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Methotrexate neurotoxicity: risk factors & outcome
Table 2. Clinical risk factors significantly associated with methotrexate neurotoxicity in regression analysis.
Clinical Risk Factor
Age at diagnosis (continuous) Age≥10 years
HR/VHR treatmenta
Bilirubin at diagnosis
Peak bilirubinb
Peak bilirubin > Grade 3b
Peak ALTb
Peak ALT > Grade 3b
Peak ASTb
Peak AST > Grade 3b
Positive blood cultureb
Peak creatinine > 2 x baseline and abnormalb Insulin requirementb
Hyperglycemiab
Univariate Multivariate
P OR 95%CI P OR 95%CI
<0.001 1.01 <0.001 2.65 0.003 2.05 0.026 1.03 0.04 1.01
0.03 2.6 0.029 1.001 0.043 1.62 0.018 1.001 0.004 2.38 0.011 1.81 0.005 3.27
<0.001 4.39 0.001 2.42
1.006-1.014
1.69-4.14
1.29-3.28
1.003-1.05
1.000-1.014
1.10-6.13
1.000-1.002
1.02-2.57
1.000-1.002
1.33-4.26 0.005 2.31 1.28-4.16 1.15-2.85
1.44-7.45
2.36-8.19
1.43-4.10
0.003 2.43
1.35-4.38
Factors that were associated with methotrexate (MTX) neurotoxicity in logistic regression analysis at a significance level P<0.05 (2-tailed) are listed. aComparison was made between a combined high-risk cohort (high-risk "HR" and very high-risk "VHR" ALL) versus a combined non high-risk cohort (standard and medium risk ALL). bIn induction/consolidation.ALT:alanine aminotransferase;AST:aspartate aminotransferase;OR:odds ratio;CI:Confidence Interval.ALT and AST elevation > grade 3 refers to levels >5x upper limit of normal (ULN). Bilirubin >grade 3 is >3x ULN based on NCI CTCAE v4.03 criteria. Significance levels were set at P<0.0014 and P<0.05 for univariate and multi- variate analyses respectively.
SNP for evaluation in the GWAS for MTX neurotoxicity were 10,838,245. Imputation was conducted on 388,439 SNP (including SNP on the X chromosome) using IMPUTE2.16 GWAS was con- ducted correlating potential SNP with MTX neurotoxicity, using age, sex and principal components as covariates.
Results
Incidence of methotrexate neurotoxicity
The clinical cohort consisted of 1,251 children with ALL/LBL (Online Supplementary Figure S1) from six tertiary Australian pediatric oncology centers. There were 1,033 children treated on BFM-based protocols and 218 on COG-based protocols (Table 1). The median age at diag- nosis was 59 months (range, 9-218 months) with a median duration of follow-up of 78 months (range, 3-186 months). Five-year OS, LFS and EFS were 92±0.8%, 85.6±1.1% and 83.8±1.1% respectively.
Comparative IT, IV MTX and leucovorin (folinic acid) doses according to each protocol are listed in the Online Supplementary Appendix and the Online Supplementary Table S1. IT MTX was given during induction, consolidation, CNS-directed phases, reinduction, reconsolidation and in some protocols IT MTX continued in maintenance. There were a varying number of IT MTX doses in induction. In consolidation, all protocols used IT MTX, while most used cyclophosphamide and cytarabine. Age-directed doses varied between protocols for children aged 9 years and older. For protocols that used IV MTX, doses varied considerably and could be divided into protocols that administered low (0-2.5 g/m2 total IV MTX doses) and high (20-35 g/m2total IV MTX dose) doses.
Ninety-five children (7.6% of the cohort) fulfilled the criteria for MTX neurotoxicity. Ninety-one patients expe- rienced MTX neurotoxicity within 21 days following IV or IT MTX (Online Supplementary Table S2). Of four patients with MTX neurotoxicity and leukoencephalopa- thy >21 days following MTX, three patients had typical symptoms and leukoencephalopathy diagnosed at 22, 30
and 47 days post MTX, while one patient had seizures and leukoencephalopathy 56 days after MTX. Further information is contained in the Online Supplementary Table S2. All ninety-five patients were included in subsequent analyses.
The median time from ALL diagnosis to onset of MTX neurotoxicity was 4 months (range, 0-19 months, interquartile range [IQR], 2-6 months), occurring at a median of 8 days following IV or IT MTX administration (range, 0-56 days, IQR, 5-11 days).
The first episode of MTX neurotoxicity most frequently occurred after induction/consolidation in 55.8% (n=53 of 95), while 44.2% occurred during induction/consolida- tion. Specific timing of these events is shown in the Online Supplementary Figure S3. MTX neurotoxicity first events were associated with co-administration of IT MTX, cyclophosphamide and cytarabine in 53.2% patients (n=50 of 94; one patient unknown). In comparison, 23.2% (n=22 of 95) of first events were associated with concur- rent IV MTX and IT MTX administration. Grade 1 neuro- toxicity occurred in 4.2% of the cohort (n=4); grade 2 in 62.1% (n=59); grade 3 in 31.6% (n=30) and grade 4 in 2.1% (n=2).
Risk factors for methotrexate neurotoxicity - clinical risk factors
Clinical variables were assessed for association with MTX neurotoxicity in univariate logistic regression (Table 2 for those associated P<0.05, Online Supplementary Appendix). Variables with a P-value of association <0.0014 were considered significant, taking into account 37 vari- ables as per the Bonferroni method of adjustment for mul- tiple testing (P<0.05/37). Factors listed in Table 2 were analyzed further in a multivariable regression analysis. This demonstrated that age ≥10 years and peak serum AST during induction/consolidation were independent risk associations for MTX neurotoxicity (Table 2). Overall, 56.2% (n=703 of 1,251) of the cohort were available for multivariable analysis, due to availability of AST values during induction/consolidation. These two risk variables
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