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Denileukin diftitox

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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 Approval:1999Summary:Denileukin 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

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  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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20212249
  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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17454642
  3. Manoukian G, Hagemeister F. Denileukin diftitox: a novel immunotoxin. Expert Opin Biol Ther. 2009 Nov;9(11):1445-1451. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19817678
  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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17187516
  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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11208829
  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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21493798
  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. http://www.ncbi.nlm.nih.gov/pubmed/25199959
  8. Gooptu M, Rhoades R, Pro B. Current management of peripheral T-cell lymphomas. Cancer Treat Res. 2015;165:289-303. http://www.ncbi.nlm.nih.gov/pubmed/25655615

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