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M.K. Mateos et al.
on the basis of protocols that administered low dose or high dose MTX, and age-based IT MTX dosing. Where there were significant deviations to administered chemotherapy, this was usually captured in the data extraction and maintained in the database as additional phenotypic descriptors. However, it was impossible to calculate the total administered dose of IV and IT MTX per patient, therefore this could be attempted in future prospective trials to assess the relationship with MTX neurotoxicity occurrence. While the omission of IT MTX appears to be an important factor in patients who experi- enced a subsequent relapse, it is possible that concurrent cessation of HD MTX in one patient could have also con- tributed to relapse. There were no other treatment modi- fications identified in this cohort which could further con- tribute to relapse risk, however prospective capture and analysis of all treatment modifications would be impor- tant for future studies.
The main risk period in our study occurred when IT MTX was administered with cytarabine and cyclophos- phamide (50 of 94 cases), which is consistent with prior publications.2,5 Surprisingly, for children treated for high- risk ALL, there was a higher incidence of MTX neurotox- icity when a lower total dose of IV MTX was used com- pared to protocols using higher-dose MTX. This finding requires prospective validation and may be related to the routine use of leucovorin rescue with HD MTX.
Possible strategies for toxicity reduction include re- introducing IT MTX when cytarabine and cyclophos- phamide are not co-administered, and/or additional doses of leucovorin following IT MTX. Administration of an additional leucovorin dose reduced acute neurotoxicity in a historical cohort;30 and this could be targeted to specific risk periods such as when cyclophosphamide and cytara- bine are co-administered. Caution is advised however, due to evidence that higher leucovorin doses could be associated with increased relapse risk.31 While outside the scope of this paper, a systematic prospective study regard- ing secondary prophylaxis following IT MTX rechallenge would be important. Potential agents include leucovorin,1 aminophylline1 and the NMDA receptor antagonist dex- tromethorphan.32
In addition, drug-drug interactions that may potentiate MTX neurotoxicity or which could impact on efficacy of systemic chemotherapy such as anti-epileptic drugs should be systematically collected.33,34 Future laboratory- based modeling using neural cells derived from pluripo- tent stem cells35 could assess MTX transport, influx and efflux from the CNS including i) IT MTX pharmacokinet- ics and pharmacodynamics in the presence of cyclophos-
phamide and cytarabine and ii) MTX transport in the pres- ence of associated SNP.
In summary, this study supports the continued use of IT MTX in patients with a first episode of MTX neurotoxic- ity. Continued attempts to identify and prospectively val- idate clinical risk factors and germline variants that indi- cate high risk of MTX neurotoxicity may provide an opportunity to prevent this debilitating toxicity in the future.
Disclosures
The authors declare no competing financial interests.
Contributions
MKM developed study materials, collected data, extracted patient DNA samples, wrote the manuscript, analyzed data and helped with interpretation of GWAS results; GMM and TNT wrote the study concept, supervised writing of the manuscript and assisted with interpretation of results; PMB, CG, TR, RSK col- lected data; MCJQ performed the GWAS; CM assisted with statistical analysis; RS, JG, DC helped with extraction of patient DNA samples; RS, DB, FA, FM, LDP assisted data collection processes; JAL assisted with data interpretation; GCT and SM provided assistance with the GWAS. All authors reviewed and approved the final version of the manuscript.
Acknowledgments
The authors would like to thank the Australian and New Zealand Children’s Hematology Oncology Group, ASSET study members, data managers and clinical research associates at each site for their contribution to this project. MKM has recently com- pleted a PhD at the University of New South Wales and this work was submitted in partial fulfillment of the requirement for the PhD. The authors thank the Sydney Children’s Tumor Bank Network for providing samples for this study.
Funding
This work was supported by the Kids Cancer Alliance (a Translational Cancer Research Centre of Cancer Institute NSW), Cancer Institute NSW (ECF 181430, MKM), Royal Australasian College of Physicians - Kids Cancer Project Research Entry Scholarship (MKM), Cancer Therapeutics CRC (CTx) PhD Clinician Researcher Top-Up Scholarship (MKM), Anthony Rothe Memorial Trust (MKM, TNT), JGW Patterson Foundation United Kingdom (MKM), National Health and Medical Research Council of Australia (NHMRC Postgraduate Scholarship APP1056667, PMB; NHMRC Fellowship APP1142627, RSK). The authors thank the Sydney Children’s Tumour Bank Network for providing samples for this study, with support from the Cancer Council NSW, NHMRC Australia and Tour de Cure.
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