Summary 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.
Thromboembolism frequently occurs during acute lymphoblastic leukemia (ALL) therapy. We prospectively registered thromboembolic events during the treatment of 1772 consecutive Nordic/Baltic patients ...with ALL aged 1 to 45 years who were treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol (July 2008-April 2017). The 2.5-year cumulative incidence of thromboembolism (N = 137) was 7.9% (95% confidence interval CI, 6.6-9.1); it was higher in patients aged at least 10 years (P < .0001). Adjusted hazard ratios (HRas) were associated with greater age (range, 10.0-17.9 years: HRa, 4.9 95% CI, 3.1-7.8; P < .0001; 18.0-45.9 years: HRa, 6.06 95% CI, 3.65-10.1; P < .0001) and mediastinal mass at ALL diagnosis (HRa, 2.1; 95% CI, 1.0-4.3; P = .04). In a multiple absolute risk regression model addressing 3 thromboembolism risk factors, age at least 10 years had the largest absolute risk ratio (RRage, 4.7 95% CI, 3.1-7.1; RRenlarged lymph nodes, 2.0 95% CI, 1.2-3.1; RRmediastinal mass, 1.6 95% CI, 1.0-2.6). Patients aged 18.0 to 45.9 years had an increased hazard of pulmonary embolism (HRa, 11.6; 95% CI, 4.02-33.7; P < .0001), and patients aged 10.0 to 17.9 years had an increased hazard of cerebral sinus venous thrombosis (HRa, 3.3; 95% CI, 1.5-7.3; P = .003) compared with children younger than 10.0 years. Asparaginase was truncated in 38/128 patients with thromboembolism, whereas thromboembolism diagnosis was unassociated with increased hazard of relapse (P = .6). Five deaths were attributable to thromboembolism, and patients younger than 18.0 years with thromboembolism had increased hazard of dying compared with same-aged patients without thromboembolism (both P ≤ .01). In conclusion, patients aged at least 10 years could be candidates for preemptive antithrombotic prophylaxis. However, the predictive value of age 10 years or older, enlarged lymph nodes, and mediastinal mass remain to be validated in another cohort.
•Thromboembolism is a frequent treatment-related complication in ALL patients aged 1 to 45 years, with a cumulative incidence of 7.9%.•Patients aged ≥10 years are at highest risk during asparaginase treatment, and may be candidates for preemptive antithrombotic prophylaxis.
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During chemotherapy for childhood acute lymphoblastic leukemia, all organs can be affected by severe acute side effects, the most common being opportunistic infections, mucositis, central or ...peripheral neuropathy (or both), bone toxicities (including osteonecrosis), thromboembolism, sinusoidal obstruction syndrome, endocrinopathies (especially steroid-induced adrenal insufficiency and hyperglycemia), high-dose methotrexate-induced nephrotoxicity, asparaginase-associated hypersensitivity, pancreatitis, and hyperlipidemia. Few of the non-infectious acute toxicities are associated with clinically useful risk factors, and across study groups there has been wide diversity in toxicity definitions, capture strategies, and reporting, thus hampering meaningful comparisons of toxicity incidences for different leukemia protocols. Since treatment of acute lymphoblastic leukemia now yields 5-year overall survival rates above 90%, there is a need for strategies for assessing the burden of toxicities in the overall evaluation of anti-leukemic therapy programs.
Endothelial dysfunction has not previously been investigated as a thrombogenic risk factor among patients with acute lymphoblastic leukemia (ALL), known to be at high risk of thromboembolism. We ...retrospectively explored the association between three circulating biomarkers of endothelial dysfunction (thrombomodulin, syndecan-1, VEGFR-1) measured in prospectively collected blood samples and risk of thromboembolism in 55 cases and 165 time-matched controls, treated according to the NOPHO ALL2008 protocol. In age-, sex-, and risk group-adjusted analysis, increasing levels of thrombomodulin and VEGFR-1 were independently associated with increased odds of developing thromboembolism (OR 1.37 per 1 ng/mL 95% CI 1.20‒1.56, P < 0.0001 and OR 1.21 per 100 pg/mL 95% CI 1.02‒1.21, P = 0.005, respectively). These associations remained significant when including only samples drawn >30 days before thromboembolic diagnosis. Thrombomodulin levels were on average 3.2 ng/mL (95% CI 2.6-8.2 ng/mL) higher in samples with measurable asparaginase activity (P < 0.0001). Among single nucleotide variants located in or neighboring coding genes for the three biomarkers, none were significantly associated with odds of thromboembolism. If results are validated in another cohort, thrombomodulin and VEGFR-1 could serve as predictive biomarkers, identifying patients in need of preemptive antithrombotic prophylaxis.
Objective To assess the incidence rate (IR), changes in IR over time, risk factors, treatment, and outcomes of pediatric noncerebral thromboembolism (TE). Study design The study included all patients ...aged 0 to 18 years diagnosed with first-ever noncerebral venous thromboembolism (VTE) and/or arterial TE in Denmark between 1994 and 2006. Patients were identified in national registries, followed by validation of diagnoses by medical records review. Results We confirmed 331 cases of VTE and 46 cases of arterial TE during 15.8 million person-years of observation, with corresponding IRs of 2.09 and 0.29 per 100 000 person-years. The IR peaked in infancy (age <1 year) for both VTE and arterial TE, with an additional peak among adolescents (age 15 to 18 years) for VTE. Boys predominated in IR of VTE in infancy, whereas girls did so in adolescence ( P < .01). The IRs of VTE and arterial TE remained stable during the study period, but with an trend toward increasing VTE in 2001 to 2006 ( P = .064). Underlying diseases/external triggers were present in 86.6% of the patients, and thrombophilia was present in 47.9% of the VTE cases. All-cause and TE-related 30-day case fatalities were 4.0% and 1.6%, respectively. Conclusions We found age- and sex-related disparities in the IRs of pediatric VTE and arterial TE, but insignificant changes in IR from 1994 to 2006.
Historically, cancer predisposition syndromes (CPSs) were rarely established for children with cancer. This nationwide, population-based study investigated how frequently children with cancer had or ...were likely to have a CPS.
Children (0-17 years) in Denmark with newly diagnosed cancer were invited to participate in whole-genome sequencing of germline DNA. Suspicion of CPS was assessed according to Jongmans'/McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) criteria and familial cancer diagnoses were verified using population-based registries.
198 of 235 (84.3%) eligible patients participated, of whom 94/198 (47.5%) carried pathogenic variants (PVs) in a CPS gene or had clinical features indicating CPS. Twenty-nine of 198 (14.6%) patients harbored a CPS, of whom 21/198 (10.6%) harbored a childhood-onset and 9/198 (4.5%) an adult-onset CPS. In addition, 23/198 (11.6%) patients carried a PV associated with biallelic CPS. Seven of the 54 (12.9%) patients carried two or more variants in different CPS genes. Seventy of 198 (35.4%) patients fulfilled the Jongmans' and/or MIPOGG criteria indicating an underlying CPS, including two of the 9 (22.2%) patients with an adult-onset CPS versus 18 of the 21 (85.7%) patients with a childhood-onset CPS (p = 0.0022), eight of the additional 23 (34.8%) patients with a heterozygous PV associated with biallelic CPS, and 42 patients without PVs. Children with a central nervous system (CNS) tumor had family members with CNS tumors more frequently than patients with other cancers (11/44, p = 0.04), but 42 of 44 (95.5%) cases did not have a PV in a CPS gene.
These results demonstrate the value of systematically screening pediatric cancer patients for CPSs and indicate that a higher proportion of childhood cancers may be linked to predisposing germline variants than previously supposed.
IntroductionMore 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 analysisThis 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 disseminationThe 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.
Inequalities in research and innovations affect childhood cancer survival across Europe. Vilnius University Hospital Santaros Klinikos (VULSK, the coordinator) and eight research-intensive ...institutions from seven European countries implemented the TREL project (Twinning in Research and Education to improve survival in childhood solid tumours in Lithuania) supported by the Horizon 2020 Widening programme. TREL aimed to enhance translational, clinical, and survivorship research in paediatric CNS, neuroblastoma, and renal tumours to improve future treatment outcomes in Lithuania. From January 2021 to December 2023, 49 VULSK professionals and 55 peers from partner institutions collaborated in this twinning program. Achievements after three years were: nine educational events, the initiation of basic and clinical research on fertility preservation, ten VULSK researchers joining international research groups, six signed agreements to participate in international academic clinical trials and the implementation of the European Survivorship Passport. Thirty patients received individual treatment recommendations following multidisciplinary discussions with experts from partner institutions. Twenty-five rare genetic variants were classified by the twinning bioinformatician teams with direct consequences on patient management. In conclusion, coordination of the Horizon 2020 project enhanced VULKS’s research capacities, networking channels and attractiveness for industry and academia-initiated innovative actions that will improve survival rates in the long run.
•Five-year childhood cancer survival rates range from 71 % to 87 % across Europe.•Research gaps resulted in poorer outcomes of paediatric solid tumours in Lithuania.•The EU-funded Twinning project TREL increased research excellence in Lithuania.•Innovations in paediatric solid tumours were launched due to twinning efforts.•Twinning bridged the research and innovation gaps in childhood cancer within the EU.
Cerebral sinovenous thrombosis (CSVT) is a serious complication during asparaginase therapy in patients with acute lymphoblastic leukaemia (ALL). We identified 46 patients with CSVT among 2651 ...patients (1‒45 years) treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between 2008 and 2018. CSVT cases were prospectively registered in the NOPHO database with retrospective updates. We examined the frequency of asparaginase re‐exposure after CSVT, potential factors associated with asparaginase truncation, and sequelae after CSVT. This work was supported by the Danish Cancer Society and the Danish Childhood Cancer Foundation. The 2.5‐year cumulative incidence of CSVT was 1.9% (95% confidence interval 1.4%–2.5%). The majority of patients (74%, n = 31) were re‐exposed to asparaginase (with low‐molecular‐weight heparin coverage), one of whom had a second CSVT, without neurological sequelae. Patients re‐exposed to asparaginase were earlier in ALL treatment and lacked more asparaginase doses than non‐re‐exposed patients at CSVT diagnosis (median 50 vs. 81 days, p = 0.03; mean 11.2 vs. 8.4 asparaginase doses, p = 0.04). No other examined factors had an impact on asparaginase re‐exposure. At the last follow‐up (median 4.5 years after CSVT), 61% of patients had normal neurological status, and 57% had complete recanalisation of CSVT, with no significant difference between patients re‐exposed and non‐re‐exposed to asparaginase. Our results indicate that re‐exposure to asparaginase is safe after CSVT during anticoagulation.
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.
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.
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).
Awareness of PE is warranted during ALL treatment. Larger multicenter studies are needed to examine predictors of PE in ALL.
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