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M.K. Mateos et al.
were associated with 48.4% of MTX neurotoxicity events. There was no association between body mass index (BMI) Z scores and neurotoxicity, using BMI from diagnosis (P=0.133), end of induction (P=0.788), or end of consolidation (P=0.375).
Central nervous system disease at diagnosis
Leukemic involvement of the CNS at diagnosis was not significantly higher for children who experienced MTX neurotoxicity (P=0.414, Pearson c2) (Online Supplementary Table S3).
Dosing of methotrexate
MTX levels at 24, 48 or 54 hours following a first course of HD MTX did not correlate with incidence of MTX neu- rotoxicity (P=0.964, P=0.81 and P=0.866 respectively). Incidence of delayed MTX excretion is outlined in the Online Supplementary Appendix.
There was a significantly higher incidence of MTX neu- rotoxicity on protocols with a lower cumulative IV MTX dose (total dose 0-2.5 g/m2, n=20 of 148, 13.5%) compared to protocols with a higher cumulative IV MTX dose (20- 35 g/m2, n=69 of 863, 8.0%, P=0.031, odds ratio [OR] 1.8, 95% Confidence Interval [CI]: 1.06-3.06). This difference remained when stratified for high-risk protocols, with cumulative incidence of MTX neurotoxicity of 33% (n=11 of 33) with lower dose IV MTX protocols compared to 9.7% (n=13 of 134) with higher-dose MTX protocols respectively (P<0.001).
Other potential differences, such as use of vincristine during the IV MTX phases on COG-protocols, compared to BFM-based protocols which do not use vincristine dur-
ing the IV MTX phases (P=0.792), use of vincristine during consolidation versus no vincristine (P=0.50) or higher age- adjusted IT MTX doses for children aged ≥9 years, were not significantly associated with MTX neurotoxicity (P=0.778).
Outcome following first episode of methotrexate neurotoxicity
We assessed the incidence of several clinical outcomes: including rates of CNS relapse, LFS, recurrent MTX neuro- toxicity and long-term neurological outcomes in children who experienced a first episode of MTX neurotoxicity. Out of 95 patients who experienced MTX neurotoxicity, 48 (50.5%) had subsequent IT MTX permanently discon- tinued, 34 (35.8%) had IT MTX continued, and one patient developed MTX neurotoxicity following their last scheduled IT MTX dose. Subsequent IT management could not be determined for 12 (12.6%) cases. In patients where IT MTX was permanently discontinued, subse- quent IT therapy included cytarabine alone (n=23), cytara- bine and hydrocortisone (n=17), no further IT agents (n=2, in maintenance and Protocol M respectively), and in six patients the alternative IT regime was unknown.
We examined CNS relapse risk in patients who experi- enced MTX neurotoxicity, and assessed the impact of IT MTX continuation on CNS relapse rates. Cases were excluded if IT MTX management was unknown follow- ing neurotoxicity (n=12), where no further IT MTX doses were scheduled as per protocol (n=1), or where IT MTX was ceased due to seizures from a different etiology (n=2).
In the overall cohort where IT MTX was continued, 49 of 1.178 children experienced a CNS-based relapse (4.2%).
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.
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