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Clinical Trial
. 2011 Sep 1;17(17):5748-54.
doi: 10.1158/1078-0432.CCR-11-0556. Epub 2011 Jul 11.

Multicenter phase II trial of temozolomide in mycosis fungoides/sezary syndrome: correlation with O⁶-methylguanine-DNA methyltransferase and mismatch repair proteins

Christiane Querfeld  1 , Steven T Rosen, Joan Guitart, Alfred Rademaker, David S Pezen, M Eileen Dolan, Joseph Baron, Daniel B Yarosh, Francine Foss, Timothy M Kuzel
Affiliations
Clinical Trial

Multicenter phase II trial of temozolomide in mycosis fungoides/sezary syndrome: correlation with O⁶-methylguanine-DNA methyltransferase and mismatch repair proteins

Christiane Querfeld et al. Clin Cancer Res. .

Abstract

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 O⁶-methylguanine-DNA methyltransferase (MGMT). Malignant CD4(+) T cells of patients with mycosis fungoides/Sézary 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/m² 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.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

M.E. Dolan is coinventor of O6-benzylguanine. All other authors declared no potential conflicts of interest.

Figures

Figure 1
Figure 1
Skin biopsies of 2 responding patients showed high MLH-1 and low MSH-2 expression (A and B) and low MLH-1 and high MSH-2 expression, respectively (C and D). Skin biopsy of another patient showed low expression for both MLH-1 and MSH-2 and was associated with disease progression (E and F; original magnification: ×400).
Figure 2
Figure 2
Overall survival of patients with MF/SS stratified by MGMT expression in skin. The median overall survival is 24 months.
See this image and copyright information in PMC

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