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,
Frank Alvaro,
Françoise Mechinaud,
Daniel Catchpoole,
John A. Lawson,
Georgia Chenevix-Trench,
Stuart MacGregor,
Rishi S. Kotecha,
Luciano Dalla-Pozza,
Toby N. Trahair
Affiliations
Marion K. Mateos
Kids 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. Marshall
Kids 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. Barbaro
Children’s Medical Research Institute, University of Sydney, Sydney, Australia; Department of Haematology, Queensland Children’s Hospital, Brisbane
Michael C.J. Quinn
QIMR Berghofer Medical Research Institute, Brisbane
Carly George
Perth Children’s Hospital, Perth, Australia; Division of Paediatrics, School of Medicine, University of Western Australia, Perth
Chelsea Mayoh
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
Rosemary Sutton
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
Tamas Revesz
Women’s and Children’s Hospital, Adelaide
Jodie E. Giles
Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney
Draga Barbaric
Kids Cancer Centre, Sydney Children’s Hospital Randwick, Sydney
Frank Alvaro
John Hunter Children’s Hospital, Newcastle, Australia; University of Newcastle, Newcastle
Françoise Mechinaud
The Royal Children’s Hospital, Melbourne, Australia; Service d’Immuno-hématologie pédiatrique Hôpital Robert-Debré, Paris
Daniel Catchpoole
The Tumour Bank, Children’s Cancer Research Unit, The Children’s Hospital at Westmead, Sydney
John A. Lawson
School 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-Trench
QIMR Berghofer Medical Research Institute, Brisbane
Stuart MacGregor
QIMR Berghofer Medical Research Institute, Brisbane
Rishi S. Kotecha
Perth 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-Pozza
Children’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. Trahair
Kids 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
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.
