A prospective study of a simple algorithm to individually dose high-dose methotrexate for children with leukemia at risk for methotrexate toxicities.

Abstract

PURPOSE:

High-dose methotrexate (HDMTX) is critical to the successful treatment of pediatric acute lymphoblastic leukemia (ALL) but can cause significant toxicities. This study prospectively evaluated the effectiveness of a fixed algorithm which requires no real-time pharmacokinetic modeling and no previous patient exposure to HDMTX, to individualize HDMTX dosing for at-risk patients with the aim of avoiding methotrexate-related toxicities.

METHODS:

We developed a simple algorithm to individualize HDMTX infusions with 0-2 rate adjustments based on methotrexate levels during the infusion. This was a prospective, open-label, study; eligible patients were identified and referred by their oncologist.

RESULTS:

Fifty-four evaluable cycles of HDMTX (5 g/m2 over 24 h) were administered to 22 patients. Blood samples were obtained in 21 patients to examine single nucleotide polymorphisms (SNPs) related to methotrexate disposition. Twelve (54.5%) subjects had a history of previous HDMTX toxicities including seven (31.8%) who previously required glucarpidase rescue and seven (31.8%) with an entry glomerular filtration rate < 80 ml/min/1.73 m2. 107/110 (97.2%) of methotrexate levels were drawn properly and 100% of algorithm dosing instructions were performed correctly at the bedside. Thirty-five (64.8%) of all cycles and 24 of 33 (72.7%) cycles that required a dose-adjustment had an end 24-h methotrexate level (Cpss) within our goal range of 65 ± 15 µM with only 3 (5.6%) resulting in Cpss higher than goal. Grade 3/4 toxicities were rare; no patients developed > Grade 1 acute kidney injury.

CONCLUSION:

This algorithm is a simple, safe and effective method for individualizing HDMTX in pediatric patients with ALL. CLINICALTRIALS.

GOV REGISTRY:

NCT02076997.

• Authors: Jennifer H Foster, Patrick A Thompson, M Brooke Bernhardt, Judith F Margolin, Susan G Hilsenbeck, Eunji Jo, Deborah A Marquez-Do, Michael E Scheurer, Eric S Schafer
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 83 Issue 2 Pg. 349-360 (02 2019) ISSN: 1432-0843 [Electronic] Germany
• PMID: 30488179 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Methotrexate

Topics

• Adolescent
• Adult
• Algorithms
• Antimetabolites, Antineoplastic (administration & dosage, pharmacokinetics)
• Child
• Child, Preschool
• Dose-Response Relationship, Drug
• Drug-Related Side Effects and Adverse Reactions (prevention & control)
• Female
• Follow-Up Studies
• Humans
• Infant
• Male
• Methotrexate (administration & dosage, pharmacokinetics)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, pathology)
• Prognosis
• Prospective Studies
• Risk Factors
• Tissue Distribution
• Young Adult