O6-Methylguanine-DNA Methytransferase (MGMT) Immunohistochemistry as a Predictor of Resistance to Temozolomide in Primary CNS Lymphoma.
Xiaoyin Jiang, David A Reardon, Annick Desjardins, James J Vredenburgh, Jennifer A Quinn, Alan D Austin, James E Herndon, Roger E McLendon, Henry S Friedman. Duke University Medical Center, Durham, NC; University of North Carolina at Chapel Hill
Background: Primary central nervous system lymphoma (PCNSL) is an uncommon form of non-Hodgkin's lymphoma localized to the central nervous system(CNS). Therapy with methotrexate chemotherapy with or without radiation has a survival benefit for PCNSL patients, but these regimens carry a risk of significant toxicity, particularly for elderly patients or those with comorbidities. New therapies are needed for these patients and for recurrent disease after standard treatment. Temozolomide is an alkylating agent that exhibits good CNS penetration and is well-tolerated, with potential activity against PCNSL. Studies indicate that a major mechanism of resistance to alkylating chemotherapies such as temozolomide is the activity of O6-methylguanine-DNA methytransferase (MGMT), an enzyme that repairs the DNA changes caused by these agents. Studies have demonstrated that increased levels of MGMT activity are associated with decreased responses to temozolomide in malignant glioma.
Design: A retrospective study of PCNSL patients seen at our center from 1990-2008 was conducted to assess the effect of treatment with temozolomide on immunocompetent patients with PCNSL. We studied the predictive value of MGMT analysis for treatment response to temozolomide.
Results: We identified 20 patients with PCNSL who were treated with temozolomide as a single agent. 6/20 patients demonstrated a response. MGMT expression levels were available for the five patients with complete response (CR), with a level of 20% for three of these patients, 25% for one patient, and 70% for the remaining patient. Two patients with CR were alive and had not experienced progressive disease at last contact, 6.7 and 8.5 years out from initiation of therapy. All non-responders for whom MGMT expression levels were available had an expression level of at least 30%, with 6/9 having MGMT expression levels of greater than 60%.
Conclusions: Our results indicate that temozolomide may be an effective therapy for PCNSL not amenable to standard therapies, and that high MGMT expression by immunohistochemistry can predict resistance to temozolomide. These data may guide future studies in therapy for this disease.
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 214, Monday Morning