Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia.

Mateos, MK; Marshall, GM; Barbaro, PM; Quinn, MCJ; George, C; Mayoh, C; Sutton, R; Revesz, T; Giles, JE; Barbaric, D; Alvaro, F; Mechinaud, F; Catchpoole, D; Lawson, JA; Chenevix-Trench, G; MacGregor, S; Kotecha, RS; Dalla-Pozza, L; Trahair, TN

Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia.

Mateos, MK Marshall, GM Barbaro, PM Quinn, MCJ George, C Mayoh, C Sutton, R Revesz, T Giles, JE Barbaric, D Alvaro, F Mechinaud, F Catchpoole, D

Lawson, JA Chenevix-Trench, G MacGregor, S Kotecha, RS Dalla-Pozza, L Trahair, TN

Permalink

Publisher:: Ferrata Storti Foundation (Haematologica)
Publication Type:: Journal Article
Citation:: Haematologica, 2022, 107, (3), pp. 635-643
Issue Date:: 2022-03-01

Open Access

Copyright Clearance Process

Recently Added
In Progress
Open Access

This item is open access.

Adobe PDF

Download full textAdobe PDF (890.64 kB)

View on publisher's site

View statistics

Full metadata record

Field	Value	Language
dc.contributor.author	Mateos, MK
dc.contributor.author	Marshall, GM
dc.contributor.author	Barbaro, PM
dc.contributor.author	Quinn, MCJ
dc.contributor.author	George, C
dc.contributor.author	Mayoh, C
dc.contributor.author	Sutton, R
dc.contributor.author	Revesz, T
dc.contributor.author	Giles, JE
dc.contributor.author	Barbaric, D
dc.contributor.author	Alvaro, F
dc.contributor.author	Mechinaud, F
dc.contributor.author	Catchpoole, D https://orcid.org/0000-0001-5836-1413
dc.contributor.author	Lawson, JA
dc.contributor.author	Chenevix-Trench, G
dc.contributor.author	MacGregor, S
dc.contributor.author	Kotecha, RS
dc.contributor.author	Dalla-Pozza, L
dc.contributor.author	Trahair, TN
dc.date.accessioned	2023-04-05T01:35:24Z
dc.date.available	2023-04-05T01:35:24Z
dc.date.issued	2022-03-01
dc.identifier.citation	Haematologica, 2022, 107, (3), pp. 635-643
dc.identifier.issn	0390-6078
dc.identifier.issn	1592-8721
dc.identifier.uri	http://hdl.handle.net/10453/169133
dc.description.abstract	Symptomatic methotrexate-related central neurotoxicity (MTX neurotoxicity) is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic complications. Risk factors and long-term outcomes require further study. We conducted a systematic, retrospective review of 1,251 consecutive Australian children enrolled on Berlin-Frankfurt-Münster or Children's Oncology Group-based protocols between 1998-2013. Clinical risk predictors for MTX neurotoxicity were analyzed using regression. A genome-wide association study (GWAS) was performed on 48 cases and 537 controls. The incidence of MTX neurotoxicity was 7.6% (n=95 of 1,251), at a median of 4 months from ALL diagnosis and 8 days after intravenous or intrathecal MTX. Grade 3 elevation of serum aspartate aminotransferase (P=0.005, odds ratio 2.31 [range, 1.28-4.16]) in induction/consolidation was associated with MTX neurotoxicity, after accounting for the only established risk factor, age ≥10 years. Cumulative incidence of CNS relapse was increased in children where intrathecal MTX was omitted following symptomatic MTX neurotoxicity (n=48) compared to where intrathecal MTX was continued throughout therapy (n=1,174) (P=0.047). Five-year central nervous system relapse-free survival was 89.2 4.6% when intrathecal MTX was ceased compared to 95.4 0.6% when intrathecal MTX was continued. Recurrence of MTX neurotoxicity was low (12.9%) for patients whose intrathecal MTX was continued after their first episode. The GWAS identified single-nucletide polymorphism associated with MTX neurotoxicity near genes regulating neuronal growth, neuronal differentiation and cytoskeletal organization (P<1x10-6). In conclusion, increased serum aspartate aminotransferase and age ≥10 years at diagnosis were independent risk factors for MTX neurotoxicity. Our data do not support cessation of intrathecal MTX after a first MTX neurotoxicity event.
dc.format	Electronic
dc.language	eng
dc.publisher	Ferrata Storti Foundation (Haematologica)
dc.relation.ispartof	Haematologica
dc.relation.isbasedon	10.3324/haematol.2020.268565
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1102 Cardiorespiratory Medicine and Haematology
dc.subject.classification	Immunology
dc.subject.mesh	Antineoplastic Combined Chemotherapy Protocols
dc.subject.mesh	Australia
dc.subject.mesh	Child
dc.subject.mesh	Genome-Wide Association Study
dc.subject.mesh	Humans
dc.subject.mesh	Injections, Spinal
dc.subject.mesh	Methotrexate
dc.subject.mesh	Precursor Cell Lymphoblastic Leukemia-Lymphoma
dc.subject.mesh	Risk Factors
dc.subject.mesh	Humans
dc.subject.mesh	Methotrexate
dc.subject.mesh	Antineoplastic Combined Chemotherapy Protocols
dc.subject.mesh	Injections, Spinal
dc.subject.mesh	Risk Factors
dc.subject.mesh	Child
dc.subject.mesh	Australia
dc.subject.mesh	Precursor Cell Lymphoblastic Leukemia-Lymphoma
dc.subject.mesh	Genome-Wide Association Study
dc.subject.mesh	Antineoplastic Combined Chemotherapy Protocols
dc.subject.mesh	Australia
dc.subject.mesh	Child
dc.subject.mesh	Genome-Wide Association Study
dc.subject.mesh	Humans
dc.subject.mesh	Injections, Spinal
dc.subject.mesh	Methotrexate
dc.subject.mesh	Precursor Cell Lymphoblastic Leukemia-Lymphoma
dc.subject.mesh	Risk Factors
dc.title	Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia.
dc.type	Journal Article
utslib.citation.volume	107
utslib.location.activity	Italy
utslib.for	1102 Cardiorespiratory Medicine and Haematology
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
utslib.copyright.status	open_access	*
dc.date.updated	2023-04-05T01:35:22Z
pubs.issue	3
pubs.publication-status	Published online
pubs.volume	107
utslib.citation.issue	3

Abstract:

Symptomatic methotrexate-related central neurotoxicity (MTX neurotoxicity) is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic complications. Risk factors and long-term outcomes require further study. We conducted a systematic, retrospective review of 1,251 consecutive Australian children enrolled on Berlin-Frankfurt-Münster or Children's Oncology Group-based protocols between 1998-2013. Clinical risk predictors for MTX neurotoxicity were analyzed using regression. A genome-wide association study (GWAS) was performed on 48 cases and 537 controls. The incidence of MTX neurotoxicity was 7.6% (n=95 of 1,251), at a median of 4 months from ALL diagnosis and 8 days after intravenous or intrathecal MTX. Grade 3 elevation of serum aspartate aminotransferase (P=0.005, odds ratio 2.31 [range, 1.28-4.16]) in induction/consolidation was associated with MTX neurotoxicity, after accounting for the only established risk factor, age ≥10 years. Cumulative incidence of CNS relapse was increased in children where intrathecal MTX was omitted following symptomatic MTX neurotoxicity (n=48) compared to where intrathecal MTX was continued throughout therapy (n=1,174) (P=0.047). Five-year central nervous system relapse-free survival was 89.2 4.6% when intrathecal MTX was ceased compared to 95.4 0.6% when intrathecal MTX was continued. Recurrence of MTX neurotoxicity was low (12.9%) for patients whose intrathecal MTX was continued after their first episode. The GWAS identified single-nucletide polymorphism associated with MTX neurotoxicity near genes regulating neuronal growth, neuronal differentiation and cytoskeletal organization (P<1x10-6). In conclusion, increased serum aspartate aminotransferase and age ≥10 years at diagnosis were independent risk factors for MTX neurotoxicity. Our data do not support cessation of intrathecal MTX after a first MTX neurotoxicity event.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/169133