| 1. |
- Anastasopoulou, Stavroula, et al.
(författare)
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Acute central nervous system toxicity during treatment of pediatric acute lymphoblastic leukemia : phenotypes, risk factors and genotypes
- 2020
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Ingår i: Haematologica. - : Ferrata Storti Foundation. - 0390-6078 .- 1592-8721. ; 107:10, s. 2318-2328
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Tidskriftsartikel (refereegranskat)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.
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| 2. |
- Anastasopoulou, Stavroula, et al.
(författare)
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Does minimal central nervous system involvement in childhood acute lymphoblastic leukemia increase the risk for central nervous system toxicity?
- 2022
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Ingår i: Pediatric Blood & Cancer. - : John Wiley & Sons. - 1545-5009 .- 1545-5017. ; 69:7
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Tidskriftsartikel (refereegranskat)abstract
- Central nervous system (CNS) involvement in childhood acute lymphoblastic leukemia (ALL) implicates enhanced intrathecal chemotherapy, which is related to CNS toxicity. Whether CNS involvement alone contributes to CNS toxicity remains unclear. We studied the occurrence of all CNS toxicities, seizures, and posterior reversible encephalopathy syndrome (PRES) in children with ALL without enhanced intrathecal chemotherapy with CNS involvement (n = 64) or without CNS involvement (n = 256) by flow cytometry. CNS involvement increased the risk for all CNS toxicities, seizures, and PRES in univariate analysis and, after adjusting for induction therapy, for seizures (hazard ratio [HR] = 3.33; 95% confidence interval [CI]: 1.26-8.82; p = 0.016) and PRES (HR = 4.85; 95% CI: 1.71-13.75; p = 0.003).
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| 3. |
- Anastasopoulou, Stavroula
(författare)
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Posterior reversible encephalopathy syndrome and other severe central nervous system adverse events in the NOPHO ALL2008 protocol : clinical and radiological findings, genetic risk factors and prognosis
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The advances in the therapeutic protocols for pediatric acute lymphoblastic leukemia (ALL) have led to a current survival rate of more than 90% in developed countries. Treatment periods are, however, long and marked by complications and toxicity that may challenge treatment outcomes and quality of life for patients. Central nervous system (CNS) toxicity is common during pediatric ALL treatment and may implicate treatment postponement as well as long-term adverse effects. The aim of this thesis was to map CNS toxicities in pediatric ALL in patients treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. Methods: Patients aged 1 to 17.9 years at diagnosis of B-cell-precursor and T-cell ALL who were treated according to the NOPHO ALL2008 protocol between 2008 and 2015 were included. Detailed data on CNS toxicity were collected from the NOPHO ALL2008 registry with seven participating countries and a complementary questionnaire addressing phenotypical and work-up details. Genome-wide association studies (GWAS) and candidate single nucleotide polymorphism (SNP) analyses were performed. A validation study of significant findings from GWAS and candidate SNP analyses was made in an independent Australian cohort of pediatric ALL patients (n=797) including patients with diverse CNS toxicities (n=103) and methotrexate-related CNS-toxicity (n=48). The role of minimal CNS leukemia in CNS toxicity risk was further examined by detecting leukemic blasts in cerebrospinal fluid (CSF) by flow cytometric immunophenotyping (FCI) in addition to cytomorphological analysis (CM), which is the CSF examination method specified in the NOPHO ALL2008 protocol. Results: 1464 patients were included in the study of whom 52 (3.8%) had posterior reversible encephalopathy syndrome (PRES), and 135 (9.2%) had at least one form of CNS toxicity. Overall, 82/135 patients had at least one seizure episode (60.7%). PRES was the most common form of CNS toxicity in this cohort (38.5%). Older age, defined as each extra year of age and/or as patient group >10 years of age was a significant risk factor for PRES, seizures, and all CNS toxicities. T-cell immunophenotype was significant risk factor for PRES in univariate analysis and after adjustment for age. Leukemic blasts in CSF by CM were significantly related to PRES during induction and high-risk block treatment was related to PRES after induction. Minimal CNS leukemia, detected by FCI, was a significant risk factor for PRES, seizures, and all CNS toxicities in patients without CNS leukemia by CM in univariate analyses and for PRES and seizures after adjusting for induction therapy. Genome-wide association studies did not demonstrate any significant associations with CNS toxicities, but candidate SNP analyses showed that the ATXN1rs68082256 SNP, related to epilepsy, was associated with seizures in patients <10 years. ATXN1rs68082256 was replicated in the Australian cohort in the patient group with diverse CNS toxicities. At the last follow-up, 11.7% of survivors (12/103) who had displayed CNS toxicity were reported to have had an epilepsy diagnosis. Clinical suspicion of neurocognitive impairment was reported for 10.9% of survivors (12/110) with CNS toxicity at their last follow-up, but neuropsychiatric testing was performed in only two cases. Conclusion: Central nervous system toxicity was common during pediatric ALL treatment and PRES was the most common form of CNS toxicity in this cohort. Older patients had a greater risk of CNS toxicity as well as patients with minimal CNS leukemia. The role of ATXN1rs68082256 SNP in CNS toxicity warrants further studies. Epilepsy is rather common in ALL survivors, while the neurocognitive outcome warrants more systematic follow-up.
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| 4. |
- Anastasopoulou, Stavroula, et al.
(författare)
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Posterior reversible encephalopathy syndrome in children with acute lymphoblastic leukemia : Clinical characteristics, risk factors, course, and outcome of disease
- 2019
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Ingår i: Pediatric Blood & Cancer. - : WILEY. - 1545-5009 .- 1545-5017. ; 66:5
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Tidskriftsartikel (refereegranskat)abstract
- Background: Posterior reversible encephalopathy syndrome (PRES) is a distinct entity with incompletely known predisposing factors. The aim of this study is to describe the incidence, risk factors, clinical course, and outcome of PRES in childhood acute lymphoblastic leukemia (ALL).Procedure: Patients aged 1.0 to 17.9 years diagnosed with ALL from July 2008 to December 2015 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol were included. Patients with PRES were identified in the prospective NOPHO leukemia toxicity registry, and clinical data were collected from the medical records.Results: The study group included 1378 patients, of whom 52 met the criteria for PRES. The cumulative incidence of PRES at one month was 1.7% (95% CI, 1.1-2.5) and at one year 3.7% (95% CI, 2.9-4.9). Older age (hazard ratios [HR] for each one-year increase in age 1.1; 95% CI, 1.0-1.2, P = 0.001) and T-cell immunophenotype (HR, 2.9; 95% CI, 1.6-5.3, P = 0.0005) were associated with PRES. Central nervous system (CNS) involvement (odds ratios [OR] = 2.8; 95% CI, 1.2-6.5, P = 0.015) was associated with early PRES and high-risk block treatment (HR = 2.63; 95% CI, 1.1-6.4, P = 0.033) with late PRES. At follow-up of the PRES patients, seven patients had epilepsy and seven had neurocognitive difficulties.Conclusion: PRES is a neurotoxicity in the treatment of childhood ALL with both acute and long-term morbidity. Older age, T-cell leukemia, CNS involvement and high-risk block treatment are risk factors for PRES.
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| 5. |
- Anastasopoulou, Stavroula, et al.
(författare)
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Seizures during treatment of childhood acute lymphoblastic leukemia : A population-based cohort study
- 2020
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Ingår i: European journal of paediatric neurology. - : ELSEVIER SCI LTD. - 1090-3798 .- 1532-2130. ; 27, s. 72-77
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Tidskriftsartikel (refereegranskat)abstract
- Background: Seizures are common in children with acute lymphoblastic leukemia (ALL). As ALL survival rates are improving, the challenge to minimize treatment related side effects and late sequelae rises. Here, we studied the frequency, timing, etiology and risk factors of seizures in ALL patients. Methods: The study included children aged 1-17.9 years at diagnosis of B-cell-precursor and T cell ALL who were treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol between 2008 and 2015. Detailed patient data were acquired from the NOPHO ALL2008 registry and by review of medical records. Results: Seizures occurred in 81/1464 (5.5%) patients. The cumulative incidence of seizures at one months was 1.7% (95% CI: 1.2-2.5) and at one year 5.3% (95% CI 4.2-6.5%). Patients aged 10-17.9 years, those with T cell immunophenotype, CNS involvement, or high-risk induction with dexamethasone had higher risk for seizures in univariable analyses. Only age remained a risk factor in multivariable analyses (the cumulative incidence of seizures for patients 10-17.9 years old at one year was 9.0% (95% CI: 6.2-12.9)). Of the 81 patients with seizures, 43 had posterior reversible encephalopathy syndrome (PRES), 15 had isolated seizures, nine had sinus venous thrombosis (SVT), three had stroke-like syndrome, and 11 had other neurotoxicities. Epilepsy diagnosis was reported in totally 11 ALL survivors at last follow up. Conclusion: Seizures are relatively common in ALL patients and occur most often in patients with PRES, SVT, or as an isolated symptom. Older children have higher risk of seizures. (C) 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
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