Pharmacologic-guided trial of sequential methotrexate and thioguanine in children with advanced malignancies

Purpose: Based on in vitro studies that have shown synergistic effects of sequential administration of methotrexate (MTX) and thioguanine (6-TG), we conducted a pharmacologically guided trial of sequential MTX and 6-TG to determine the following: (1) the maximum-tolerated dose (MTD) of 6-TG; (2) the nature of the dose-limiting toxicity; and (3) the modulation effect of MTX on 6-TG given by this sequence and schedule. Patients and Methods: Thirty-one children with advanced malignancies (acute leukemia, n = 10; lymphoma n = 10; and solid tumors, n = 11) were treated weekly for 3 weeks with a 2-week rest; treatment consisted of a fixed dose of MTX (30 mg/m² over 24 hours) followed by a 2-hour infusion of 6-TG in escalating doses. Results: Measurement of plasma MTX, 6-TG, and mononuclear 5-phosphoribosyl- 1-pyrophosphate (PRPP) levels indicates that the desired biochemical modulation and serum levels were achieved. Nonhematologic toxicities were mild and the dose-limiting toxicity was bone marrow depression. A 300-mg/m² dose of 6-TG with MTX is considered the MTD. Responses were noted in patients with lymphoma. Conclusion: Encouraging antitumor effects were produced with this regimen in heavily pretreated patients with lymphoma, particularly Hodgkin's disease (HD). The durations of responses were 17, 13+, 12, 9, and 7+ months. A phase II trial of the MTX/6-TG combination is warranted for the treatment of relapsed lymphoma.