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

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, and a candidate single-nucleotide polymorphism (SNP; n=19) study were performed in 1,166 patients. Findings were validated in an independent Australian cohort of children with ALL (n=797) in whom 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 for a cumulative incidence of 8.7% (95% confidence interval: 7.31-10.20) at 12 months from diagnosis. Patients aged ≥10 years had a higher risk of CNS toxicity than had 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 SNP identified by the genome-wide association studies did not reach genomic significance (lowest P-value: 1.11x10-6), 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 cohort with diverse CNS toxicities (P=0.04). The role of ATXN1 as well as the novel SNP in neurotoxicity in pediatric ALL should be further explored.

OriginalsprogEngelsk
TidsskriftHaematologica
Vol/bind107
Udgave nummer10
Sider (fra-til)2318-2328
Antal sider11
ISSN0390-6078
DOI
StatusUdgivet - 1 okt. 2022

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