Pulmonary embolism in acute lymphoblastic leukemia - An observational study of 1685 patients treated according to the NOPHO ALL2008 protocol

Background Pulmonary embolism (PE) is a serious complication of acute lymphoblastic leukemia (ALL). We examined the cumulative incidence and clinical presentation of PE in a well-defined cohort of patients with ALL aged 1-45 years treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. Methods As part of the mandatory toxicity reporting of NOPHO ALL2008, thromboembolism including PE was reported consecutively. The cumulative incidence of first-time PE was calculated using the Aalen-Johansen estimator during a 2.5-year period from ALL diagnosis. We used Fisher's exact test to examine categorical variables and Cox logistic regression to estimate hazard ratios (HRs) for PE. Results PE was diagnosed in 32 of 1685 patients. The 2.5-year cumulative incidence of first-time PE increased with age: 0.43% (95% CI, 0.18-1.03) in children aged 1-9 years, 3.28% (95% CI, 1.72-6.22) in children aged 10-17 years, and 7.22% (95% CI, 4.61-11.21) in adults aged 18-45 years. The majority of PEs, 78% (25/32), occurred during asparaginase treatment. HRs adjusted for age and sex were associated with male sex (HR, 2.4; 95% CI, 1.0-5.6) and older age (10-17 years: HR 7.5; 95% CI, 2.5-22.2), 18-45 years: HR, 16.5; 95% CI, 6.1-44.5). In two-thirds of the patients (63%; 17/27), PE and its treatment had no impact on the administered doses of asparaginase. PE-associated 30-day mortality was 9.4% (95% CI, 1.9-25.0). Conclusions Awareness of PE is warranted during ALL treatment. Larger multicenter studies are needed to examine predictors of PE in ALL.Peer reviewe

Asymptomatic Right Atrial Thrombosis After Acute Lymphoblastic Leukemia Treatment

Right atrial thrombosis is a rare, but potentially serious complication of acute lymphoblastic leukemia treatment. We conducted a retrospective multicenter study to assess the incidence, treatment, and outcome of asymptomatic right atrial thrombosis detected at routine echocardiography of children after acute lymphoblastic leukemia treatment in the Nordic and Baltic countries. Eleven (2.7%, 95% confidence interval, 1.4-4.9) of 406 patients had asymptomatic right atrial thrombosis, ranging from 10 to 25 mm at detection. Three patients were treated with anticoagulation. None of the thromboses affected cardiac function, and they showed neither sign of progress nor spontaneous or treatment-related regress at follow-up.Peer reviewe

Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus

Although there are high survival rates for children with acute lymphoblastic leukaemia, their outcome is often counterbalanced by the burden of toxic effects. This is because reported frequencies vary widely across studies, partly because of diverse definitions of toxic effects. Using the Delphi method, 15 international childhood acute lymphoblastic leukaemia study groups assessed acute lymphoblastic leukaemia protocols to address toxic effects that were to be considered by the Ponte di Legno working group. 14 acute toxic effects (hypersensitivity to asparaginase, hyperlipidaemia, osteonecrosis, asparaginase-associated pancreatitis, arterial hypertension, posterior reversible encephalopathy syndrome, seizures, depressed level of consciousness, methotrexate-related stroke-like syndrome, peripheral neuropathy, high-dose methotrexate-related nephrotoxicity, sinusoidal obstructive syndrome, thromboembolism, and Pneumocystis jirovecii pneumonia) that are serious but too rare to be addressed comprehensively within any single group, or are deemed to need consensus definitions for reliable incidence comparisons, were selected for assessment. Our results showed that none of the protocols addressed all 14 toxic effects, that no two protocols shared identical definitions of all toxic effects, and that no toxic effect definition was shared by all protocols. Using the Delphi method over three face-to-face plenary meetings, consensus definitions were obtained for all 14 toxic effects. In the overall assessment of outcome of acute lymphoblastic leukaemia treatment, these expert opinion-based definitions will allow reliable comparisons of frequencies and severities of acute toxic effects across treatment protocols, and facilitate international research on cause, guidelines for treatment adaptation, preventive strategies, and development of consensus algorithms for reporting on acute lymphoblastic leukaemia treatment

Candidate single nucleotide polymorphisms and thromboembolism in acute lymphoblastic leukemia - A NOPHO ALL2008 study

Introduction: Thromboembolism is a serious toxicity of acute lymphoblastic leukemia treatment, and contributes to substantial morbidity and mortality. Several single nucleotide polymorphisms have been associated with thromboembolism in the general population; however, their impact in patients with acute lymphoblastic leukemia, particularly in children, remains uncertain. Materials and methods: We collected constitutional DNA and prospectively registered thromboembolic events in 1252 patients, 1-45 years, with acute lymphoblastic leukemia included in the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol in the Nordic and Baltic countries (7/2008-7/2016). Based on previously published data and a priori power calculations, we selected four single nucleotide polymorphisms: F5 rs6025, F11 rs2036914, FGG rs2066865, and ABO rs8176719. Results: The 2.5 year cumulative incidence of thromboembolism was 7.1% (95% confidence interval (CI) 5.6-8.5). F11 rs2036914 was associated with thromboembolism (hazard ratio (HR) 1.52, 95%CI 1.11-2.07) and there was a borderline significant association for FGG rs2066865 (HR 1.37, 95%CI 0.99-1.91), but no association for ABO rs8176719 or F5 rs6025 in multiple cox regression. A genetic risk score based on F11 rs2036914 and FGG rs2066865 was associated with thromboembolism (HR 1.45 per risk allele, 95%CI 1.15-1.81), the association was strongest in adolescents 10.0-17.9 years (HR 1.64). Conclusion: If validated, a F11 rs2036914/FGG rs2066865 risk prediction model should be tested as a stratification tool for prevention of thromboembolism in patients with acute lymphoblastic leukemia.Peer reviewe

National, clinical cohort study of late effects among survivors of acute lymphoblastic leukaemia:The ALL-STAR study protocol

Introduction More than 90% of patients diagnosed with childhood acute lymphoblastic leukaemia (ALL) today will survive. However, half of the survivors are expected to experience therapy-related chronic or late occurring adverse effects, reducing quality of life. Insight into underlying risk trajectories is warranted. The aim of this study is to establish a Nordic, national childhood ALL survivor cohort, to be investigated for the total somatic and psychosocial treatment-related burden as well as associated risk factors, allowing subsequent linkage to nation-wide public health registers.Methods and analysis This population-based observational cohort study includes clinical follow-up of a retrospective childhood ALL survivor cohort (n=475), treated according to a common Nordic ALL protocol during 2008–2018 in Denmark. The study includes matched controls. Primary endpoints are the cumulative incidence and cumulative burden of 197 health conditions, assessed through self-report and proxy-report questionnaires, medical chart validation, and clinical examinations. Secondary endpoints include organ-specific outcome, including cardiovascular and pulmonary function, physical performance, neuropathy, metabolic disturbances, hepatic and pancreatic function, bone health, oral and dental health, kidney function, puberty and fertility, fatigue, and psychosocial outcome. Therapy exposure, acute toxicities, and host genome variants are explored as risk factors.Ethics and dissemination The study is approved by the Regional Ethics Committee for the Capital Region in Denmark (H-18035090/H-20006359) and by the Danish Data Protection Agency (VD-2018–519). Results will be published in peer-reviewed journals and are expected to guide interventions that will ameliorate the burden of therapy without compromising the chance of cure

Genome-Wide Association Meta-Analysis of Single-Nucleotide Polymorphisms and Symptomatic Venous Thromboembolism during Therapy for Acute Lymphoblastic Leukemia and Lymphoma in Caucasian Children

Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied. Methods: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included. Results: No SNPs reached genome-wide significance (p <5 x 10(-8)) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p <1 x 10(-6)), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 x 10(-7)) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 x 10(-7)) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease. Conclusion: This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.Peer reviewe

Predictive value of pediatric thrombosis diagnoses in the Danish National Patient Registry

Ruta Tuckuviene1, Soeren Risom Kristensen1, Jon Helgestad2, Anette Luther Christensen1, Soeren Paaske Johnsen31Department of Clinical Biochemistry, Center for Cardiovascular Research, 2Department of Pediatrics, 3Department of Clinical Epidemiology, Aarhus University Hospital, Aalborg and Aarhus, DenmarkAbstract: Data on the validity of pediatric thrombosis diagnoses are missing. We aimed to examine the predictive value of a diagnosis of venous and arterial thrombosis using the Danish National Patient Registry (DNPR). We identified all first-time diagnoses among children and adolescents (aged 0&amp;ndash;18 years) between 1994 and 2006 in DNPR. In total, 1138 potential cases of thrombosis were identified; the medical records were retrieved for 1112 (97.7%) and the positive predictive value (PPV) computed. Overall, the diagnosis of thrombosis was verified in 598 of the 1112 cases, corresponding to a PPV of 53.7% (95% confidence interval [CI]: 50.8&amp;ndash;56.7). Diagnoses from wards had the PPV of 62.5% (95% CI: 59.4&amp;ndash;65.6). The predictive value of a thrombosis diagnosis from wards was age-dependent, with a higher PPV (77.4%, 95% CI: 68.7&amp;ndash;84.7) in neonates (&amp;lt;28 days) and adolescents (15&amp;ndash;18 years) (68.2%; 95% CI: 63.2&amp;ndash;72.5)) than in children (28 days&amp;ndash;14 years) (51.2%; (95% CI: 46.0&amp;ndash;56.4)). The PPV of a thrombosis diagnosis was improved by restricting the analysis to diagnoses from wards, primary diagnoses, and admissions with a length of stay of three or more days. The results indicate that an interpretation of nonvalidated hospital discharge data for pediatric thrombosis in a registry like DNPR should be made with caution.Keywords: pediatric thrombosis, discharge diagnosis, registry, positive predictive valu