Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: Clinical and pharmacologic factors affecting outcome

Brigitte C. Widemann, Frank M. Balis, AeRang Kim, Matthew Boron, Nalini Jayaprakash, Aiman Shalabi, Michelle O'Brien, Michelle Eby, Diane E. Cole, Robert F. Murphy, Elizabeth Fox, Percy Ivy, Peter C. Adamson

Research output: Contribution to journalArticle

Abstract

Purpose: To assess the role of the recombinant bacterial enzyme, glucarpidase (carboxypeptidase-G2), leucovorin, and thymidine in the management and outcome of patients with high-dose methotrexate (HDMTX) -induced nephrotoxicity. Methods: Patients with HDMTX-induced nephrotoxicity received one to three doses of intravenous (IV) glucarpidase and leucovorin rescue. The initial cohort (n = 35) also received thymidine by continuous IV infusion. Subsequently, thymidine was restricted to patients with prolonged exposure (> 96 hours) to methotrexate (MTX) or with substantial MTX toxicity at study entry. Plasma MTX, leucovorin, and 5-methyltetrahydrofolate (5-mTHF) concentrations were measured pre- and postglucarpidase. Toxicities were monitored, and logistic regression analysis was used to assess the relationship of baseline characteristics to the development of severe toxicity and death. Results: Glucarpidase was administered at a median of 96 hours (receiving thymidine, n = 44) and 66 hours (not receiving thymidine, n = 56) after the start of the MTX infusion. Plasma MTX concentrations decreased within 15 minutes of glucarpidase by 98.7%. Plasma 5-mTHF concentrations also decreased more than 98% after administration of glucarpidase. Of 12 deaths, six were directly attributed to irreversible MTX toxicity. Presence of grade 4 toxicity before administration of glucarpidase, inadequate initial increase in leucovorin dosing, and administration of glucarpidase more than 96 hours after the start of the MTX infusion were associated with development of grade 4 and 5 toxicity. Conclusion: Early intervention with the combination of leucovorin and glucarpidase is highly effective in patients who develop HDMTX-induced renal dysfunction. Severe toxicity and mortality occurred in patients in whom glucarpidase rescue was delayed and occurred despite thymidine administration.

Original languageEnglish (US)
Pages (from-to)3979-3986
Number of pages8
JournalJournal of Clinical Oncology
Volume28
Issue number25
DOIs
StatePublished - Sep 1 2010
Externally publishedYes

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Leucovorin
Methotrexate
Thymidine
Kidney
gamma-Glutamyl Hydrolase
Intravenous Infusions
Logistic Models
Regression Analysis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction : Clinical and pharmacologic factors affecting outcome. / Widemann, Brigitte C.; Balis, Frank M.; Kim, AeRang; Boron, Matthew; Jayaprakash, Nalini; Shalabi, Aiman; O'Brien, Michelle; Eby, Michelle; Cole, Diane E.; Murphy, Robert F.; Fox, Elizabeth; Ivy, Percy; Adamson, Peter C.

In: Journal of Clinical Oncology, Vol. 28, No. 25, 01.09.2010, p. 3979-3986.

Research output: Contribution to journalArticle

Widemann, BC, Balis, FM, Kim, A, Boron, M, Jayaprakash, N, Shalabi, A, O'Brien, M, Eby, M, Cole, DE, Murphy, RF, Fox, E, Ivy, P & Adamson, PC 2010, 'Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: Clinical and pharmacologic factors affecting outcome', Journal of Clinical Oncology, vol. 28, no. 25, pp. 3979-3986. https://doi.org/10.1200/JCO.2009.25.4540
Widemann, Brigitte C. ; Balis, Frank M. ; Kim, AeRang ; Boron, Matthew ; Jayaprakash, Nalini ; Shalabi, Aiman ; O'Brien, Michelle ; Eby, Michelle ; Cole, Diane E. ; Murphy, Robert F. ; Fox, Elizabeth ; Ivy, Percy ; Adamson, Peter C. / Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction : Clinical and pharmacologic factors affecting outcome. In: Journal of Clinical Oncology. 2010 ; Vol. 28, No. 25. pp. 3979-3986.
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abstract = "Purpose: To assess the role of the recombinant bacterial enzyme, glucarpidase (carboxypeptidase-G2), leucovorin, and thymidine in the management and outcome of patients with high-dose methotrexate (HDMTX) -induced nephrotoxicity. Methods: Patients with HDMTX-induced nephrotoxicity received one to three doses of intravenous (IV) glucarpidase and leucovorin rescue. The initial cohort (n = 35) also received thymidine by continuous IV infusion. Subsequently, thymidine was restricted to patients with prolonged exposure (> 96 hours) to methotrexate (MTX) or with substantial MTX toxicity at study entry. Plasma MTX, leucovorin, and 5-methyltetrahydrofolate (5-mTHF) concentrations were measured pre- and postglucarpidase. Toxicities were monitored, and logistic regression analysis was used to assess the relationship of baseline characteristics to the development of severe toxicity and death. Results: Glucarpidase was administered at a median of 96 hours (receiving thymidine, n = 44) and 66 hours (not receiving thymidine, n = 56) after the start of the MTX infusion. Plasma MTX concentrations decreased within 15 minutes of glucarpidase by 98.7{\%}. Plasma 5-mTHF concentrations also decreased more than 98{\%} after administration of glucarpidase. Of 12 deaths, six were directly attributed to irreversible MTX toxicity. Presence of grade 4 toxicity before administration of glucarpidase, inadequate initial increase in leucovorin dosing, and administration of glucarpidase more than 96 hours after the start of the MTX infusion were associated with development of grade 4 and 5 toxicity. Conclusion: Early intervention with the combination of leucovorin and glucarpidase is highly effective in patients who develop HDMTX-induced renal dysfunction. Severe toxicity and mortality occurred in patients in whom glucarpidase rescue was delayed and occurred despite thymidine administration.",
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T1 - Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction

T2 - Clinical and pharmacologic factors affecting outcome

AU - Widemann, Brigitte C.

AU - Balis, Frank M.

AU - Kim, AeRang

AU - Boron, Matthew

AU - Jayaprakash, Nalini

AU - Shalabi, Aiman

AU - O'Brien, Michelle

AU - Eby, Michelle

AU - Cole, Diane E.

AU - Murphy, Robert F.

AU - Fox, Elizabeth

AU - Ivy, Percy

AU - Adamson, Peter C.

PY - 2010/9/1

Y1 - 2010/9/1

N2 - Purpose: To assess the role of the recombinant bacterial enzyme, glucarpidase (carboxypeptidase-G2), leucovorin, and thymidine in the management and outcome of patients with high-dose methotrexate (HDMTX) -induced nephrotoxicity. Methods: Patients with HDMTX-induced nephrotoxicity received one to three doses of intravenous (IV) glucarpidase and leucovorin rescue. The initial cohort (n = 35) also received thymidine by continuous IV infusion. Subsequently, thymidine was restricted to patients with prolonged exposure (> 96 hours) to methotrexate (MTX) or with substantial MTX toxicity at study entry. Plasma MTX, leucovorin, and 5-methyltetrahydrofolate (5-mTHF) concentrations were measured pre- and postglucarpidase. Toxicities were monitored, and logistic regression analysis was used to assess the relationship of baseline characteristics to the development of severe toxicity and death. Results: Glucarpidase was administered at a median of 96 hours (receiving thymidine, n = 44) and 66 hours (not receiving thymidine, n = 56) after the start of the MTX infusion. Plasma MTX concentrations decreased within 15 minutes of glucarpidase by 98.7%. Plasma 5-mTHF concentrations also decreased more than 98% after administration of glucarpidase. Of 12 deaths, six were directly attributed to irreversible MTX toxicity. Presence of grade 4 toxicity before administration of glucarpidase, inadequate initial increase in leucovorin dosing, and administration of glucarpidase more than 96 hours after the start of the MTX infusion were associated with development of grade 4 and 5 toxicity. Conclusion: Early intervention with the combination of leucovorin and glucarpidase is highly effective in patients who develop HDMTX-induced renal dysfunction. Severe toxicity and mortality occurred in patients in whom glucarpidase rescue was delayed and occurred despite thymidine administration.

AB - Purpose: To assess the role of the recombinant bacterial enzyme, glucarpidase (carboxypeptidase-G2), leucovorin, and thymidine in the management and outcome of patients with high-dose methotrexate (HDMTX) -induced nephrotoxicity. Methods: Patients with HDMTX-induced nephrotoxicity received one to three doses of intravenous (IV) glucarpidase and leucovorin rescue. The initial cohort (n = 35) also received thymidine by continuous IV infusion. Subsequently, thymidine was restricted to patients with prolonged exposure (> 96 hours) to methotrexate (MTX) or with substantial MTX toxicity at study entry. Plasma MTX, leucovorin, and 5-methyltetrahydrofolate (5-mTHF) concentrations were measured pre- and postglucarpidase. Toxicities were monitored, and logistic regression analysis was used to assess the relationship of baseline characteristics to the development of severe toxicity and death. Results: Glucarpidase was administered at a median of 96 hours (receiving thymidine, n = 44) and 66 hours (not receiving thymidine, n = 56) after the start of the MTX infusion. Plasma MTX concentrations decreased within 15 minutes of glucarpidase by 98.7%. Plasma 5-mTHF concentrations also decreased more than 98% after administration of glucarpidase. Of 12 deaths, six were directly attributed to irreversible MTX toxicity. Presence of grade 4 toxicity before administration of glucarpidase, inadequate initial increase in leucovorin dosing, and administration of glucarpidase more than 96 hours after the start of the MTX infusion were associated with development of grade 4 and 5 toxicity. Conclusion: Early intervention with the combination of leucovorin and glucarpidase is highly effective in patients who develop HDMTX-induced renal dysfunction. Severe toxicity and mortality occurred in patients in whom glucarpidase rescue was delayed and occurred despite thymidine administration.

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