- Title
- Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia
- Creator
- Mateos, Marion K.; Marshall, Glenn M.; Alvaro, Frank; Mechinaud, Françoise; Catchpoole, Daniel; Lawson, John A.; Chenevix-Trench, Georgia; MacGregor, Stuart; Kotecha, Rishi S.; Dalla-Pozza, Luciano; Trahair, Toby N.; Barbaro, Pasquale M.; Quinn, Michael C. J.; George, Carly; Mayoh, Chelsea; Sutton, Rosemary; Revesz, Tamas; Giles, Jodie E.; Barbaric, Draga
- Relation
- Haematologica Vol. 107, Issue 3, p. 635-643
- Publisher Link
- http://dx.doi.org/10.3324/haematol.2020.268565
- Publisher
- Fondazione Ferrata Storti
- Resource Type
- journal article
- Date
- 2022
- Description
- 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.
- Subject
- neurotoxicity; central nervous system; risk factors; Australia; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1452786
- Identifier
- uon:44512
- Identifier
- ISSN:0390-6078
- Language
- eng
- Reviewed
- Hits: 2577
- Visitors: 2574
- Downloads: 0