A phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma

Blood. 2005 Jul 15;106(2):454-7. doi: 10.1182/blood-2004-11-4570. Epub 2005 Apr 5.

Abstract

Denileukin diftitox, a genetically engineered fusion protein combining the enzymatically active domains of diphtheria toxin and the full-length sequence for interleukin-2 (IL-2), efficiently targets lymphoma cells expressing the high-affinity IL-2 receptor (IL-2R) consisting of the alpha/p55/CD25, beta/p75/CD122, and gamma/p64/CD132 chains. In vitro studies demonstrated that the retinoid X receptor (RXR) retinoid, bexarotene, at biologically relevant concentrations of 10(-6) M to 10(-8) M, upregulated both the p55 and p75 subunits of the IL-2R and enhanced 5- to 10-fold the susceptibility of T-cell leukemia cells to denileukin diftitox. To determine whether this biomodulatory effect could be recapitulated in vivo, we treated 14 patients with relapsed or refractory cutaneous T-cell lymphoma with escalating doses of bexarotene (75 mg/day-300 mg/day) and denileukin diftitox (18 mcg/kg per day x 3 days every 21 days) in a phase 1 trial. Overall response was 67% (4 complete responses, 4 partial responses). Modulation of IL-2R expression was observed at or above a bexarotene dose of 150 mg/day. Four patients experienced grade 2 or 3 leukopenia, and 2 had grade 4 lymphopenia. Our results demonstrate that the combination of denileukin diftitox and bexarotene is well tolerated and that even low doses (150 mg/day) of bexarotene are capable of in vivo upregulation of CD25 expression on circulating leukemia cells.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Bexarotene
  • Diphtheria Toxin / administration & dosage*
  • Diphtheria Toxin / adverse effects
  • Drug Tolerance
  • Female
  • Humans
  • Interleukin-2 / administration & dosage*
  • Interleukin-2 / adverse effects
  • Lymphoma, T-Cell, Cutaneous / drug therapy*
  • Lymphoma, T-Cell, Cutaneous / immunology
  • Male
  • Middle Aged
  • Receptors, Interleukin-2 / metabolism
  • Recombinant Fusion Proteins / administration & dosage*
  • Recombinant Fusion Proteins / adverse effects
  • Recurrence
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / immunology
  • Tetrahydronaphthalenes / administration & dosage*
  • Tetrahydronaphthalenes / adverse effects
  • Up-Regulation / drug effects

Substances

  • Diphtheria Toxin
  • Interleukin-2
  • Receptors, Interleukin-2
  • Recombinant Fusion Proteins
  • Tetrahydronaphthalenes
  • denileukin diftitox
  • Bexarotene