Evidence map›Paper›PMID 33567813›Full record

ArticleHaematologica2022

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

Marion K Mateos, Glenn M Marshall, Pasquale M Barbaro, Michael C J Quinn, Carly George, Chelsea Mayoh, Rosemary Sutton, Tamas Revesz, Jodie E Giles, Draga Barbaric and 9 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Haematologica, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
33citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

33 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Article
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  6. Article
  7. Article
  8. Review
  9. Novel Therapeutic Approaches in Pediatric Acute Lymphoblastic Leukemia.International journal of molecular sciences · 2025
    Review
  10. Article
  11. Review
  12. Review
  13. Intrathecal treatment of Anti-N-Methyl-D-Aspartate receptor encephalitis: a promising approach for refractory cases.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025
    Review
  14. Article
  15. Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

19 authors.

Marion K MateosKids Cancer Centre, Sydney Children's Hospital Randwick, Sydney, Australia; School of Women and Children's Health, University of New South Wales (UNSW), Sydney, Australia; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia; Northern Institute for Cancer Research, Wolfson Childhood Cancer Research Centre, Newcastle-Upon-Tyne.
Glenn M MarshallKids Cancer Centre, Sydney Children's Hospital Randwick, Sydney, Australia; School of Women and Children's Health, University of New South Wales (UNSW), Sydney, Australia; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney.
Pasquale M BarbaroChildren's Medical Research Institute, University of Sydney, Sydney, Australia; Department of Haematology, Queensland Children's Hospital, Brisbane.
Michael C J QuinnQIMR Berghofer Medical Research Institute, Brisbane.
Carly GeorgePerth Children's Hospital, Perth, Australia; Division of Paediatrics, School of Medicine, University of Western Australia, Perth.
Chelsea MayohSchool of Women and Children's Health, University of New South Wales (UNSW), Sydney, Australia; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney.
Rosemary SuttonSchool of Women and Children's Health, University of New South Wales (UNSW), Sydney, Australia; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney.
Tamas ReveszWomen's and Children's Hospital, Adelaide.
Jodie E GilesChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney.
Draga BarbaricKids Cancer Centre, Sydney Children's Hospital Randwick, Sydney.
Frank AlvaroJohn Hunter Children's Hospital, Newcastle, Australia; University of Newcastle, Newcastle.
Françoise MechinaudThe Royal Children's Hospital, Melbourne, Australia; Service d'Immuno-hématologie pédiatrique Hôpital Robert-Debré, Paris.
Daniel CatchpooleThe Tumour Bank, Children's Cancer Research Unit, The Children's Hospital at Westmead, Sydney.
John A LawsonSchool of Women and Children's Health, University of New South Wales (UNSW), Sydney, Australia; Department of Neurology, Sydney Children's Hospital Randwick, Sydney.
Georgia Chenevix-TrenchQIMR Berghofer Medical Research Institute, Brisbane.
Stuart MacGregorQIMR Berghofer Medical Research Institute, Brisbane.
Rishi S KotechaPerth Children's Hospital, Perth, Australia; Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia; School of Pharmacy and Biomedical Sciences, Curtin University, Perth.
Luciano Dalla-PozzaChildren's Medical Research Institute, University of Sydney, Sydney, Australia; Cancer Centre for Children, The Children's Hospital at Westmead, Sydney, Australia; Children's Cancer Research Unit, The Children's Hospital at Westmead, Sydney.
Toby N TrahairKids Cancer Centre, Sydney Children's Hospital Randwick, Sydney, Australia; School of Women and Children's Health, University of New South Wales (UNSW), Sydney, Australia; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney. toby.trahair@health.nsw.gov.au.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

Genome-Wide Association StudyPrecursor Cell Lymphoblastic Leukemia-LymphomaAntineoplastic Combined Chemotherapy ProtocolsAustraliaChildHumansInjections, SpinalMethotrexateRisk FactorsMethotrexate

Identifiers

PMID33567813
PMCPMC8883571

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.