Response Rate of 16% and High Incidence of Adverse Events In Placebo-Treated Patients with CD25 Assay-Positive Cutaneous T-Cell Lymphoma (CTCL): An Analysis of Patient Characteristics and Predictors of Response
Authors: Prince Miles , Duvic Madeleine , Martin Ann , Sterry Wolfram , Assaf Chalid , Straus David 
Published: October 2019

Abstract
Abstract 4158

Background:
CTCLs are rare, extranodal non-Hodgkin's lymphomas characterized by the accumulation of malignant T lymphocytes in the skin; mycosis fungoides (MF) and Sézary syndrome (SS) are the most common variants. Their clinical course is typically chronic and progressive, despite multiple therapeutic interventions. Observational studies of patients with CTCL, although limited by rarity, are necessary to improve understanding of prognostic factors.

Aims:
The goals of this analysis were to describe the initial disease characteristics, prognostic factors, and natural history of disease observed in 44 patients with CD25-positive, recurrent/persistent CTCL included in the placebo arm of Study L4389-11. We were particularly interested to determine if there were any characteristics peculiar to the 16% of patients treated with placebo who were observed to have a response in this study.

Methods:
This multicenter, randomized, double-blind, placebo-controlled phase III trial compared 2 different doses of denileukin diftitox (9 or 18 μ g/kg/day) with placebo in 144 patients with histopathologically confirmed stage IA to III MF/SS who had received ≤3 previous therapies. Medications essential for patient welfare (cardiac medications, narcotics, anti-nausea agents, vitamins, or laxatives) and transfusions were also allowed. The primary efficacy endpoint was overall response rate (ORR); progression-free survival (PFS) was a secondary endpoint. Relationships between baseline covariates and clinical outcomes were assessed by multivariate regression analyses.

Results:
Placebo-treated patients had a median age of 59.0 years, and the majority were white (77.3%), had early-stage disease (stage <IIA; 68.2%), had a diagnosis of MF (84.1%), and had <20% circulating abnormal lymphocytes (85.4%) at baseline. The ORR was 15.9% (95% exact confidence interval [CI]: 6.6%-30.1%) for patients receiving placebo (complete response: 2.3%; partial response: 13.6%), reflecting a possible baseline rate of spontaneous disease remission expected in untreated CTCL. Of the 7 responding patients, 3 were treated during the trial with systemic anti-staphylococcal antibiotics (2 pts with IIB, 1pt with erythroderma). Of the remaining 4 pts the stages were 1A (1), IB (2), IIB (1). Median PFS according to Kaplan-Meier analysis was 124 days (4.1 months) (95% exact CI: 92–176 days (3.0-5.8 months)), and the median values for patients with stage ≤IIA disease and stage ≥IIB disease at baseline were 107 days (3.5 months) and 211 days (6.9 months), respectively. Multivariate analyses identified no significant effects of any baseline factors on either ORR or PFS, although there was a trend toward poorer PFS associated with advanced age (hazard ratio: 1.21; 95% CI: 0.97–1.52; P=.0947). These analyses were likely limited by small sample size. A total of 95.5% of patients in the placebo arm used rescue medications (skin moisturizers etc.) at least once during the treatment period. Adverse events (AEs) and treatment-related AEs occurred in 90.9% and 59.1% of placebo-treated patients, respectively. General disorders and administration site conditions were the most common types of treatment-related AEs (52.3%), which included fatigue (22.7%), rigors (15.9%), peripheral edema (15.9%), pyrexia (13.6%), and pain (2.3%). Sepsis occurred significantly more often with placebo versus active treatment (6.8% vs. 0%; P < .05). Three of the 7 (43%) responders had received systemic antibiotics and 14/37 non-responders had received systemic antibiotics (38%).

Conclusion:
The findings from this study demonstrate that responses can be observed in patients with MF/SS in the absence of anti-tumor treatment. Likely contributing factors to these ‘spontaneous responses' are the use of systemic antibiotics, aggressive ‘rescue medication' use and the waxing and waning nature of skin lesions, particularly in early-stage disease. All future studies should carefully document the use of systemic antibiotics during therapy. These results can serve as standard comparators for other active-treatment studies that lack a placebo control arm.

Disclosures:
Prince: Eisai: Consultancy, Honoraria. Duvic:Eisai: Consultancy, Research Funding, Speakers Bureau. Assaf:Eisai: Consultancy, Honoraria. Straus:Eisai: Consultancy, Honoraria.