ePrints

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

Lookup NU author(s): Dr Marion Mateos

Downloads

• Published version [.pdf]

Licence

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).

Abstract

© 2022 Ferrata Storti Foundation. 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.

Publication metadata

Author(s): 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

Publication type: Article

Publication status: Published

Journal: Haematologica

Year: 2022

Volume: 107

Issue: 3

Pages: 635-643

Print publication date: 01/03/2022

Online publication date: 11/02/2021

Acceptance date: 02/02/2021

Date deposited: 06/04/2022

ISSN (print): 0390-6078

ISSN (electronic): 1592-8721

Publisher: Ferrata Storti Foundation

URL: https://doi.org/10.3324/haematol.2020.268565

DOI: 10.3324/haematol.2020.268565

PubMed id: 33567813

Altmetrics

Funding

Share