; Centrocor: Honoraria, Research Funding; Abbott: Honoraria, Research Funding, Speakers Bureau; Warner Chilcott: Honoraria, Speakers Bureau; Allergan: Research Funding; Ferndale: Research Funding; Graceway: Research Funding; Biolife: Consultancy, Research Funding; Merck: Honoraria, Research Funding; Pfizer: Research Funding; Galderma: Honoraria, Research Funding; Aspreva: Research Funding; Astellas: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Perrigo: Research Funding; Organogenesis: Research Funding; Ligand: Research Funding; Connetics: Research Funding; Stiefel/GSK: Honoraria; Clay-Park Labs: Research Funding; Jacobus: Research Funding; Smith and Nephew: Research Funding; Dow Pharma: Research Funding; Therakos: Research Funding; Seragen: Research Funding; Convatec: Research Funding. Prince:Eisai: Consultancy, Honoraria.