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

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.

Characteristics of white blood cell count in acute lymphoblastic leukemia: A COST LEGEND phenotype-genotype study.

BACKGROUND: White blood cell count (WBC) as a measure of extramedullary leukemic cell survival is a well-known prognostic factor in acute lymphoblastic leukemia (ALL), but its biology, including impact of host genome variants, is poorly understood. METHODS: We included patients treated with the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-2008 protocol (N = 2347, 72% were genotyped by Illumina Omni2.5exome-8-Bead chip) aged 1-45 years, diagnosed with B-cell precursor (BCP-) or T-cell ALL (T-ALL) to investigate the variation in WBC. Spline functions of WBC were fitted correcting for association with age across ALL subgroups of immunophenotypes and karyotypes. The residuals between spline WBC and actual WBC were used to identify WBC-associated germline genetic variants in a genome-wide association study (GWAS) while adjusting for age and ALL subtype associations. RESULTS: We observed an overall inverse correlation between age and WBC, which was stronger for the selected patient subgroups of immunophenotype and karyotypes (ρBCP-ALL  = -.17, ρT-ALL  = -.19; p < 3 × 10-4 ). Spline functions fitted to age, immunophenotype, and karyotype explained WBC variation better than age alone (ρ = .43, p << 2 × 10-6 ). However, when the spline-adjusted WBC residuals were used as phenotype, no GWAS significant associations were found. Based on available annotation, the top 50 genetic variants suggested effects on signal transduction, translation initiation, cell development, and proliferation. CONCLUSION: These results indicate that host genome variants do not strongly influence WBC across ALL subsets, and future studies of why some patients are more prone to hyperleukocytosis should be performed within specific ALL subsets that apply more complex analyses to capture potential germline variant interactions and impact on WBC.

Seizures during treatment of childhood acute lymphoblastic leukemia: A population-based cohort study.

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.

Childhood cancer incidence and survival trends in Estonia (1970-2016): a nationwide population-based study.

BACKGROUND: Childhood cancers represent a small proportion of all cancers but are still a major public health problem. The study analysed long-term trends in childhood cancer incidence and survival in Estonia in relation to societal and health care transition. METHODS: Data on all malignant tumours, diagnosed in children aged 0-14 during 1970-2016, were derived from the Estonian Cancer Registry. Age-standardised (World standard) incidence rates were calculated by ICCC-3 site groups and joinpoint regression was used to estimate annual percentage change (APC) for incidence trends. Cohort and period approach were used to estimate 5-year survival. Internal age standardisation was applied. RESULTS: A total of 1628 incident cancer cases were diagnosed during the study period and overall incidence increased significantly at a rate of 0.5% per year. Significant increases were seen for neuroblastoma and germ cell tumours, for lymphoid leukemias and some CNS sub-sites. At the same time, decline in incidence was seen in almost all subgroups of unspecified neoplasms. The overall 5-year survival improved from 24% in 1970-1979 to 73% in 2010-2016, with the largest changes occurring in the 1990s and 2000s. For many sites, survival increase thereafter has been marginal. CONCLUSION: In this first comprehensive population-based study of childhood cancer incidence and survival in Estonia, long-term trends are shown in the context of societal and health care changes. Even though the increasing incidence of some sites may, at least partially, be explained by improved diagnostics reflected in the decreased incidence of unspecified neoplasms, the overall cancer incidence in children seems to be rising. Rapid progress in diagnosis and care have improved childhood cancer survival immensely, but deficit in Estonia persists compared to other European countries. Results of the study accentuate the need for a more in-depth analysis of clinical data, but also for the prioritization of childhood cancer in Estonia, to ensure access to standard care and innovative treatments.

Usability, Acceptability, Feasibility, and Effectiveness of a Gamified Mobile Health Intervention (Triumf) for Pediatric Patients: Qualitative Study.

BACKGROUND: Mental disorders are notably prevalent in children with chronic illnesses, whereas a lack of access to psychological support might lead to potential mental health problems or disruptions in treatment. Digitally delivered psychological interventions have shown promising results as a supportive treatment measure for improving health outcomes during chronic illness. OBJECTIVE: This study aimed to evaluate the usability, acceptability, and feasibility of providing psychological and treatment support in a clinical setting via a mobile game environment. In addition, the study aimed to evaluate the preliminary effectiveness of the mobile health game. METHODS: Patients aged 7 to 14 years with less than a year from their diagnosis were eligible to participate in the study. In total, 15 patients were invited to participate by their doctor. A total of 9 patients (age range: 7-12 years; mean age 9.1 years) completed the 60-day-long study in which the Triumf mobile health game was delivered as a digital intervention. In an engaging game environment, patients were offered psychological and treatment support, cognitive challenges, and disease-specific information. The fully digital intervention was followed by a qualitative interview conducted by a trained psychologist. The results of the interview were analyzed in conjunction with patient specific in-game qualitative data. Ethical approval was obtained to conduct the study. RESULTS: Patients positively perceived the game, resulting in high usability and acceptability evaluations. Participants unanimously described the game as easy to use and engaging in terms of gamified activities, while also providing beneficial and trustworthy information. Furthermore, the overall positive evaluation was emphasized by an observed tendency to carry on gaming post study culmination (67%, 10/15). Psychological support and mini games were the most often used components of the game, simultaneously the participants also highlighted the education module as one of the most preferred. On average, the patients sought and received psychological support or education on 66.6 occasions during the 60-day intervention. Participants spent the most time collecting items from the city environment (on average 15.6 days, SD 8.1), indicative of exploratory behavior, based on the quantitative in-game collected data. During the intervention period, we observed a statistically significant decrease in general health problems (P=.003) and saw a trend toward a decrease in depression and anxiety symptoms. CONCLUSIONS: This study demonstrated that a game environment could be a promising medium for delivering comprehensive supportive care to pediatric patients with cancer alongside standard treatment, with potential application across a variety of chronic conditions. Importantly, the results indicate that the study protocol was feasible with modifications to randomized controlled trials, and the game could be considered applicable in a clinical context. By giving an empirical evaluation of delivering psychological support via the game environment, our work stands to inform future mobile health interventions.

Posterior reversible encephalopathy syndrome in children with acute lymphoblastic leukemia: Clinical characteristics, risk factors, course, and outcome of disease.

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.

The impact of under-reporting of cases on the estimates of childhood cancer incidence and survival in Estonia.

About 35 new childhood cancer cases are diagnosed in Estonia (population 1.3 million in 2011) every year. Despite continuous improvements in the healthcare system and available cancer treatment options, the survival rates for childhood cancers have appeared to remain lower than the European average. These observations and the accompanying decrease in incidence led us to hypothesize that some nonfatal cases might be missing from the Estonian Cancer Registry (ECR). The aim of this study was to evaluate the completeness of reporting of childhood cancer cases to the ECR and its impact on the estimates of cancer incidence and survival. All cases of benign and malignant tumours, diagnosed in 2000-2011 among children aged 0-17 years and eligible for registration in the ECR, were included in the study. Completeness of reporting was evaluated for cases aged 0-17 years, and incidence and survival were analysed for cases aged 0-14 for international comparisons. The total number of new cancer cases increased from 459 to 515. Overall completeness of case ascertainment was estimated to be 89.5%. After adding the missing cases, the overall incidence rate increased from 12.9 to 14.9/100 000 (from 3.4 to 4.7 for leukaemias). The 2010-2014 period estimate of the 5-year survival increased from 70 to 76% for all sites combined and from 71 to 82% for leukaemias. In conclusion, the under-reporting of nonfatal childhood cancer cases to the ECR had an important impact on incidence and survival rates, causing a considerable underestimation of both.