Tailored Temozolomide Therapy for Elderly Patients with Acute Myeloid Leukemia.

Alternative treatment modalities are greatly needed for elderly patients with acute myeloid leukemia (AML). Previous preclinical data and clinical observations show that only patients lacking expression of O6-alkylguanine-DNA alkyltransferase (AGAT) in leukemic blasts are sensitive to temozolomide. Furthermore, AGAT enzymatic activity can be significantly decreased by protracted exposure to low doses of temozolomide. Based on these data, we have designed a phase II clinical trial tailoring temozolomide therapy to elderly patients with AML according to AGAT status. AGAT promoter methylation status was determined in pretreatment leukemic samples. Patients demonstrating evidence of AGAT promoter methylation were stratified to conventional doses of temozolomide at 200mg/m2 orally x 7 days. Patients demonstrating lack of AGAT promoter methylation (unmethylated) were stratified to receive protracted doses of temozolomide (100mg/m2 orally x 14 days) followed by conventional doses of temozolomide. Those patients who achieved CR were given up to 5 similar consolidation treatments. Eleven patients have been treated to date. The median age was 78 (71–83) and 6 were male. Seven patients were newly diagnosed and 6 patients had a normal karyotype. Nine patients had an unmethylated AGAT promoter in their leukemic blasts. Correlative AGAT protein expression in leukemic blasts will be presented at the meeting. All patients had an intact mismatch repair pathway. Median HCT-CI score was 1 (0–5). Four patients (4/10) achieved a complete remission after 1 cycle of therapy (1/2 for patients with methylated AGAT promoter and 3/8 for patients with unmethylated AGAT promoter). Nonhematologic toxicities attributed were minimal. Drug-related hematologic toxicities were difficult to distinguish from disease-related cytopenias. Six patients developed neutropenic fever (four patients developed neutropenic fever before the start of therapy). Three (3/10) patients remain alive with a median duration of remission of 4.5 months (4–5 months). Four patients have died from disease progression. And two patients died of neutropenic sepsis. One patient who achieved a CR, experienced prolonged marrow aplasia (47 days) following consolidation cycle #1 and withdrew from the study. The trial is ongoing with an accrual goal of 36 patients. These preliminary results suggest that temozolomide therapy may be individually tailored to elderly patients with AML according to AGAT promoter status.