Denileukin diftitox

Compound Name:Denileukin diftitoxMolecular Target:IL-2 ReceptorMolecular Structure:recombinant fusion protein expressing amino acid residues of diphtheria toxin fragment A & B, followed by the sequence for IL-2Licensed Indication:recurrent CD25 positive, cutaneous T-cell lymphomaManufacturer and/or Distributor:EisaiInitial FDA Approval1999SummaryDenileukin diftitox (Ontak) is a recombinant DNA-derived cytotoxic protein composed of the active domains of diphtheria toxin (fragments A and B) fused to human interleukin-2. After binding to the IL-2 receptor on the cell surface, denileukin diftitox is internalized by receptor-mediated endocytosis. The fusion protein is subsequently cleaved, which releases the diphtheria toxin enzymatic and translocation domains from the IL-2 fragment. The toxin then inhibits protein synthesis and causes cell death. Deniluekin difitox is administered intravenously in 5 day cycles every 3 weeks.

 In 1999, the FDA approved the use of this drug for treatment of persistent or recurrent cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the IL-2 receptor.

 The most common adverse reactions (≥20%) are pyrexia, nausea, fatigue, rigors, vomiting, diarrhea, headache, peripheral edema, cough, dyspnea and pruritus. Three serious potential adverse reactions are of particular concern: 1) infusion reactions during the 24 hours after infusion; 2) capillary leak syndrome, which was defined as the occurrence of at least 2 of 3 key symptoms (hypotension, edema, serum albumin <3.0 g/dL) at any time during Ontak therapy; 3) loss of visual acuity, usually with loss of color vision, with or without retinal pigment mottling.References

Package Insert:

1.  Prince HM, Duvic M, Martin A, Sterry W, Assaf C, Sun Y, et al. Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2010 Apr 10;28(11):1870-1877.

2.  Park M, Liu GT, Piltz-Seymour J, Wisda CL, Rook AH, Junkins-Hopkins JM, et al. Vision loss following denileukin diftitox treatment: a case report of possible posterior ischemic optic neuropathy. Leuk Lymphoma. 2007 Apr;48(4):808-811.

3.  Manoukian G, Hagemeister F. Denileukin diftitox: a novel immunotoxin. Expert Opin Biol Ther. 2009 Nov;9(11):1445-1451.

4.  Turturro F. Denileukin diftitox: a biotherapeutic paradigm shift in the treatment of lymphoid-derived disorders. Expert Rev Anticancer Ther. 2007 Jan;7(1):11-17.

5.  Olsen E, Duvic M, Frankel A, Kim Y, Martin A, Vonderheid E, et al. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol. 2001 Jan 15;19(2):376-388.

6.  Foss FM, Zinzani PL, Vose JM, Gascoyne RD, Rosen ST, Tobinai K. Peripheral T-cell lymphoma. Blood. 2011 Jun 23;117(25):6756-6767.

7. Coiffier B, Federico M, Caballero D, Dearden C, Morschhauser F et al. Therapeutic options in relapsed or refractory peripheral T-cell lymphoma. Cancer Treat Rev. 2014 Oct;40(9):1080-8.

8. Gooptu M, Rhoades R, Pro B. Current management of peripheral T-cell lymphomas. Cancer Treat Res. 2015;165:289-303.