TY - JOUR
T1 - Acute central nervous system toxicity during treatment of pediatric acute lymphoblastic leukemia
T2 - phenotypes, risk factors and genotypes
AU - Anastasopoulou, Stavroula
AU - Nielsen, Rikke Linnemann
AU - Als-Nielsen, Bodil
AU - Banerjee, Joanna
AU - Eriksson, Mats A.
AU - Helenius, Marianne
AU - Heyman, Mats M.
AU - Johannsdottir, Inga Maria
AU - Jonsson, Olafur Gisli
AU - MacGregor, Stuart
AU - Mateos, Marion K.
AU - Mayoh, Chelsea
AU - Mikkel, Sirje
AU - Myrberg, Ida Hed
AU - Niinimäki, Riitta
AU - Schmiegelow, Kjeld
AU - Taskinen, Mervi
AU - Vaitkeviciene, Goda
AU - Warnqvist, Anna
AU - Wolthers, Benjamin
AU - Harila-Saari, Arja
AU - Ranta, Susanna
N1 - Publisher Copyright:
© 2022 Ferrata Storti Foundation Published under a CC BY-NC license.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
U2 - 10.3324/haematol.2021.280016
DO - 10.3324/haematol.2021.280016
M3 - Journal article
C2 - 35354251
AN - SCOPUS:85138584864
VL - 107
SP - 2318
EP - 2328
JO - Haematologica
JF - Haematologica
SN - 0390-6078
IS - 10
ER -