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

被引:7
作者
Anastasopoulou, Stavroula [1 ,2 ]
Nielsen, Rikke Linnemann [3 ,4 ,19 ]
Als-Nielsen, Bodil [3 ]
Banerjee, Joanna [5 ]
Eriksson, Mats A. [1 ]
Helenius, Marianne [3 ,4 ]
Heyman, Mats M. [1 ,2 ,6 ]
Johannsdottir, Inga Maria [7 ]
Jonsson, Olafur Gisli [8 ]
MacGregor, Stuart [9 ]
Mateos, Marion K. [10 ,11 ,12 ]
Mayoh, Chelsea [11 ,12 ]
Mikkel, Sirje [13 ]
Myrberg, Ida Hed [2 ,14 ]
Niinimaeki, Riitta [15 ]
Schmiegelow, Kjeld [3 ,16 ]
Taskinen, Mervi [5 ]
Vaitkeviciene, Goda [17 ]
Warnqvist, Anna [14 ]
Wolthers, Benjamin [3 ]
Harila-Saari, Arja [18 ]
Ranta, Susanna [1 ,2 ]
机构
[1] Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Stockholm, Sweden
[2] Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Stockholm, Sweden
[3] Univ Hosp, Dept Pediat & Adolescent Med, Rigshosp, Copenhagen, Denmark
[4] Tech Univ Denmark, Dept Hlth Technol, Lyngby, Denmark
[5] Univ Helsinki, Helsinki Univ Hosp, Div Pediat Hematol & Oncol & Stem Cell Transplanta, Helsinki, Finland
[6] Karolinska Inst, Dept Womens & Childrens Hlth, Neuropediat Unit, Stockholm, Sweden
[7] Oslo Univ Hosp, Dept Pediat Hematol Oncol, Oslo, Norway
[8] Landspitali Univ Hosp, Dept Pediat, Reykjavik, Iceland
[9] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia
[10] Sydney Childrens Hosp Randwick, Kids Canc Ctr, Sydney, NSW, Australia
[11] Univ New South Wales, Sch Clin Med, Discipline Paediat & Child Hlth, Sydney, NSW, Australia
[12] Univ New South Wales, Childrens Canc Inst, Lowy Canc Res Ctr, Sydney, NSW, Australia
[13] Univ Tartu, Dept Hematol & Oncol, Tartu, Estonia
[14] Karolinska Inst, Inst Environm Med, Div Biostat, Stockholm, Sweden
[15] Univ Oulu, Oulu Univ Hosp, Dept Children & Adolescents, PEDEGO Res Unit, Oulu, Finland
[16] Univ Copenhagen, Inst Clin Med, Fac Med, Copenhagen, Denmark
[17] Vilnius Univ, Vilnius Univ Hosp Santaros Klin, Childrens Hosp, Vilnius, Lithuania
[18] Uppsala Univ, Dept Womens & Childrens Hlth, Uppsala, Sweden
[19] Novo Nordisk Res Ctr Oxford, Oxford, Oxfordshire, England
关键词
REVERSIBLE ENCEPHALOPATHY SYNDROME; ACUTE NEUROTOXICITY; CHILDREN; COMPLICATIONS; SEIZURES; CHEMOTHERAPY; METHOTREXATE; ADULTS;
D O I
10.3324/haematol.2021.280016
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:2318 / 2328
页数:11
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