Capillary leak syndrome in a patient treated with interleukin 2fusion toxin for cutaneous T-cell lymphoma

Abstract

The case report by Railan et al (J Am Acad Dermatol 2000;43:323-4 [letter]) described a classic case of vascular leak syndrome (VLS), a known side effect of administration of denileukin diftitox (Ontak). In general, manifestations of VLS become evident in the week after a course of denileukin diftitox, and in most cases VLS is self-limited. This letter is intended to comment on several topics discussed in the letter to the Editor by Railan et al. Their 80-year-old patient was assigned initially to the placebo arm of a trial designed to evaluate the efficacy of denileukin diftitox in patients with cutaneous T-cell lymphoma and was subsequently enrolled in an open-label study. Peripheral edema was noted 2 days after cessation of the initial 5-day course of denileukin diftitox, followed by more edema and other complications such as staphylococcal bacteremia not related to the denileukin diftitox therapy. Denileukin diftitox is an interleukin 2 receptor (IL-2R)-specific fusion toxin protein, which consists of the enzymatically active and membrane-translocation domains of diphtheria toxin coupled to human IL-2. The IL-2 portion replaces the diphtheria toxin receptor binding domain sequences, resulting in a molecule that is cytotoxic for cells bearing the target IL-2R. In a concentration-dependent manner, denileukin diftitox selectively binds to the high-affinity IL-2R. Once bound to the surface receptor, the molecule is internalized via receptor-mediated endocytosis in an acidified vesicle. Upon acidification, the enzymatic portion of the fusion toxin passes into the cytosol where it inhibits protein synthesis via adenosine diphosphate ribosylation of elongation factor 2, ultimately resulting in cell death. Capillary leak syndrome or VLS is a toxicity associated with clinical use of many biologic agents, including immunotoxins and IL-2. The sequence of events in VLS is largely unknown. Theories include indirect cytokine effects induced by IL-2, or more likely in the case of immunotoxins, direct damage of endothelial cells mediated by contact with toxin itself.1Baluna R Vitetta ES Vascular leak syndrome: a side effect of immunotherapy.Immunopharmacology. 1997; 37: 117-132Crossref PubMed Scopus (226) Google Scholar To date there are no clinical data supporting cytokine-induced vascular trauma for other immunotoxins such as denileukin diftitox.2Frankel AE Kreitman RJ Sausville EA Targeted toxins.Clin Cancer Res. 2000; 6: 326-334PubMed Google Scholar We are not aware of any available laboratory tests that could differentiate whether VLS may be characterized as being due to indirect cytokine-induced effects versus a direct effect of the fusion toxin. As mentioned in the letter by Railan et al, by retrospective definition VLS was reported in 27% (38/143) of patients in the clinical trials. VLS for 30 of these patients was managed on an outpatient basis. Pre-existing low serum albumin has been identified as a risk factor for the development of VLS, and the package insert recommends that administration of denileukin diftitox should be delayed until serum albumin level is 3.0 g/dL or higher. Pre-existing edema may also contribute to the development of the syndrome, and special caution should be taken in patients with known cardiovascular disease. Management of VLS includes attention to fluid balance, and the package insert also recommends careful monitoring of signs of edema, weight increase, and serum albumin levels on an outpatient basis for patients treated with denileukin diftitox. VLS is usually self-limited and any therapeutic intervention should depend on the primary clinical problem (edema or hypotension), with intravenous fluid or pressor support if required, and usually avoidance of diuretics. Finally, it should be noted that it is generally agreed that corticosteroid prophylaxis may be effective in reducing hypersensitivity reactions, but the role of corticosteroid prophylaxis for reduction of VLS is not clear. Reports in the literature have suggested either a protective3Siegall C Liggitt D Chace D Tepper M Fell H Prevention of immunotoxin-mediated vascular leak syndrome in rats with retention of antitumor activity.Proc Natl Acad Sci U S A. 1994; 91: 9514-9518Crossref PubMed Scopus (61) Google Scholar, 4Frankel AE Hall PD Kreitman RJ Steroid prophylaxis prevents systemic inflammatory response syndrome (SIRS) in AML patients treated with diphtheria fusion protein.Blood. 1999; 94: 229bGoogle Scholar, 5Foss F Bacha P Kuzel T Biological correlates of acute hypersensitivity events with DAB 389 IL-2 in NHL: decreased frequency and severity with steroid premedication.Blood. 1999; 94: 98aGoogle Scholar or an equivocal6Conry RM Kazaeli MB Saleh MN Ghetie V Vitetta ES Liu T LoBuglio AF Phase I trial of an anti-CD19 deglycosylated ricin A chain immunotoxin in non-Hodgkins lymphoma: effect of an intensive schedule of administration.J Immunother Emphasis Tumor Immunol. 1995; 18: 231-241Crossref PubMed Scopus (54) Google Scholar effect in blocking immunotoxin-mediated VLS. Ongoing studies are seeking to determine the value of corticosteroid premedication before treatment with denileukin diftitox for the prevention of VLS.