Denileukin diftitox (ONTAK)

A recombinant DNA-derived cytotoxic fusion protein that targets cells with high affinity interleukin-2 receptors such as T-cell, B-cells and macrophages.

Contains IL-2 fused to fragments of diphtheria toxin and the IL-2 portion binds to IL-2 receptors on malignant cells allowing fragment of diphtheria toxin to enter the cell by endocytosis inhibiting protein synthesis and cause cell death.

Genetically designed DNA fusion protein combining A and B fragments of diptheria toxin with IL-2 sequence designed to target IL-2 receptors on malignant cell surfaces and some normal lymphocytes, leading to apoptosis within hours.

Diptheria toxin mediates inhibition of protein synthesis by adenosine diphosphate ribosylation of elongation factor-2 leading to apoptosis.

Indicated for cutaneous T-cell lymphoma expressing CD25 component of the interleukin-2 receptor, but the drug has activity when CD 25 expression is low or nondetectable.

More than twice as effective associated placebo in achieving a clinical response in patients with CD25+ CTCL.

A phase III study of 144 patients with CTCL treated with low dose (9 mcg/kg/day x 5 days q 3 weeks) or high dose (18 mcg/kg/day 5 days q 3 weeks) Denileukin or placebo: overall response rate 37.8% low dose, 49.1% in high dose and 15.9% in placebos groups, median progression free survival of 794, greater than 971 and 124 days, respectively (Negro-Vilar).

Adverse reactions include nausea, fever, fatigue, chills, headache, emesis, edema, rash, diarrhea, myalgia, weakness, asthenia, pruritus, back pain, arthralgias.

!0% of patients have capillary leak/vascular leak syndrome.

Serious adverse reactions occur in less than 4% of cases and include capillary leak syndrome, dehydration, hypotension fever, rash, chest pain fatigue, and hypersensitivity reactions.

May be associated with loss of visual acuity, color visual impairment, and possible retinal pigment mottling, which may be persistent.

Vascular leak manifested by hypotension, hypoalbuminemia and edema which may be seen within 2 weeks of treatment and may require hospitalization in up to 6% of patients.

Use in patients with cardiovascular disease require special precautions.

Response rate of 25% with relapsed/refractory B cell NHL.

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