Multicenter Phase II Trial of Temozolomide in Mycosis Fungoides/Sezary Syndrome: Correlation with O-6-Methylguanine-DNA Methyltransferase and Mismatch Repair Proteins

作者：Querfeld Christiane; Rosen Steven T; Guitart Joan; Rademaker Alfred; Pezen David S; Dolan M Eileen; Baron Joseph; Yarosh Daniel B; Foss Francine; Kuzel Timothy M^*

来源：Clinical Cancer Research, 2011, 17(17): 5748-5754.

DOI：10.1158/1078-0432.CCR-11-0556

Purpose: Temozolomide (TMZ) is an oral derivative of dacarbazine that induces DNA damage by methylating nucleotide bases. Resistance has been associated with high levels of O-6-methylguanine-DNA methyltransferase (MGMT). Malignant CD4(+) T cells of patients with mycosis fungoides/Sezary syndrome (MF/SS) have been shown to have low levels of MGMT and may be particularly sensitive to this methylator.
Experimental Design: The efficacy of TMZ was evaluated in a multicenter phase II trial of patients with advanced stages of MF/SS. TMZ was given orally at daily doses of 200 mg/m(2) for 5 days every 28 days. MGMT and mismatch repair protein expression was assessed by quantitative immunofluorescence and immunohistochemistry in skin and blood samples.
Results: Twenty-six patients (stages IB-IVB) were evaluable for response. Patients had a median of four prior treatments. Median follow-up time was 19 months (range, 1-95). The overall response was 27% with two complete remissions (8%) and five partial remissions (19%). Median disease-free survival was 4 months. The median overall survival was 24 months. The most frequent toxicities included constitutional symptoms, gastrointestinal symptoms, and hematologic toxicities. Treatment was discontinued in three patients following grade 3 thrombocytopenia, lymphopenia, and skin reaction. The relationship between pretreatment MGMT and mutL homolog 1 (MLH1)/mutS homolog 2 (MSH2) mismatch repair protein expression levels in skin biopsies of cutaneous lesions and clinical response to TMZ were evaluated.
Conclusions: Pretreatment levels of MGMT and MLH1/MSH2 protein levels are not predictive of response to TMZ in MF/SS, suggesting that other resistance mechanisms are important. Clin Cancer Res; 17(17); 5748-54.

• 出版日期2011-9-1
• 单位西北大学