A66
Predicting the myelotoxicity of chemotherapy using O6-methylguanine-DNA methyltransferase
Wasir Saka1, Rachel Waters1, Ami Sabharwal1, Andrew Clamp2, Sarah Danson2, Paul Lorigan2, Nick Thatcher2, Geoff Margison3, Mark Middleton1
1University of Oxford, UK, 2Christie Hospital, Manchester, UK, 3Paterson Institute, Manchester, UK
The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is a key element of cellular resistance to cytotoxic chemotherapies that alkylate the O6 position on guanine. Inhibitors of MGMT have not improved the efficacy of O6-alkylating agents in melanoma or colorectal cancer, but have been associated with greater haematological toxicity. To assess the value of pre-treatment MGMT expression in peripheral blood mononuclear cells (PBMC) in predicting haematological toxicity with O6-alkylating agent chemotherapy, we explored this relationship retrospectively in melanoma patients.
Ninety-three patients treated with temozolomide or dacarbazine in four clinical trials were evaluated, using white cell and platelet counts during the course of chemotherapy. A model of the interaction between MGMT expression and haematological toxicity was constructed. The relationships between pre-treatment MGMT and worst grade of myelotoxicity, or between MGMT and dose intensity sustainable were also assessed.
The rate of grade 3 or 4 haematological toxicity varied, according to the regimen used, from 10% to 73%. Nadir white cell and platelet counts were related to, and hence could be predicted from, pre-treatment MGMT. Leucopaenia and thrombocytopaenia were more prevalent amongst patients with low pre-treatment MGMT, according to the highest grades of toxicity experienced and/or the dose intensity patients could sustain. Addition of interferon to chemotherapy or compression of the temozolomide schedule increased toxicity.
The model predicts significant myelotoxicity where PBMC MGMT is inactivated, consistent with the experience in the clinic with lomeguatrib and O6-benzylguanine. Determination of MGMT in PBMC can identify patients at greatest risk of toxicity or who are suitable for dose intensification.
