Optimizing bexarotene therapy for cutaneous T-cell lymphoma.

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Talpur R, Ward S, Apisarnthanarax N, Breuer-Mcham J, Duvic M

Optimizing bexarotene therapy for cutaneous T-cell lymphoma.

J Am Acad Dermatol. 2002 Nov;47(5):672-84.

PubMed ID

12399758 [ View in PubMed

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Abstract

BACKGROUND: Bexarotene (Targretin oral capsules), the first RXR-selective retinoid "rexinoid" approved for all stages of cutaneous T-cell lymphoma (CTCL), had a response rate (RR) of 45% at the optimal dose of 300 mg/m(2) per day in 2 multicenter trials. With hypertriglyceridemia reported at 79%, bexarotene is often administered with lipid-lowering agents (LLAs). Statins (inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase) may modulate class II major histocompatibility class expression and T-cell responses. OBJECTIVE: We attempted to optimize the clinical response to bexarotene by controlling dose-limiting hypertriglyceridemia and combining bexarotene with other active agents. METHODS: We prospectively evaluated 70 patients with CTCL at M. D. Anderson Cancer Center who were treated with oral bexarotene as monotherapy or in combination with other active agents. RESULTS: Fifty-four patients receiving bexarotene monotherapy achieved an overall RR of 48%. Thirteen had stage IA-IIA disease (RR = 53%, 1 complete response [CR]); 41 had stage IIB-IVB disease (RR = 46%, 2 CRs). Forty-two (77%) of these also required one or more LLAs: atorvastatin (n = 29, RR 43%), atorvastatin plus fenofibrate (n = 10, RR 90%), or gemfibrozil (n = 3, RR 33%). Gemfibrozil was discontinued because it increased bexarotene and triglyceride levels. Patients taking 2 LLAs had a significantly higher RR of 90% during monotherapy than those taking one or no LLAs (P <.0001). Forty of 54 patients (74%) received thyroid hormone replacement to normalize thyroxine levels. Four patients receiving monotherapy have complete CRs of >3 years' duration and received maintenance dosing. Sixteen patients with advanced disease treated with bexarotene (225-750 mg/d) in combination with other CTCL therapies achieved an overall RR of 69% (11/16) with concomitant statin therapy. Bexarotene was safely combined with psoralen ultraviolet A (PUVA) plus interferon alfa (IFN-alpha) (n = 2, RR = 50%), with extracorporeal photopheresis (ECP) (n = 8, RR = 75%, 1 CR), with ECP/IFN-alpha (n = 4, RR =50%), with ECP/IFN-alpha/PUVA (n = 1, RR = 100%), and with IFN-alpha/PUVA/topical nitrogen mustard (n = 1, RR = 100%). Two patients receiving IFN-alpha had slight leukopenia, but rhabdomyolysis associated with multiple LLAs did not occur. CONCLUSION: This single-center study supports the safety and efficacy of bexarotene as both a monotherapy and a combination therapy for CTCL. Long durable CRs may be achieved with oral monotherapy. Use of statins with bexarotene may also increase RRs by permitting higher doses to be administered without interruption, by modulating the immune response, or both. When bexarotene is combined with other active CTCL therapies, higher RRs were achieved in patients with advanced disease, without unacceptable side effects.

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Drug Interactions

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Pharmaco-metabolomics

Drug	Drug Groups	Metabolite	Change	Description
Cerivastatin	Approved Withdrawn	Triglycerides	decreased	Cerivastatin decreases the level of Triglycerides in the blood
Bexarotene	Approved Investigational	Triglycerides	increased	Bexarotene increases the level of Triglycerides in the blood
Fluvastatin	Approved	Triglycerides	decreased	Fluvastatin decreases the level of Triglycerides in the blood
Gemfibrozil	Approved	Triglycerides	decreased	Gemfibrozil decreases the level of Triglycerides in the blood
Atorvastatin	Approved	Triglycerides	decreased	Atorvastatin decreases the level of Triglycerides in the blood
Niacin	Approved Investigational Nutraceutical	Triglycerides	decreased	Niacin decreases the level of Triglycerides in the blood
Lovastatin	Approved Investigational	Triglycerides	decreased	Lovastatin decreases the level of Triglycerides in the blood
Simvastatin	Approved	Triglycerides	decreased	Simvastatin decreases the level of Triglycerides in the blood