Clinical Relevance of the Dose of Cytarabine in the Upfront Treatment of Primary CNS Lymphomas with Methotrexate-Cytarabine Combination

Background. The combination of high doses of methotrexate (MTX) and cytarabine (araC) is the standard chemotherapy for patients with primary CNS lymphoma (PCNSL). The addition of an alkylating agent could improve MTX-araC efficacy because it is active against quiescent G0 cells and increases antimetabolites cytotoxicity. A pilot experience with high doses of MTX, araC, and thiotepa (MAT regimen) was performed to investigate feasibility and efficacy of adding an alkylating agent. With respect to MTX-araC combination, araC dose was halved to minimize toxicity. Herein, we report tolerability, activity, and efficacy of MAT regimen and compare these results to those previously reported with MTX/ara-C combination. Methods. Twenty HIV-negative patients with PCNSL treated with MAT regimen and whole-brain irradiation and selected according to eligibility criteria of the International Extranodal Lymphoma Study Group (IELSG) #20 trial were analyzed. Results. Patient characteristics of MAT and MTX-araC series were similar. G4 hematologic toxicity was common after MAT chemotherapy, with dose reductions in 60% of patients, infections in 20%, G4 non-hematologic toxicity in 15%, and one (5%) toxic death. Response after chemotherapy was complete in four patients (clinical response rate, 20%; 95% confidence interval, 3%–37%) and partial in three (overall response rate, 35%; 95% confidence interval, 15%–55%). Fifteen patients experienced failure and 16 died (median follow-up, 26 months), with a 2-year overall survival of 24% ± 9%. Conclusions. MAT and MTX-araC combinations showed similar tolerability, whereas araC dose reduction was associated with a remarkably lower efficacy, hiding any potential benefit of thiotepa. Four doses of araC 2 g/m2 per course are recommended in patients with PCNSL.