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

Abstract

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.

Figure 1.

Cumulative incidence of central nervous system relapse, according to intrathecal methotrexate strategy. Children who had intrathecal (IT) methotrexate (MTX) omitted permanently following symptomatic MTX neurotoxicity (n=48), had an increased risk of central nervous system (CNS) relapse compared to children who had IT MTX continued through ALL treatment (n=1,174) (P=0.047). Five-year CNS relapse-free survival was 95.4±0.6% when IT MTX was continued compared to 89.2±4.6%, when IT MTX was ceased.

Figure 2.

Timing of methotrexate neurotoxicity and risk of leukemic relapse. There is a significantly increased rate of leukemic relapse in children who experienced methotrexate (MTX) neurotoxicity early in therapy (induction/consolidation) compared to later in therapy (after consolidation, P=0.011). Five-year leukemia-free survival (LFS) in children who experienced early MTX neurotoxicity was 79.3±6.5% compared to 96±2.8% for children who experienced late MTX neurotoxicity.