A phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma.
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.
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GENE-Y GENE-N GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-N CHEMICAL GENE-N GENE-Y GENE-Y GENE-N CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-N GENE-Y GENE-Y
IL-2 IL-2 receptor IL-2R p55 CD25 p75 CD122 p64 CD132 retinoid X receptor bexarotene RXR p55 p75 IL-2R bexarotene bexarotene bexarotene bexarotene bexarotene IL-2R CD25 interleukin-2