Adverse Effects of Denileukin Diftitox and Their Management in Patients With Cutaneous T-Cell Lymphoma

Abstract

Cutaneous T-cell lymphoma (CTCL) is a rare non-Hodgkin lymphoma with predominant skin manifestations and a relatively indolent course at early stages, but it can be fatal in advanced settings. In the absence of cure, the goal of therapy for CTCL is to induce long-term remissions without further compromising a patient's immune system or quality of life. Denileukin diftitox (DD) is a fusion protein chemotherapeutic agent used for the treatment of persistent or recurrent CTCL. It binds selectively to the high- and intermediate-affinity interleukin-2 receptor (CD25+) on lymphocytes and is internalized by these cells. Inside the cells, the diphtheria toxin portion of fusion protein is cleaved by proteolytic enzymes, causing cell death. DD produces durable responses and may forestall disease progression. This article reviews DD phase III clinical trial data and summarizes one institution's clinical experience in the management of the most frequent and clinically significant adverse effects of DD (e.g., acute infusion reactions, capillary leak syndrome, hypoalbuminemia, visual changes, constitutional symptoms, rash, hepatobiliary disorders). Many DD-associated adverse effects can be managed effectively without dose reduction or interruption of treatment with prudent use of supportive care measures.

Advances in Anticancer Immunotoxin Therapy

“…Side effects include flu-like symptoms (e.g., fever, fatigue, rigors, diarrhea, and nausea), infusion-related events, disruption of color vision, VLS with hypotension, and frequent grade 3-4 hypoalbuminemia. Supportive measures that can be used to ameliorate side effects have been described previously [38].…”

Monoclonal Antibodies

“…46,47 The data indicate that DD showed a significant overall RR, progressionfree survival (PFS), and failure of progression of disease when compared with placebo. The significant toxicity observed in clinical trials can be reduced using a premedication regimen 40 and resolved to placebo levels after the second or third course of treatment. Recently, as a part of a postmarketing commitment, the pharmaceutical company Eisai has conducted a clinical trial to assess the efficacy and safety of E7777 (improved purity DD) in patients with persistent and recurrent CTCL: the results of this clinical trial are pending.…”

“…Premedication with dexamethasone, diphenhydramine, and acetaminophen is recommended, and adequate saline hydration should continue because this has also shown to diminish the incidence of vascular leak syndrome. 40 Since FDA approval, there have been case reports of other AEs, including thyrotoxicosis, retinopathy, and vision loss. [41][42][43] To improve DD efficacy, combination therapies were investigated in small clinical trials, including with HDAC inhibitors, bexarotene (Targretin), and systemic steroids.…”

Managing adverse effects of cutaneous T-cell lymphoma treatment with supportive care measures

“…Capillary leak syndrome is defined as having at least two of the following: edema, hypotension or serum albumin <3.0 g/dl at any time during treatment [11]. The exact etiology is not clear but may be associated with an increase in capillary permeability, dehydration and/or hypoalbuminemia.…”

“…Hypotension should be treated with slow hydration, while patients with systemic or pulmonary edema need diuretic therapy [11]. Brentuximab vedotin, a chimeric monoclonal antibody to CD30 conjugated to monomethyl auristatin E, a synthetic cytotoxic anti-tubulin agent, is in clinical trial for use in CTCL.…”