Phase I Study of Temozolomide and Cisplatin in Patients with Acute Leukemia.

We previously demonstrated that temozolomide has significant activity in patients with acute leukemia (Seiter K, et al JCO 2002). Cisplatin can increase the activity of temozolomide through depletion of MGMT, the enzyme that rescues cells from temozolomide toxicity. We performed a phase I study of temozolomide in 17 patients with relapsed or refractory acute leukemia. Median age: 53 (range 26–73); M/F: 9/8; Dx: AML: 12, ALL: 3, biphenotypic: 2; median # of prior regimens: 2 (range 1–7); duration of 1^st remission: primary refractory: 8 patients, 1–6 months: 3 patients, 7–12 months: 4 patients, greater than 1 yr: 2 patients; cytogenetics: good: 2, intermediate: 11, poor: 4; prior AHD: 6 patients; Cisplatin (50–100 mg/m2) was given on day 1; temozolomide (200 mg/m2/d for 5–7 days) was administered daily beginning 4 hours after cisplatin. Cisplatin was administered in the inpatient setting. Twenty-one cycles were administered. To date, no dose limiting toxicity has been observed. The median number of hospital days was 10 (range 2–37). Neutropenic fever occurred in 11/21 cycles. Other grade 3 non-hematologic toxicity included orthostatic hypotension, syncope, and constipation in one patient each, and elevated bilirubin in 2 patients. Four patients had grade 2 elevations of creatinine that resolved with hydration. Other grade 1/2 non-hematologic toxicity included fatigue, nausea/vomiting, constipation, bradycardia, diarrhea, hypokalemia and hypomagnesemia. The median number of RBC transfusions was 3U (range 0–8); the median number of platelet transfusions was 3 (range 0–12). No complete remissions were seen. However significant antileukemic activity was seen: the median pretreatment WBC was 3.2 (range 0.3–78.3); the median nadir WBC was 0.4 (range 0.1–9.6). Four patients had a significant reduction in bone marrow blasts: 40 to 22%, 87 to 38%, 69 to 3%, and 87 to 5%, respectively. The three latter patients were treated at the highest dose level. Cisplatin and temozolomide was well tolerated. We are continuing to accrue patients at the highest dose level to further assess efficacy.