TY - JOUR
T1 - Multicenter phase II trial of temozolomide in mycosis fungoides/ sézary syndrome
T2 - Correlation with O 6-methylguanine-DNA methyltransferase and mismatch repair proteins
AU - Querfeld, Christiane
AU - Rosen, Steven T.
AU - Guitart, Joan
AU - Rademaker, Alfred
AU - Pezen, David S.
AU - Eileen Dolan, M.
AU - Baron, Joseph
AU - Yarosh, Daniel B.
AU - Foss, Francine
AU - Kuzel, Timothy M.
PY - 2011/9/1
Y1 - 2011/9/1
N2 - 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/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/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.
AB - 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/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/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.
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U2 - 10.1158/1078-0432.CCR-11-0556
DO - 10.1158/1078-0432.CCR-11-0556
M3 - Article
C2 - 21747120
AN - SCOPUS:80052478641
SN - 1078-0432
VL - 17
SP - 5748
EP - 5754
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 17
ER -