Leucovorin Versus Levoleucovorin Rescue After High-dose Methotrexate in Central Nervous System Lymphoma

Leucovorin is the standard folinic acid rescue agent after high-dose methotrexate, whereas levoleucovorin is the pharmacologically active L-isomer of leucovorin. During a leucovorin supply interruption in Japan, levoleucovorin was used as an alternative; however, comparative data in patients with primary or secondary central nervous system lymphoma (PCNSL/SCNSL) are limited.

We retrospectively studied adult patients with PCNSL or SCNSL who received high-dose methotrexate with or without rituximab between April 2019 and March 2026 at a single center. Patients were categorized into the leucovorin and levoleucovorin groups according to the rescue agent used. The analysis between the two groups was based on the first high-dose methotrexate course. Outcomes included delayed methotrexate elimination, hematologic and nonhematologic adverse events, rescue utilization, and direct rescue drug cost.

Fifty-three patients were included (leucovorin, n=33; levoleucovorin, n=20). No significant differences between groups were observed in delayed methotrexate elimination, nonhematologic adverse events, or hematologic adverse events other than grade ≥3 thrombocytopenia, which was less frequent in the levoleucovorin group than in the leucovorin group (0.0% vs. 24.2%, p=0.019). However, total rescue vial/ampule use per course was lower in the levoleucovorin group (14 vs. 75, p<0.001), as was direct rescue drug cost per course (5,516 vs. 19,200 JPY, p<0.001).

In this study of patients with PCNSL or SCNSL receiving high-dose methotrexate, the use of levoleucovorin in place of leucovorin during a supply interruption was not associated with worse short-term safety outcomes and was associated with lower rescue utilization and direct rescue drug cost in our setting.