|Bexarotene in the Treatment of Cutaneous T-Cell Lymphoma (CTCL)|
by Herschel S. Zackheim, M.D.
Bexarotene (Targretin®) (Ligand Pharmaceuticals) is a novel FDA-approved retinoid X receptor (RXR)-selective rexinoid currently in widespread use for the treatment of early and late stage CTCL. There has been considerable experience with the older retinoids etretinate and isotretinoin in the treatment of CTCL (Zackheim, HS. Dermatologic Therapy 1998;7:15-20); however, as single agents, the results were not impressive. Better responses were obtained when used in combination with other agents such as PUVA or alfa-interferon.
The first major report of the use of bexarotene for advanced stage CTCL was that of Duvic et al (J Clin Oncol 2001;19:2456-71) involving 94 patients, 43 of the patients were tumor stage, 31 erythroderm, 16 had lymph node involvement, and 10 had visceral disease. 45% of the patients receiving the optimum 300 mg/m_/d dose achieved clinical complete and partial responses. Thus, given the advanced stage of disease the response rate in this study is certainly encouraging.
The most frequent adverse events were hypertriglyceridemia, hypothroidism, and hypercholesterolemia. The greatest concern is elevation of serum triglycerides which occurred in about 25% of the patients. This can be marked (>600 mg/dL) and often occurs rapidly within the first few weeks of therapy. Values of ≥1000 mg/dL are not rare. This poses a risk of pancreatitis which may be life-threatening. Therefore blood lipids should be obtained weekly, at least during the initial phase of treatment. Patients are advised to go on a strict low-fat diet. At UCSF at the first sign of elevated triglycerides patients are put on a lipid-lowering agent such as atorvastatin (Lipitor) or fenofigrate (Tricor). Some investigators place patients on a prophylatic lipid-lowering agent prior to starting bexarotene.
The second most common side effect was hypothyroidism, occurring in about 21% of the patients. Thyroid function tests should be obtained at least monthly and the patient should be closely observed for clinical signs of hypothyroidism. Thyroid hormone should be administered as indicated. Some investigators give thyroid hormone as a prophylaxis at the start of treatment. Hypercholesterolemia occurred in about 18% and is managed by antilipid measures.
Bexarotene in gel form has recently received FDA approval for topical therapy of early stage CTCL. In a three university-based study (Breneman D, et al. Arch Dermatol 2002;138:325-32) 65 patients were treated at concentrations of 0.1% to 1.0% from 1-4 times daily. Most patients tolerated the 1% gel twice daily. An overall response rate of 63% and a clinical complete response rate of 21% was achieved. 265 of the patients experienced mild, 40% moderate, and 21% severe adverse events consisting mostly of rash, pruritus, and pain. In our limited experience at UCSF we have noted a high frequency of local irritation. In order to minimize these side effects some investigators advocate alternate applications of bexarotene and topical corticosteriods, or applying both compounds at the same time. Further experience is needed to better define the value of bexarotene gel in early CTCL.
In summary, the addition of bexarotene to our armamentarium of drugs useful in the treatment of CTCL is a most welcome development. Results of additional studies with this agent are eagerly awaited.