TY - JOUR AU - Mateos, Marion K. AU - Marshall, Glenn M. AU - Barbaro, Pasquale M. AU - Quinn, Michael C.J. AU - George, Carly AU - Mayoh, Chelsea AU - Sutton, Rosemary AU - Revesz, Tamas AU - Giles, Jodie E. AU - Barbaric, Draga AU - Alvaro, Frank AU - Mechinaud, Françoise AU - Catchpoole, Daniel AU - Lawson, John A. AU - Chenevix-Trench, Georgia AU - MacGregor, Stuart AU - Kotecha, Rishi S. AU - Dalla-Pozza, Luciano AU - Trahair, Toby N. PY - 2022/03/01 Y2 - 2024/03/29 TI - Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia JF - Haematologica JA - haematol VL - 107 IS - 3 SE - Articles DO - 10.3324/haematol.2020.268565 UR - https://haematologica.org/article/view/haematol.2020.268565 SP - 635-643 AB - 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. ER -