Multicenter phase II trial of temozolomide in mycosis fungoides/ sézary syndrome: Correlation with O 6-methylguanine-DNA methyltransferase and mismatch repair proteins

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)5748-5754
Number of pages7
JournalClinical Cancer Research
Volume17
Issue number17
DOIs
StatePublished - Sep 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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