Pilot Study of Glucarpidase in Combination with Rituximab and Methotrexate (MTX) in CNS Lymphoma (CNSL)
Lauren Schaff1, Ugur Sener1, Igor Gavrilovic1, Alexandra Miller1, Jacqueline Stone1, Anna Skakodub1, Juli Madzsar1, Alyssa Schumpp1, Edward Acosta3, Mina Lobbous5, Kevin Ryan4, Dean Carlow2, Burt Nabors5, Christian Grommes1
1Neurology, 2Pathology, Memorial Sloan Kettering Cancer Center, 3Pharmacology and Toxicology, University of Alabama at Birmingham, 4University of Alabama at Birmingham, 5Neurology, University of Alabama Medical Center
Objective:
To explore the empiric use of glucarpidase administered with repeated doses of MTX and rituximab in patients with CNSL
Background:

MTX-based regimens are standard treatment for CNSL. Administration requires aggressive hydration and inpatient monitoring to prevent toxicity. Glucarpidase results in rapid and sustained reduction of serum MTX levels without crossing the blood brain barrier. Efficacy of repeated doses is unknown as development of anti-glucarpidase antibodies is described. Empiric use in the treatment of CNSL has not been adequately studied.

Design/Methods:

Eligible adult patients had isolated CNSL and KPS ≥ 50. Rituximab with MTX 3 g/m2 or 6 g/m2 was administered for eight cycles. Glucarpidase was given 24 hours following start of each MTX infusion. MTX concentrations were monitored in serum and CSF.

Results:
Five of six patients have enrolled to date, with 24 doses of MTX administered (3 g/m2 (20) or 6 g/m2 (4)), each followed by glucarpidase. Treatment is complete in 2 patients. Glucarpidase resulted in at least a 95% reduction in serum MTX levels within 15 minutes in 23/24 doses (96%). A 93% decrease was seen with the remaining dose. A transient increase in MTX levels above 100 nmol/L followed 8 of 24 doses (33%) (median 290 nmol/L; range 119-516 nmol/L). CSF MTX concentrations following glucarpidase remained cytotoxic in the 2 patients analyzed to date. Radiographic response: complete (1), partial (2), stable (1), not yet evaluable (1). Three grade 3 adverse events (AEs) unrelated to glucarpidase occurred: lung infection (pneumocystis pneumonia), central line infection, and decreased lymphocyte count. There were no grade 4/5 AEs. Anti-glucarpidase antibody data is pending.
Conclusions:
Administration of glucarpidase 24 hours after MTX results in repeated and consistent rapid reduction of serum MTX levels. In patients analyzed to date, CSF MTX levels remain therapeutic and clinical response is seen. Enrollment is ongoing.