Clinicians managing children with ALL or or lymphoblastic lymphoma should not cease intrathecal MTX therapy after a first episode of MTX neurotoxicity, especially when it occurs early in therapy.
An Australian study of 1251 children from six paediatric oncology centres found 7.6% of the cohort fulfilled the criteria for MTX neurotoxicity.
MTX neurotoxicity included symptoms of motor deficits, speech deficits, visual disturbances, seizures and altered level of consciousness temporally related to IV or intrathecal (IT) MTX, where MTX was the most likely cause, and where other causes had been reasonably excluded.
Most of the events occurred within 21 days of IV or IT MTX. The first episode of MTX neurotoxicity occurred most frequently after induction/consolidation (55.8%) rather than during induction/consolidation (44.2%).
The study found that age ≥10 years and peak serum AST during induction/consolidation were independent risk associations for MTX neurotoxicity.
“There was a significantly higher incidence of MTX neurotoxicity on protocols with a lower cumulative IV MTX dose (total dose 0-2.5g/m2, n=20/148, 13.5%) compared to protocols with a higher cumulative IV MTX dose (20-35g/m2, n=69/863, 8.0%, P=0.031, odds ratio (OR) 1.8, 95% Confidence Interval (CI) 1.06-3.06.)”
Of the children who experienced MTX neurotoxicity, half (50.5%) had subsequent IT MTX permanently discontinued, 35.8% had IT MTX continued, and one patient developed MTX neurotoxicity following their last scheduled IT MTX dose.
“Cumulative incidence of CNS relapse was increased in children where IT MTX was omitted permanently following symptomatic MTX neurotoxicity (n=48) compared to children who had IT MTX continued through ALL treatment (n=1174 with available LFS data) (P=0.047),” the study said.
“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.”
The study also found recurrence of MTX neurotoxicity occurred in 12.9% of evaluable patients upon IT MTX re-exposure.
Most patients (95.8%) who had IT MTX ceased after a first MTX neurotoxicity event did not experience further neurotoxicity episodes.
A small number of children (1.3%) were diagnosed with epilepsy at last follow-up. There was no reported mortality due to long-term neurological problems following MTX neurotoxicity.
The study, published in Haematologica, concluded that MTX treatment should be continued in patients with a first episode of MTX neurotoxicity.
“Continued attempts to identify and prospectively validate clinical risk factors and germline variants that indicate high risk of MTX neurotoxicity may provide an opportunity to prevent this debilitating toxicity in the future.”