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 Wolthers,
Arja Harila-Saari,
Susanna Ranta
Affiliations
Stavroula Anastasopoulou
Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm
Rikke Linnemann Nielsen
Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark; Department of Health Technology, Technical University of Denmark, Kgs. Lyngby, Denmark; Present address: Novo Nordisk Research Centre Oxford, Oxford, OX3 7FZ
Bodil Als-Nielsen
Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen
Joanna Banerjee
Division of Pediatric Hematology and Oncology and Stem Cell Transplantation, Helsinki University Hospital and Helsinki University, Helsinki
Mats A. Eriksson
Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden; Neuropediatric Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm
Marianne Helenius
Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark; Department of Health Technology, Technical University of Denmark, Kgs. Lyngby
Mats M. Heyman
Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm
Inga Maria Johannsdottir
Department of Pediatric Hematology/Oncology, Oslo University Hospital, Oslo, Norway
Olafur Gisli Jonsson
Department of Pediatrics, Landspitali University Hospital, Reykjavík, Iceland
Stuart MacGregor
QIMR Berghofer Medical Research Institute, Brisbane
Marion K. Mateos
Kids Cancer Centre, Sydney Children’s Hospital Randwick, Sydney, Australia; School of Clinical Medicine, Discipline of Paediatrics and Child Health, School of Clinical Medicine, UNSW MEDICINE and HEALTH, UNSW Sydney; Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney
Chelsea Mayoh
School of Clinical Medicine, Discipline of Paediatrics and Child Health, School of Clinical Medicine, UNSW MEDICINE and HEALTH, UNSW Sydney; Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney
Sirje Mikkel
Department of Hematology and Oncology, University of Tartu, Tartu
Ida Hed Myrberg
Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Division of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm
Riitta Niinimäki
Department of Children and Adolescents, Oulu University Hospital and University of Oulu, PEDEGO Research Unit, Oulu
Kjeld Schmiegelow
Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark; Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen
Mervi Taskinen
Division of Pediatric Hematology and Oncology and Stem Cell Transplantation, Helsinki University Hospital and Helsinki University, Helsinki
Goda Vaitkeviciene
Children’s Hospital, affiliate of Vilnius University Hospital Santaros Klinikos and Vilnius University, Vilnius
Anna Warnqvist
Division of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm
Benjamin Wolthers
Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen
Arja Harila-Saari
Department of Women’s and Children’s Health, Uppsala University, Uppsala
Susanna Ranta
Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm
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.
