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M.K. Mateos et al.
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 sur- vival (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.
children who had IT MTX continued through ALL treat- ment (n=1.174 with available LFS data) (P=0.047) (Figure 1). 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.
For children who experienced MTX neurotoxicity and had IT MTX ceased (n=48) or continued (n=34), there was no difference in CNS status (P=0.536) or age (age <10 vs. ≥10 years, P=0.560) (Online Supplementary Table S4). There was a difference in risk group status, however regression analysis did not show an impact of risk group on inci- dence of CNS relapse among the whole cohort (P=0.291, HR for high-risk group 0.72, 95% CI: 0.39-1.32). Age ≥10 years was also not associated with risk of CNS relapse (P=0.56, HR 0.83, 95% CI: 0.45-1.55). Distribution of MTX neurotoxicity by protocols and cases evaluable for recurrent MTX neurotoxicity are outlined in the Online Supplementary Table S5.
In the group where IT MTX was ceased, two of 48 had HD MTX ceased, three of 48 had HD MTX reduced, two of 48 had asparaginase ceased after neurotoxicity, and one of 48 had dexamethasone ceased in maintenance after development of osteonecrosis.
Overall, there were ten relapses in patients who experi- enced MTX neurotoxicity, six of whom had IT MTX ceased (and one of these patients also had HD MTX ceased). There were no other treatment modifications in these patients who experienced relapse. Specifically, in HR patients who experienced relapse (n=4), two had IT MTX ceased, two had IT MTX continued, and there were no other treatment alterations. Radiotherapy details are con- tained in the Online Supplementary Appendix.
Recurrent neurotoxicity
Six patients had recurrent neurotoxicity events, four of
whom had received further IT MTX and two where ongo- ing IT MTX exposure could not be determined. An addi- tional three patients who had been re-exposed to MTX did not have enough clinical information available to determine whether a subsequent neurotoxicity episode occurred. Therefore, recurrence of MTX neurotoxicity in evaluable patients occurred in 12.9% (n=4 of 31) upon IT MTX re-exposure. Three of the four patients did not receive any further IT MTX following recurrent MTX neurotoxicity. Further information regarding recurrent neurotoxicity events is shown in the Online Supplementary Tables S5 and S6.
For patients who were rechallenged with IT MTX, six patients were treated according to protocols that suggest oral leucovorin with IT rechallenge, and 28 were treated on protocols without that recommendation. Of those patients evaluable for recurrent MTX neurotoxicity, there was one recurrence out of five patients who were treated on protocols that recommended oral leucovorin; and three recurrences out of 26 patients who were treated on proto- cols that did not recommend oral leucovorin with IT rechallenge.
Of the patients who had IT MTX ceased after a first MTX neurotoxicity event, 95.8% (n=46 of 48) did not experience further neurotoxicity episodes. One patient experienced unusual ataxic episodes during a phase where oral MTX was administered, however further clinical information was not available and in the other patient the information was unknown.
Methotrexate neurotoxicity: negative impact of occurrence during early therapy
Those who experienced MTX neurotoxicity early (dur- ing induction/consolidation, n=42) had a higher subse- quent risk of leukemia relapse (all sites) compared to those
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