Abstract : PURPOSE Although alkylators are known to be effective against some myeloid leukemias resistance is
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Abstract : PURPOSE Although alkylators are known to be effective against some myeloid leukemias resistance is often mediated via O6-alkylguanine-DNA alkyltransferase (AGT). Temozolomides inhibition of AGT may sensitize leukemia cells to the novel alkylator laromustine. We conducted a phase I translational study to evaluate the toxicities and estimate the maximum tolerated dose (MTD) of laromustine when administered with temozolomide (TMZ) in patients with hematologic malignancies.|PATIENTS AND METHODS TMZ was delivered twice daily for 5 doses followed by a single infusion of laromustine. The target TMZ dose was the dose that would reliably result in gt 90 AGT depletion. Once the target TMZ dose was identified the laromustine dose was escalated. A total of 35 patients with relapsed/refractory leukemia were treated.|RESULTS Treatment with TMZ 300 mg for 5 doses resulted in gt 90 depletion of AGT levels in 5 of 6 patients. The MTD of the combination was established at TMZ 1500 mg and laromustine 300 mg/m2. Three of the 7 patients assayed from cohort 1 achieved gt 90 depletion of AGT activity (range 77-100 depletion median 88). Five of 6 patients enrolled in cohort 2 achieved gt 90 depletion of AGT activity (range 92-100 depletion median 93.5). This established that the 300-mg dose of TMZ (1500 mg total) would be maintained in subsequent cohorts. The majority of adverse events were primarily hematologic with infectious and pulmonary complications also noted. Three (9) of the patients with previous refractory disease achieved a complete remission and 5 (14) of the patients achieved a morphologic leukemia-free but persistent hypocellular bone marrow status.|CONCLUSION: Laromustine in combination with TMZ is tolerable and manageable at doses that predictably suppress AGT. Reliable TMZ-induced inhibition of AGT was observed in doses that are clinically tolerable. Evidence of antitumor effect was observed with this combination, suggesting that further efficacy studies should be performed.|
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