Vascular Leak syndrome

Denileukin diftitox is a combination of the active sections of interleukin 2 and diphtheria toxin. It binds to high-affinity interleukin 2 receptors on the cancer cell (and other cells), and the toxin portion of the molecule inhibits protein synthesis to result in cell death. The pharmacokinetics of denileukin diftitox are best described by a two-compartment model, with an a half-life of 2 to 5 minutes and a terminal half-life of 70 to 80 minutes. Denileukin diftitox is used for the treatment of persistent or recurrent cutaneous T-cell lymphoma whose cells express the CD25 receptor. Side effects include vascular leak syndrome, fevers/chills, hypersensitivity reactions, hypotension, anorexia, diarrhea, and nausea and vomiting. 

H6. Hack, C. E., Ogilvie, A. C., Eisele, B., Jansen, P. M Wagstaff, J., and Thijs, L. G Initial studies on the administration of Cl-esterase inhibitor to patients with septic shock or with a vascular leak syndrome induced by interleukin-2 therapy. Prog. Clin. Biol. Res. 388, 335-357 (1994). 

The major clinical study underpinning product approval was a randomized, double blind study in which 71 CTCL patients were administered the product at one of two dosage levels (9 or 18 [tg kg 1 day ) overall, 30 per cent of patients experienced an objective tumour response. Serious side effects potentially associated with product administration include acute hypersensitivity-type reactions, vascular leak syndrome and visual impairment. Additional adverse reactions include flu-like symptoms, headache, hyper- or hypo-tension, as well as digestive upset. Ontak is manufactured by Seragen Inc. and is distributed by Ligand Pharmaceuticals. 

Limitations to IT therapy include their immunogenicity and toxicity. Dose-limiting side-effects of IT therapy include hepatotoxicity and vascular leak syndrome. 

Toxins as effector molecules have been widely studied in vitro and applied in vivo in pre-clin-ical and clinical studies. A frequent observation with immunotoxins in the clinic is the occurrence of vascular leak syndrome. This toxicity is associated with the toxin moiety of the im-munotoxin and sometimes demands cessation of therapy or administration of snb-optimal dosages [92]. Another approach with high potential is to selectively inhibit tnmonr blood flow by selectively targeting the blood coagnlation-mdndng activity of the tnmonr endothelium. 

Also when the cytokine interleukin 2 (IL-2) was used for cancer treatment, serious adverse effects were noted resulting in the so-called vascular leak syndrome (VLS) [98, 99]. VLS is a life-threatening toxicity marked by vasopermeability with hypotension induced during high dose IL-2 treatment of cancer patients [100]. VLS is caused by endothelial activation and can be induced in lungs and liver of mice by IL2 administration [99]. The mechanism of IL-2-induced VLS is still poorly understood and at present there is no specific therapy for VLS. For the investigation of these... 

Guan, H., Nagarkatti, P.S. and Nagarkatti, M. (2007) Blockade of hyaluronan inhibits lL-2-induced vascular leak syndrome and maintains effectiveness of IL-2 treatment for metastatic melanoma. Journal of Immunolq (Baltimore, MD, 1950), 179, 3715-3723. 

Vascular leak syndrome a side effect of immunotherapy. Immunopharmacology, 37, 117-132. 

Siegall CB, Liggett D. Characterization of vascular leak syndrome induced by the toxin component of pseudomonas exotoxin-based immunotoxin and its protential inhibition with nonsteroidal anti-inflammatory drugs. Clin Cancer Res 1997 3 339-45. 

Siegall CB, Liggitt D. Prevention of immunotoxin-mediated vascular leak syndrome in rats with retention of antitiumor activity. Proc Natl Acad Sci USA 1994 91 9514-18. 

Baluna, R., Rizo, J., Gordon, B.E., Ghetie, V., Vitetta, E.S. (1999). Evidence for a structural motif in toxins and inter-leukin-2 that may be responsible for binding to endothelial cells and initiating vascular leak syndrome. Proc. Natl Acad. Set USA 96 3957-62. 

About 60% had an acute hypersensitivity reaction, with dyspnea, back pain, hypotension, and chest pain or tightness within 24 hours of infusion. A vascular leak syndrome, as defined by the presence of at least two of edema, hypoalbuminemia, and hypotension, occurred in 25%. 

A dose-escalation study in 35 patients with psoriasis confirmed that constitutional symptoms in response to denileukin diftitox were dose-related and less frequent at lower doses (below 5 micrograms/kg/day) (17). There was only one case of mild vascular leak syndrome. Skin reactions compatible with delayed hypersensitivity reactions were noted in three patients, including one case of exfoliative dermatitis. 

The more severe adverse effects of denileukin diftitox consisted of acute hypersensitivity reactions during or within 24 hours of infusion in 69% of patients, and a vascular leak syndrome in 27% of patients, which was severe in 6%. In contrast to acute hypersensitivity reactions, the vascular leak sjmdrome was typically delayed and occurred within the first 2 weeks of infusion (18). Whether this was due to a direct action of denileukin diftitox or to tumor lysis syndrome is unknown. 

Aldesleukin-induced increase in lung capillary permeability or direct cardiac dysfunction is thought to be a likely mechanism of this adverse effect, and a localized vascular leak syndrome, attributed to activation of eosinophils in the lung and subsequent deposition of the eosinophil major basic protein, has also been suggested, as reported in a 49-year-old woman with breast cancer (31). 

A prerenal mechanism secondary to the vascular leak syndrome is commonly involved in the pathophysiology of acute renal insufficiency. In addition it has been suggested that a direct intrinsic intrarenal effect of aldesleukin with a higher than expected reduction in glomerular filtration rate or tubular dysfunction (85,89) is involved. Several isolated cases of acute interstitial or tubulointerstitial nephritis with predominant T lymphocjde infiltration of the kidneys (90-92) and the exacerbation of a subchnical IgA glomerulonephritis (93) suggested altered cell-mediated immunity. 

A rapidly reversible first-dose syndrome (dyspnea, hypoxia, tachycardia, and hypotension) can occur within the first hour after the first continuous infusion in 15-30% of patients (5). A dose-limiting vascular leak syndrome was consistently described in patients receiving GM-CSF 30 micrograms/kg/day or more, but lower doses were also reported to induce a clinically relevant capillary leak syndrome (SEDA-22, 408) (20,21). Continuation of GM-CSF treatment at the same dose or lower and careful management was possible in some patients. Endothelial cell damage with an increase in the transcapUlary escape rate of albumin and the possible role of IL-1 and TNE production by GM-CSF-activated monocjdes were... 

Hypotension, exacerbation or new onset of atrial fibrillation, and dyspnea were infrequently observed in clinical trials (6). Although weight gain and peripheral edema can develop, only one fatal case, compatible with a capillary vascular leak syndrome, has been reported (SEDA-20, 335). 

The vascular leak syndrome was observed at a dose of 15 micrograms/kg by bolus or continuous intravenous administration, but a moderate capillary leak syndrome was also noted at lower subcutaneous doses (4). 

Rosentein et al. [21] injected high dose IL-2 into mice followed by intravenous bovine serum albumin as a marker of capillary leak. The severity of the vascular leak syndrome was dependent upon the number of days of treatment and the dose given. Severity could be reduced by immune suppression with cyclophosphamide, corticosteriods, or whole body irradiation implying that lymphokines released by lymphocytes placed a role in the induction of the vascular leak phenomenon. 

Rafj-Janajreh AQ, Chen D, Schmits R, MakTW, Grayson RL, Sponenberg DP, Nagarkatti M, Nagarkatti PS Evidence forthe involvement ofCD44 in endothelial cell injury and induction of vascular leak syndrome by IL-2, J Immunol 1999,163 1619-1627... 

Denileukin diftitox is indicated for cutaneous T-cell lynt phoma in patients whose malignant cells express IL-2 recefs tors. " After administration, it exhibiLs two-compartnicni behavior with a distribution half-life of 2 to 5 minutes anl a terminal-phase half-life of 70 to 80 minutes. It is metaho lized by proteolytic degradation. Toxic manifestations include hypersensitivity reactions in 69% of patients, whicli result in hypotension, back pain, dyspnea, rash, chest pnia and tachycardia. Patients also experience vascular leak syndrome. (31 toxicity, and infections. 

Denileukin diftitox is a fusion protein that combines portions of the IL-2 molecule with the diphtheria toxin to destroy cells with the IL-2 receptor by inhibition of protein synthesis. It is used primarily in cutaneous T-cell lymphoma (CTCL) in patients whose disease expresses the CD 25 component of the IL-2 receptor. Its major toxicity is hypersensitivity reactions and the vascular leak syndrome. 

Vascular leak syndrome (hypotension, edema, hypoalbuminemia) anemia infection anorexia asthenia increased aminotransferase activity hypocalcemia... 

Hurwitz N, Probst A, Zufferey G> et al. Fatal vascular leak syndrome with extensive hemorrhage, peripheral neuropathy and reactive erythrophagocytosis an unusual complication of recombinant IL-3 therapy. Leuk Lymphoma 1996 20 337-40. 

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