Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia

Deepa Bhojwani, Noah D. Sabin, Deqing Pei, Jun J. Yang, Raja B. Khan, John C. Panetta, Kevin R. Krull, Hiroto Inaba, Jeffrey E. Rubnitz, Monika L. Metzger, Scott Howard, Raul C. Ribeiro, Cheng Cheng, Wilburn E. Reddick, Sima Jeha, John T. Sandlund, William E. Evans, Ching Hon Pui, Mary V. Relling

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Purpose: Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. Patients and Methods: Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. Results: Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity. Conclusion: MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.

Original languageEnglish (US)
Pages (from-to)949-959
Number of pages11
JournalJournal of Clinical Oncology
Volume32
Issue number9
DOIs
StatePublished - Mar 20 2014

Fingerprint

Leukoencephalopathies
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Methotrexate
Genome-Wide Association Study
Pharmacokinetics
Recurrence
Leucovorin
Neurogenesis
Therapeutics
Genes
Logistic Models
Magnetic Resonance Imaging

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Bhojwani, D., Sabin, N. D., Pei, D., Yang, J. J., Khan, R. B., Panetta, J. C., ... Relling, M. V. (2014). Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. Journal of Clinical Oncology, 32(9), 949-959. https://doi.org/10.1200/JCO.2013.53.0808

Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. / Bhojwani, Deepa; Sabin, Noah D.; Pei, Deqing; Yang, Jun J.; Khan, Raja B.; Panetta, John C.; Krull, Kevin R.; Inaba, Hiroto; Rubnitz, Jeffrey E.; Metzger, Monika L.; Howard, Scott; Ribeiro, Raul C.; Cheng, Cheng; Reddick, Wilburn E.; Jeha, Sima; Sandlund, John T.; Evans, William E.; Pui, Ching Hon; Relling, Mary V.

In: Journal of Clinical Oncology, Vol. 32, No. 9, 20.03.2014, p. 949-959.

Research output: Contribution to journalArticle

Bhojwani, D, Sabin, ND, Pei, D, Yang, JJ, Khan, RB, Panetta, JC, Krull, KR, Inaba, H, Rubnitz, JE, Metzger, ML, Howard, S, Ribeiro, RC, Cheng, C, Reddick, WE, Jeha, S, Sandlund, JT, Evans, WE, Pui, CH & Relling, MV 2014, 'Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia', Journal of Clinical Oncology, vol. 32, no. 9, pp. 949-959. https://doi.org/10.1200/JCO.2013.53.0808
Bhojwani, Deepa ; Sabin, Noah D. ; Pei, Deqing ; Yang, Jun J. ; Khan, Raja B. ; Panetta, John C. ; Krull, Kevin R. ; Inaba, Hiroto ; Rubnitz, Jeffrey E. ; Metzger, Monika L. ; Howard, Scott ; Ribeiro, Raul C. ; Cheng, Cheng ; Reddick, Wilburn E. ; Jeha, Sima ; Sandlund, John T. ; Evans, William E. ; Pui, Ching Hon ; Relling, Mary V. / Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. In: Journal of Clinical Oncology. 2014 ; Vol. 32, No. 9. pp. 949-959.
@article{6951f39365884d37b8da2146571f3f2d,
title = "Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia",
abstract = "Purpose: Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. Patients and Methods: Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. Results: Fourteen patients (3.8{\%}) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6{\%}) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74{\%} of asymptomatic and 58{\%} of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity. Conclusion: MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.",
author = "Deepa Bhojwani and Sabin, {Noah D.} and Deqing Pei and Yang, {Jun J.} and Khan, {Raja B.} and Panetta, {John C.} and Krull, {Kevin R.} and Hiroto Inaba and Rubnitz, {Jeffrey E.} and Metzger, {Monika L.} and Scott Howard and Ribeiro, {Raul C.} and Cheng Cheng and Reddick, {Wilburn E.} and Sima Jeha and Sandlund, {John T.} and Evans, {William E.} and Pui, {Ching Hon} and Relling, {Mary V.}",
year = "2014",
month = "3",
day = "20",
doi = "10.1200/JCO.2013.53.0808",
language = "English (US)",
volume = "32",
pages = "949--959",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "9",

}

TY - JOUR

T1 - Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia

AU - Bhojwani, Deepa

AU - Sabin, Noah D.

AU - Pei, Deqing

AU - Yang, Jun J.

AU - Khan, Raja B.

AU - Panetta, John C.

AU - Krull, Kevin R.

AU - Inaba, Hiroto

AU - Rubnitz, Jeffrey E.

AU - Metzger, Monika L.

AU - Howard, Scott

AU - Ribeiro, Raul C.

AU - Cheng, Cheng

AU - Reddick, Wilburn E.

AU - Jeha, Sima

AU - Sandlund, John T.

AU - Evans, William E.

AU - Pui, Ching Hon

AU - Relling, Mary V.

PY - 2014/3/20

Y1 - 2014/3/20

N2 - Purpose: Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. Patients and Methods: Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. Results: Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity. Conclusion: MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.

AB - Purpose: Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. Patients and Methods: Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. Results: Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity. Conclusion: MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.

UR - http://www.scopus.com/inward/record.url?scp=84899638189&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899638189&partnerID=8YFLogxK

U2 - 10.1200/JCO.2013.53.0808

DO - 10.1200/JCO.2013.53.0808

M3 - Article

VL - 32

SP - 949

EP - 959

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 9

ER -