Ctni-61. Pilot Study of Repeated Planned Glucarpidase Following High Dose Methotrexate (Hd-Mtx) in CNS Lymphoma (Cnsl)

Abstract

This study explores the repeated use of glucarpidase following HD-MTX in patients with CNSL. HD-MTX requires aggressive hydration and inpatient monitoring to prevent toxicity. Glucarpidase 50 units(u)/kg for delayed MTX clearance results in a reduction of systemic MTX levels without crossing the blood brain barrier. This study explores the use of 1000 or 2000 units of glucarpidase following repeated cycles of MTX 3–8 g/m2. Eligible adult patients had isolated CNSL, CrCl ≥ 60 mL/min, and KPS ≥ 50. Rituximab with MTX was administered for eight cycles. Glucarpidase was given 24 hours after each MTX infusion. MTX concentrations were monitored in serum and cerebrospinal fluid (CSF). Twelve patients enrolled to date and data are available for 50 doses of MTX (3 g/m2 (20), 6 g/m2 (21), 8 g/m2 (9)). Glucarpidase 1000u (14) or 2000u (36) resulted in at least a 95% reduction in serum MTX levels within 15 minutes following 49/50 doses. A 93% decrease was seen with the remaining dose. Glucarpidase was not detected in the CSF of 7 patients analyzed. Potentially cytotoxic MTX concentrations (10–6 M) were observed in CSF 1 hour (7/7) and 6 hours (4/7) after glucarpidase administration. Radiographic responses are evaluable in 9 patients: complete response (5), partial response (2), stable disease (1), and progressive disease (1). No grade 3 events were attributed to glucarpidase; one grade 4 event of anaphylaxis occurred. Anti-glucarpidase antibodies were detected in 2/5 patients analyzed. In summary, administration of low-dose glucarpidase 24 hours after MTX 3–8 g/m2 results in a reproducible rapid reduction in serum MTX levels in non-renally impaired patients. CSF MTX levels remain therapeutic and clinical response expected from MTX-based therapy does not appear compromised. Anti-glucarpidase antibodies may develop though significance remains unclear. Study is ongoing. Future directions will explore glucarpidase use for reduction of inpatient stay with HD-MTX.

High-dose methotrexate and rituximab induction regimen in immunocompetent patients with primary CNS lymphoma: a retrospective single-center study of survival predictors

“…Similarly, a recent cohort by Li et al has reported that a higher MTX dose (HD-MTX dose of 8 g/m2) is signi cantly associated with better clinical response rates and higher progression free survival in managing PCNSL [40]. An ongoing study using scheduled glucarpidase with HD-MTX may facilitate administering higher doses of MTX while minimizing side effects that may result from HD-MTX [41]. The increasing incidence of elderly PCNSL demands trials speci cally targeting this patient population to facilitate delivering higher therapeutic doses of methotrexate in elderly patients without compromising their renal function.…”

Central Nervous System Lymphoma

“…The role of site-specific therapy for patients with leptomeningeal or ocular involvement of primary CNS lymphoma remains controversial. High-dose IV methotrexate achieves cytotoxic concentrations in the CSF 20 and vitreous space, 21 obviating the need for direct intrathecal or intraocular administration. Increasingly, many practitioners reserve intrathecal chemotherapy for persistent or refractory leptomeningeal disease.…”

Primary Central Nervous System Lymphoma in Elderly Patients: Management and Perspectives

“…In addition, HD-MTX must be monitored with dose reduction schedules based on the urinary clearance rate before each treatment cycle [ 63 ]. As a last resort, glucarpidase (carboxypeptidase-G2) can be used to reduce very rapidly an important increase in the serum concentration of methotrexate [ 64 ].…”