Acute central nervous system toxicity during treatment of pediatric acute lymphoblastic leukemia: phenotypes, risk factors and genotypes

Stavroula Anastasopoulou*, Rikke Linnemann Nielsen, Bodil Als-Nielsen, Joanna Banerjee, Mats A. Eriksson, Marianne Helenius, Mats M. Heyman, Inga Maria Johannsdottir, Olafur Gisli Jonsson, Stuart MacGregor, Marion K. Mateos, Chelsea Mayoh, Sirje Mikkel, Ida Hed Myrberg, Riitta Niinimäki, Kjeld Schmiegelow, Mervi Taskinen, Goda Vaitkeviciene, Anna Warnqvist, Benjamin WolthersArja Harila-Saari, Susanna Ranta

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Central nervous system (CNS) toxicity is common at diagnosis and during treatment of pediatric acute lymphoblastic leukemia (ALL). We studied CNS toxicity in 1 464 children aged 1.0-17.9 years, diagnosed with ALL and treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol. Genome-wide association studies (GWAS), and a candidate single-nucleotide polymorphism (SNP; n=19) study were performed in 1 166 patients. Findings were validated in an Australian independent cohort of children with ALL (n=797) where two phenotypes were evaluated: diverse CNS toxicities (n=103) and methotrexate-related CNS toxicity (n=48). In total, 135/1 464 (9.2%) patients experienced CNS toxicity with cumulative incidence of 8.7% (95% CI: 7.31-10.20) at 12 months from diagnosis. Patients aged ≥10 years had higher risk of CNS toxicity than younger patients (16.3% vs 7.4%; p <0.001). The most common CNS toxicities were posterior reversible encephalopathy syndrome (n=52, 43 with seizures), sinus venous thrombosis (n=28, 9 with seizures), and isolated seizures (n=16). The most significant SNPs identified by GWAS did not reach genomic significance (lowest P-value: 1.11e-06), but several were annotated in genes regulating neuronal functions. In candidate SNP analysis, ATXN1 rs68082256, related to epilepsy, was associated with seizures in patients <10 years (P=0.01). ATXN1 rs68082256 was validated in the Australian diverse CNS toxicities cohort (P=0.04). The role of ATXN1 as well as the novel SNPs in neurotoxicity in pediatric ALL should be further explored.
Original languageEnglish
JournalHaematologica
ISSN0390-6078
DOIs
Publication statusAccepted/In press - 2022

Keywords

  • Pediatric acute lymphoblastic leukemia
  • Neurotoxicity
  • Epilepsy
  • SNP
  • GWAS

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