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 language | English |
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Journal | Haematologica |
Volume | 107 |
Issue number | 10 |
Pages (from-to) | 2318-2328 |
ISSN | 0390-6078 |
DOIs | |
Publication status | Published - 2022 |
Keywords
- Pediatric acute lymphoblastic leukemia
- Neurotoxicity
- Epilepsy
- SNP
- GWAS