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Blood, 15 July 2005, Vol. 106, No. 2, pp. 454-457. Prepublished online as a Blood First Edition Paper on April 5, 2005; DOI 10.1182/blood-2004-11-4570.
Submitted December 1, 2004
Hematology/Oncology Department, Tufts New England Medical Center, Boston, MA, USA * Corresponding author; email: ffoss{at}tufts-nemc.org.
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
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| Copyright © 2005 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
/p55/CD25, 
/p75/CD122, and 
/p64/CD132 chains. In vitro studies demonstrated that the RXR retinoid, bexarotene, at biologically relevant concentrations of 10-6 to 10-8M, upregulated both the p55 and p75 subunits of the IL-2R and enhanced
5-10 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 (75-300 mg/day) and denileukin diftitox (18 mcg/kg/day x 3 days every 21 days) in a Phase I 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 two 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.
