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M.K. Mateos et al.
Introduction
Methotrexate-related central neurotoxicity (MTX neu- rotoxicity) occurs in 3-7% of children treated for child- hood acute lymphoblastic leukemia (ALL)1-3 and is charac- terized by seizures, stroke-like symptoms, speech distur- bances and encephalopathy.4 Although commonly encountered during clinical practice, questions remain relating to risk factors, choice of further intrathecal (IT) chemotherapy following MTX neurotoxicity and long- term neurological outcomes, which are not well defined.
Previously described risk factors for symptomatic MTX neurotoxicity include older age1,3,5 and an interaction with cytarabine and cyclophosphamide treatment blocks.5 Upon re-exposure to MTX in children with ALL, MTX neurotoxicity recurs in 7-24% of cases.1,3,5 However, there is a paucity of data on central nervous system (CNS) relapse rates if CNS-directed therapy is modified follow- ing MTX neurotoxicity.6 Genomic risk predictors may relate to neuronal development, MTX clearance or folate metabolism by-products such as homocysteine.1,7-11
Here we sought to analyze clinical and germline DNA factors that may predict susceptibility to MTX neurotoxi- city during treatment for childhood ALL. Additionally, we assessed the incidence of neurological sequelae following an episode of MTX neurotoxicity, and, the impact that changes made to therapy following MTX neurotoxicity had on subsequent relapse risk.
Methods
We conducted a national Australian retrospective review of chil- dren diagnosed with ALL or lymphoblastic lymphoma (LBL). Consecutive patients treated on frontline Berlin-Frankfurt- Munster (BFM) or Children’s Oncology Group (COG) ALL proto- cols between 1998 and 2013, were eligible for inclusion (see the Online Supplementary Appendix). The cohorts were assembled as part of the ERASE (Evaluation of Risk of ALL treatment-related Side-Effects) study.12 Complete clinical data were collected for 1,251 children (Online Supplementary Figure S1). The study was approved by Hunter New England Human Research Ethics Committee (HNEHREC reference number: 12/11/21/4.01).
We defined MTX neurotoxicity as symptomatic neurotoxicity, with or without leukoencephalopathy, temporally related to intra- venous (IV) or IT MTX, where MTX was deemed clinically or through record review as the most likely cause, and where other causes had been reasonably excluded. Symptomatic neurotoxicity included motor deficits, speech deficits, visual disturbances, seizures and altered level of consciousness. Toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03.13
Long-term neurological outcomes occurring after ALL/LBL diag- nosis, focusing on epilepsy, were collected on all patients where available (n=522).
Statistical analysis was performed using IBM SPSS for Macintosh, Versions 23.0/24.0 (see the Online Supplementary Appendix). Overall survival (OS) was computed from date of diag- nosis through to date of last contact or death from any cause. Event-free survival (EFS) was assessed as time from diagnosis to first event or last contact date in first complete remission (CR1). An event was defined as relapse, death from any cause or second- ary malignancy. Leukemia-free survival (LFS) was determined from date of remission to first relapse or last contact date in CR1. CNS relapse was defined as leukemic relapse involving the CNS,
Table 1. Baseline demographics. Diagnostic information
Male DIAGNOSIS
Pre-B-ALL
B-lymphoblastic lymphoma (B-LBL) T-ALL
T-lymphoblastic lymphoma (L-LBL) Other (ALL/LBL, not specified)
TREATMENT PROTOCOL
BFM-based protocols
ANZCHOG Study 7 (1998-2002)36 BFM-95 (1998-2002)37 ANZCHOG Study 8 (2002-2012)38 COG A5971 (2003-2009)39 iBFM-Study 9 (2012-2016)40
COG-based protocols
CCG1882 1991-1995)41
CCG1952 (1996-2000)42
CCG1961 (1996-2002)43
CCG1991 (2000-2005)44,45
AALL0031 (2002-2006)46
AALL0232 (2004-2011)47
AALL0331 (2005-2010)48
AALL0434 (2007-2014)45,48 AALL08P1 (2009-2011)49
AALL0932 (2010 - 2018)45
AALL1131 (2012 –[part-closure])45
Number % of (n=1,251) cohort
696 55.64
1,068 85.37 14 1.12 110 8.79 39 3.12 20 1.6
(n=1,033)
239 19.10 125 9.99 608 48.60 21 1.68 40 3.20
(n=218)
1 0.08 16 1.28 36 2.88 54 4.32 2 0.16 49 3.92 25 2.00 12 0.96 2 0.16 17 1.36 4 0.32
B-ALL: B-cell acute lymphoblastic leukemia; T-ALL: T-cell acute lymphoblastic leukemia; B-LBL: B-cell lymphoblastic lymphoma; BFM: Berlin-Franfurt-Münster; COG: or Children's Oncology Group.
either as an isolated CNS or combined CNS relapse. Thirty-seven variables were assessed in univariate logistic regression. Factors from univariate logistic regression analysis with a P-value <0.0014 were considered significant, using Bonferroni correction for multiple testing. Variables associated with MTX neurotoxicity (unadjusted P<0.10) were further assessed in multivariable regression analysis, adjusting for gender
(see the Online Supplementary Appendix).
Genome-wide association study methods
Genotyping was conducted on the Illumina Infinium OncoArray-530K Beadchip (533,000 single-nucleotide polymor- phisms [SNP]), using stored bone marrow or peripheral blood DNA, collected in remission14 from children treated on BFM-based protocols.
Of the 1,021 patients treated using BFM-based therapy, 932 had an available banked DNA sample. After quality control and filter- ing (see the Online Supplementary Appendix), the resultant cohort included 707 individuals of European ancestry, as previously described.15 Children who experienced neurotoxicity, either cen- tral or peripheral, other than MTX neurotoxicity were excluded (n=122), but those who experienced MTX neurotoxicity in addi- tion to another type of neurotoxicity were included. The resultant genome-wide association study (GWAS) cohort of 585 patients included 48 cases and 537 controls (Online Supplementary Figure S2). After filtering for information score >0.4, the total number of
636
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