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Complications in Hematology
Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia
Marion K. Mateos,1-4 Glenn M Marshall,1-3 Pasquale M. Barbaro,5,6
Michael C.J. Quinn,7 Carly George,8,9 Chelsea Mayoh,2,3 Rosemary Sutton,2,3 Tamas Revesz,10 Jodie E Giles,3 Draga Barbaric,1 Frank Alvaro,11,12 Françoise Mechinaud,13,14 Daniel Catchpoole,15 John A. Lawson,2,16
Georgia Chenevix-Trench,7 Stuart MacGregor,7 Rishi S.Kotecha,8,17,18 Luciano Dalla-Pozza5,19,20 and Toby N. Trahair1-3
1Kids Cancer Center, Sydney Children’s Hospital Randwick, Sydney, New South Wales, Australia; 2School of Women and Children’s Health, University of New South Wales (UNSW), Sydney, New South Wales, Australia; 3Children’s Cancer Institute, Lowy Cancer Research Center, UNSW, Sydney, New South Wales, Australia; 4Northern Institute for Cancer Research, Wolfson Childhood Cancer Research Center, Newcastle-Upon-Tyne, UK; 5Children’s Medical Research Institute, University of Sydney, Sydney, New South Wales, Australia; 6Department of Hematology, Queensland Children’s Hospital, Brisbane, Queensland, Australia; 7QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; 8Perth Children’s Hospital, Perth, Western Australia, Australia; 9Division of Pediatrics, School of Medicine, University of Western Australia, Perth, Western Australia, Australia; 10Women’s and Children’s Hospital, Adelaide, New South Wales, Australia; 11John Hunter Children’s Hospital, Newcastle, New South Wales, Australia; 12University of Newcastle, Newcastle, New South Wales, Australia; 13The Royal Children’s Hospital, Melbourne, Victoria, Australia; 14Service d’Immuno- hématologie Pédiatrique, Hôpital Robert-Debré, Paris, France; 15The Tumor Bank, Children’s Cancer Research Unit, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia; 16Department of Neurology, Sydney Children’s Hospital Randwick, Sydney, New South Wales, Australia; 17Telethon Kids Cancer Center, Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia; 18School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Western Australia, Australia; 19Cancer Center for Children, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia and 20Children’s Cancer Research Unit, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia
ABSTRACT
Symptomatic methotrexate-related central neurotoxicity (MTX neurotox- icity) is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic complica- tions. Risk factors and long-term outcomes require further study. We conduct- ed 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 neuro- toxicity was 7.6% (n=95 of 1,251), at a median of 4 months from ALL diag- nosis 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 inci- dence 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 dif- ferentiation and cytoskeletal organization (P<1x10-6). In conclusion, increased serum aspartate aminotransferase and age ≥10 years at diagnosis were inde- pendent risk factors for MTX neurotoxicity. Our data do not support cessation of intrathecal MTX after a first MTX neurotoxicity event.
Ferrata Storti Foundation
Haematologica 2022 Volume 107(3):635-643
Correspondence:
MARION K. MATEOS
m.mateos@unsw.edu.au
Received: August 18, 2020. Accepted: February 2, 2021. Pre-published: February 11, 2021.
https://doi.org/10.3324/haematol.2020.268565 ©2022 Ferrata Storti Foundation
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