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The dynamic growth of the skeleton during childhood and adolescence renders it vulnerable to adverse effects of cancer treatment. The lifetime risk and patterns of skeletal morbidity have not been described in a population-based cohort of childhood cancer survivors. A cohort of 26,334 one-year cancer survivors diagnosed before 20 years of age was identified from the national cancer registries of Denmark, Finland, Iceland and Sweden as well as a cohort of 127,531 age- and sex-matched comparison subjects randomly selected from the national population registries in each country. The two cohorts were linked with data from the national hospital registries and the observed numbers of first-time hospital admissions for adverse skeletal outcomes among childhood cancer survivors were compared with the expected numbers derived from the comparison cohort. In total, 1,987 childhood cancer survivors had at least one hospital admission with a skeletal adverse event as discharge diagnosis, yielding a rate ratio (RR) of 1.35 (95% CI, 1.29-1.42). Among the survivors, we observed an increased risk for osteonecrosis with a RR of 25.9 (15.0-44.5), osteoporosis, RR 4.53 (3.28-6.27), fractures, RR 1.27 (1.20-1.34), osteochondropathies, RR 1.57 (1.28-1.92) and osteoarthrosis, RR 1.48 (1.28-1.72). The hospitalization risk for any skeletal adverse event was higher among survivors up to the age of 60 years, but the lifetime pattern was different for each type of skeletal adverse event. Understanding the different lifetime patterns and identification of high-risk groups is crucial for developing strategies to optimize skeletal health in childhood cancer survivors. This article is protected by copyright. All rights reserved.

Purpose Low doses of folinic acid (FA) rescue after high-dose methotrexate (HD-MTX) have been associated with increased toxicity, whereas high doses may be related to a decreased antileukemic effect. The optimal dosage and duration of FA rescue remain controversial. This study was designed to investigate, whether a shorter duration of FA rescue in the setting of rapid HD-MTX clearance is associated with increased toxicity. Methods We reviewed the files of 44 children receiving a total of 350 HD-MTX courses during treatment for acute lymphoblastic leukemia according to the NOPHO ALL-2000 protocol. Following a 5 g/m2 HD-MTX infusion, pharmacokinetically guided FA rescue commenced at hour 42. As per local guidelines, the patients received only one or two 15 mg/m2 doses of FA in the case of rapid MTX clearance (serum MTX ≤ 0.2 μmol/L at hour 42 or hour 48, respectively). Data on MTX clearance, FA dosing, inpatient time, and toxicities were collected. Results Rapid MTX clearance was observed in 181 courses (51.7%). There was no difference in the steady-state MTX concentration, nephrotoxicity, hepatotoxicity, neutropenic fever, or neurotoxicity between courses followed by rapid MTX clearance and those without. One or two doses of FA after rapid MTX clearance resulted in a 7.8-h shorter inpatient time than if a minimum of three doses of FA would have been given. Conclusion A pharmacokinetically guided FA rescue of one or two 15 mg/m2 doses of FA following HD-MTX courses with rapid MTX clearance results in a shorter hospitalization without an increase in toxic effects.

Osteonecrosis is a burdensome treatment-related toxicity that is mostly diagnosed during or soon after 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy for acute lymphoblastic leukemia (ALL), possibly indicating a pathogenic role of these drugs. We prospectively registered symptomatic osteonecrosis during treatment of 1234 patients aged 1.0–45.9 years treated according to the Nordic Society of Hematology and Oncology (NOPHO) ALL2008 protocol. MTX/6MP metabolites were measured as part of the NOPHO ALL2008 maintenance therapy study. After a median follow-up of 5.6 years [interquartile range (IQR) 3.6–7.5], 68 patients had been diagnosed with symptomatic osteonecrosis. The cumulative incidence was 2.7% [95% confidence interval (CI) 1.6–3.8%] for patients aged 0.99), methylated 6MP metabolites (p = 0.37), MTX polyglutamates (p = 0.98) nor DNA-TG (p = 0.53) were significantly associated with the hazard of osteonecrosis in Cox models stratified by the three age groups and adjusted for sex. Maintenance therapy intensity determined by 6MP and MTX metabolites was not associated with the risk of developing osteonecrosis in the NOPHO ALL2008 cohort.

Purpose This study aimed to explore educational outcomes in individuals diagnosed with lymphoma in childhood concerning school grade year 9 and attendance in high school and post-compulsory education. Whether sex or age at diagnosis affected the assessed variables was also explored. Methods Data from 174 children born 1988–1996 and diagnosed with lymphoma before age 15 were matched with approximately five controls per patient. The mean time since diagnosis to receiving school year 9 grades was 4.88 years for Hodgkin lymphoma (HL) cases (mean age at diagnosis 10.62, 11.76, and 10.05 years for all, girls, and boys, respectively) and 7.79 years for non-Hodgkin lymphoma (NHL) cases (mean age at diagnosis 7.85, 7.87, and 7.84 years for all, girls, and boys, respectively). Results We observed statistically significant differences between cases and controls in physical education, both for failing (p = 0.041) and the highest grade (p = 0.015). Compared with controls, HL cases were three times more likely to fail mathematics, and significantly fewer individuals in the whole lymphoma (p = 0.011) and NHL (p = 0.035) groups attended the third year of high school. Conclusions Educational outcomes are impacted for children treated for lymphoma, especially in physical education. Since patients with HL are treated without central nervous system-directed therapy, other factors, such as absence from school, may affect school results. Physical late complications in lymphoma survivors warrant special attention. Implications for Cancer Survivors The problems childhood lymphoma survivors face should be known by schools and parents, to enable their management. Children treated for lymphoma should be closely monitored and included in follow-up programs when needed, for example, to support physical activity.

Purpose Survivors of childhood brain tumors (BT) are at high risk for long-term physical and psychological sequelae. Still, knowledge about health-related quality of life (HRQL) and associated factors in this population is sparse. This study investigated HRQL and its predictors in long-term survivors of childhood BT. Methods Survivors of childhood BT (mean age = 28.1 years, SD = 6.8, n = 60) underwent clinical examination and neurocognitive examination, and completed self-rating questionnaires assessing HRQL (RAND-36) and depressive symptoms (Beck Depression Inventory-II). Socio-demographic information was gathered via a questionnaire. Tumor- and treatment-related information was collected from medical records. Control group data were collected from age-matched controls (n = 146) without a history of cancer, randomly selected from the local population registry. Multiple linear regression models were used to investigate predictors of HRQL; separate models were fitted for each domain of the RAND-36. Results Male survivors (mean age = 27.0, SD = 6.0, n = 39) reported significantly lower HRQL than male controls in the domains of physical functioning, general health, vitality, social functioning, and role limitations-emotional. Female survivors (mean age = 30.2 years, SD = 7.6, n = 21) reported comparable levels as female controls in all domains except physical functioning. A higher burden of late effects, not working/studying, being diagnosed with BT during adolescence, and reporting current depressive symptoms were significant predictors of lower HRQL. Conclusion Our results highlight that male survivors of childhood BT are at particular risk of impaired HRQL. Also, results point to the close relation between symptoms of depression and impaired HRQL in survivors of childhood BT which should be acknowledged by long-term follow-up care.

Background Children develop symptomatic coronavirus disease 2019 (COVID-19) more rarely than adults upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pediatric oncology and hematology patients may be at increased risk of severe COVID-19 due to their underlying disease or treatment. We investigated COVID-19 and seroprevalence of anti-SARS-CoV-2 antibodies, respectively, in a Swedish cohort of pediatric oncology and hematology patients. Procedure Patients (n = 136) were recruited between June 2020 and September 2021 at Uppsala University Children's Hospital, Sweden. Up to six consecutive blood samples per patient were analyzed for wild-type anti-S1 IgM and IgG antibodies (including after vaccination, n = 4). Clinical data on COVID-19 (including polymerase chain reaction [PCR] test results) were collected from electronic medical records. A questionnaire was completed at recruitment. Results A cumulative seroprevalence (IgM and IgG) of 33% (45/136 patients, 95% confidence interval: 25%–41%) was observed in this patient cohort, of whom 66% (90/136 patients) were under severe immunosuppressive treatment during the study period. Increasing patient age (p = .037) and PCR test results (p < .002) were associated with seropositivity in nonvaccinated cases. Most seropositive, nonvaccinated cases (32/43, 74%) were never PCR-verified for SARS-CoV-2 infection. Of the 13 patients with PCR-verified infection, nine (69%) reported mild disease. A majority (63%) reported continued school attendance during the pandemic. Conclusions Swedish pediatric oncology and hematology patients developed antibodies against SARS-CoV-2, despite their diagnosis and/or treatment, and the observed seroprevalence was similar to that in national pediatric outpatients. PCR-verified cases underestimate the true incidence of COVID-19 in this patient cohort.

Late mortality of European five-year survivors of childhood or adolescent cancer has dropped over the last 60 years, but excess mortality persists. There is little information concerning secular trends in cause-specific mortality among older European survivors. PanCareSurFup pooled data from 12 cancer registries and clinics in 11 European countries from 77 423 five-year survivors of cancer diagnosed before age 21 between 1940 to 2008 followed for an average age of 21 years and a total of 1.27 million person-years to determine their risk of death using cumulative mortality, standardized mortality ratios (SMR), absolute excess risks (AER), and multivariable proportional hazards regression analyses. At the end of follow-up 9166 survivors (11.8%) had died compared to 927 expected (SMR 9.89, 95% confidence interval [95%CI] 9.69-10.09), AER 6.47 per 1000 person-years, (95%CI 6.32-6.62). At 60-68 years of attained age all-cause mortality was still higher than expected (SMR = 2.41, 95%CI 1.90-3.02). Overall cumulative mortality at 25 years from diagnosis dropped from 18.4% (95%CI 16.5-20.4) to 7.3% (95%CI 6.7-8.0) over the observation period. Compared to the diagnosis period 1960-69, the mortality hazard ratio declined for first neoplasms (p for trend

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).

[EN] 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 (rho(BCP-ALL )= -.17, rho(T-ALL )= -.19; p < 3 x 10(-4)). Spline functions fitted to age, immunophenotype, and karyotype explained WBC variation better than age alone (rho = .43, p << 2 x 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. Ingenior Otto Christensens Fond; Kirsten and Freddy Johansen Foundation; Kraeftens Bekaempelse, Grant/Award Number: R-257-A14720; Novo Nordisk Fonden; the Nordic Cancer Union; European Cooperation in Science and Technology, Grant/Award Number: Lekemia gene discovery by data sharing, mining and collaboration, CA16223; Barncancerfonden; Bornecancerfonden, Grant/Award Numbers: 2018-3755, 2019-5934; University Hospital Rigshospitalet; Interreg Oresund-Kattegat-Skagerak European Regional Development Fund, Grant: The interregional childhood oncology precision medicine exploration (iCOPE) project

PURPOSE Asparaginase-associated pancreatitis (AAP) is common in patients with acute lymphoblastic leukemia (ALL), but risk differences across age groups both in relation to first-time AAP and after asparaginase re-exposure have not been explored. PATIENTS AND METHODS We prospectively registered AAP (n = 168) during treatment of 2,448 consecutive ALL patients aged 1.0-45.9 years diagnosed from July 2008 to October 2018 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. RESULTS Compared with patients aged 1.0-9.9 years, adjusted AAP hazard ratios (HRa) were associated with higher age with almost identical HRa (1.6; 95% CI, 1.1 to 2.3; P = .02) for adolescents (10.0-17.9 years) and adults (18.0-45.9 years). The day 280 cumulative incidences of AAP were 7.0% for children (1.0-9.9 years: 95% CI, 5.4 to 8.6), 10.1% for adolescents (10.0 to 17.9 years: 95% CI, 7.0 to 13.3), and 11.0% for adults (18.0-45.9 years: 95% CI, 7.1 to 14.9; P = .03). Adolescents had increased odds of both acute (odds ratio [OR], 5.2; 95% CI, 2.1 to 13.2; P = .0005) and persisting complications (OR, 6.7; 95% CI, 2.4 to 18.4; P = .0002) compared with children (1.0-9.9 years), whereas adults had increased odds of only persisting complications (OR, 4.1; 95% CI, 1.4 to 11.8; P = .01). Fifteen of 34 asparaginase-rechallenged patients developed a second AAP. Asparaginase was truncated in 17/21 patients with AAP who subsequently developed leukemic relapse, but neither AAP nor the asparaginase truncation was associated with increased risk of relapse. CONCLUSION Older children and adults had similar AAP risk, whereas morbidity was most pronounced among adolescents. Asparaginase re-exposure should be considered only for patients with an anticipated high risk of leukemic relapse, because multiple studies strongly indicate that reduction of asparaginase treatment intensity increases the risk of relapse.

Acute lymphoblastic leukemia (ALL) is a rare disease in infants. Asparaginase is an essential part of the treatment, and there Acute is a need to evaluate the efficiency and safety of this drug in this age group. We evaluated the pharmacokinetics of intramuscularly administered native E. coli asparaginase (Asparaginase Medac®) and PEG-asparaginase (Oncaspar®) as well as hypersensitivity reactions during treatment in Interfant-06 ( www.clinicaltrials.gov : NCT01025804). All patients without hypersensitivity had sufficiently high enzyme activity levels during treatment with both preparations. Patients with hypersensitivity reactions during treatment, characterized by the presence of either or not of clinical symptoms and no measurable enzyme activity, received ineffective therapy. For optimization of the bad prognosis in infant ALL, therapeutic drug monitoring should be performed for identification of patients who should be switched to a different asparaginase preparation because of inactivation of the drug.

The mechanisms driving clonal heterogeneity and evolution in relapsed pediatric acute lymphoblastic leukemia (ALL) are not fully understood. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients. Somatic point mutations and large-scale structural variants were called using individually matched remission samples as controls, and allelic expression of the mutations was assessed in ALL cells using RNA-sequencing. We observed an increased burden of somatic mutations at relapse, compared to diagnosis, and at second relapse compared to first relapse. In addition to 29 known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, we identified putative non-protein coding mutations in regulatory regions of seven additional genes that have not previously been described in ALL. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression from diagnosis to relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients. Funding Agencies|CancerfondenSwedish Cancer Society [CAN2018/623] Funding Source: Medline; Barncancerfonden [PR2017-0023, PR2019-0046] Funding Source: Medline

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Central nervous system (CNS) involvement by cytospin is associated with increased risk of relapse in childhood acute lymphoblastic leukemia. We investigated if flow cytometric analysis of cerebrospinal fluid (CSF) at diagnosis improves the prediction of relapse. This prospective cohort study included patients (1.0–17.9 years) treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol. CSF flow cytometry samples were obtained at 17 centers, preserved with Transfix®, and analyzed at a central laboratory. One-hundred and seventy-one (25.4%) of 673 patients were positive by flow cytometry (CNSflow+). The 4-year cumulative incidence of relapse was higher for patients with cytospin positivity (CNScyto+) (17.1% vs. 7.5%), CNSflow+ (16.5% vs. 5.6%), and cytospin and/or flow positivity (CNScomb+) (16.7% vs. 5.1%). In Cox regression analysis stratified by immunophenotype and minimal residual disease day 29 and adjusted by sex, predictors of relapse were age (hazard ratio [HR] 1.1, 95% CI 1.1–1.2, P < 0.001), white blood cell count at diagnosis (HR 1.4, 95% CI 1.1–1.6, P < 0.001), and CNScomb+ (HR 2.2, 95% CI 1.0–4.7, P = 0.042). Flow cytometric analysis of CSF improves detection of CNS leukemia, distinguishes patients with high and low risk of relapse, and may improve future risk stratification and CNS-directed therapy.

Children and adolescents with leukemia are potentially at high risk of vitamin D inadequacy, which may have clinical relevance for skeletal morbidity, infections, and cancer outcome. This study aimed to evaluate vitamin D status at the time of diagnosis to investigate its predictors and association with overall survival in children with leukemia.We included all 295 children and adolescents diagnosed with leukemia at our institution between 1990 and 2016 who had available serum sample from the time of diagnosis. We analyzed serum 25-hydroxyvitamin D and parathyroid hormone levels and correlated them with clinical data.The 25-hydroxyvitamin D level was deficient ( 25 nmol/L), insufficient (25-50 nmol/L), sufficient (50-75 nmol/L), and optimal ( 75 nmol/L) in 6.4%, 26.8%, 39.7%, and 27.1% of the children, respectively. Older age and a more recent time of sampling (calendar year) predicted lower 25-hydroxyvitamin D level. In preschool children (age ≤6 years), lower 25-hydroxyvitamin D level was also associated with acute myeloid leukemia, and a 25-hydroxyvitamin D level 50 nmol/L was associated with inferior overall survival. In school-aged children (age 6 years), the 25-hydroxyvitamin D level showed significant seasonal variation.It remains unclear whether vitamin D supplementation in pediatric leukemia patients will improve outcome.

Intrachromosomal amplification of chromosome 21 (iAMP21) is a cytogenetic subtype associated with relapse and poor prognosis in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL). The biology behind the high relapse risk is unknown and the aim of this study was to further characterize the genomic and transcriptional landscape of iAMP21. Using DNA arrays and sequencing, we could identify rearrangements and aberrations characteristic for iAMP21. RNA sequencing revealed that only half of the genes in the minimal region of amplification (20/45) were differentially expressed in iAMP21. Among them were the top overexpressed genes (p < 0.001) in iAMP21 vs. BCP ALL without iAMP21 and three candidate genes could be identified, the tyrosine kinase gene DYRK1A and chromatin remodeling genes CHAF1B and SON. While overexpression of DYRK1A and CHAF1B is associated with poor prognosis in malignant diseases including myeloid leukemia, this is the first study to show significant correlation with iAMP21-positive ALL.

Compromised physical fitness and cognitive difficulties have been reported as late effects of cancer treatment during childhood. To assess this issue, the military rankings of cancer survivors in medical checkups at call-up, and conscripts' physical and cognitive performance during the first weeks of compulsory military education were compared to those of matched population controls without a history of cancer.A total of 1680 male patients born between 1960 and 1992 with a malignancy diagnosed before the age of 16 who were alive at the call-up age (18 years) were identified using the Finnish Cancer Registry, and five age, sex and place of residence matched controls for each patient using the Population Register Centre. Data on military service were gathered from Finnish Defense Forces. A conditional logistic regression analysis, the GEE-method with the cumulative logit link function, the chi-square test, the chi-square test for trend and a one-way analysis of variance were used in different analyses.Cancer survivors were exempted from military service more often than the controls (p .001). The fit-for-service frequency was highest for survivors of kidney tumors (68%) and lowest after irradiated brain tumors (19%). In service, the results of the 12-min running test were poorer than those of controls for leukemia/non-Hodgkin lymphoma (p = .03) and brain tumor (p = .01) survivors. Interestingly, the standing long-jump test was the only muscle test for which survivor groups performed worse than controls. Performance on cognitive tests only differed from controls in brain tumor survivors.Exemption from service is still common under the current guidelines, but fit-for-service survivors do well in military education. These results can be used for reassuring survivors that completion of military service is possible for those fulfilling the national general guidelines for military fitness.

Background: Extracorporeal membrane oxygenation (ECMO) is used in severe respiratory and/or circulatory failure when conventional critical care fails. Studies on patients with hematological malignancies on ECMO have shown contradictory results; immunosuppression and coagulopathy are relative contraindications to ECMO. Observations: This nationwide Swedish retrospective chart review identified 958 children with hematological malignancies of whom 12 (1.3%) required ECMO support. Eight patients survived ECMO, 7 the total intensive care period, and 6 survived the underlying malignancy. Conclusions: ECMO may be considered in children with hematological malignancy. Short-term and long-term survival, in this limited group, was similar to that of children on ECMO at large. (Less)

Background: Childhood cancer survivors treated before 1992, when blood donor screening for hepatitis C virus (HCV) infection was introduced, are at risk of transfusion-transmitted HCV infection. A national HCV screening campaign targeting blood transfusion recipients was launched in Sweden in 2007-2010. The aims of this study were to, among adult childhood cancer survivors in Stockholm County, investigate the prevalence of HCV infection, the natural course of infection, treatment outcome and anti-HCV testing frequency before, during and after the screening campaign and finally to actively screen the untested ones. Material and Methods: This was a combined retrospective register based and prospective screening study of adult childhood cancer survivors (n=686) treated for malignancy in Stockholm before 1992. In the first part, we investigated the prevalence of HCV infection and previous anti-HCV testing, and in the second part, we actively traced and HCV-screened the remaining untested cohort living in Stockholm. Analysis of previous documented anti-HCV tests in medical records, laboratory records, and the national communicable disease registry was performed. In the second part, 231 presumably untested individuals were contacted by mail and offered an anti-HCV test. The natural course of HCV infection and treatment outcome was analyzed for those found to be chronically infected. Results: In total, 235 patients were tested and 11 were HCV-RNA positive. The overall prevalence of chronic HCV infection among the tested childhood cancer survivors was thus 4.7% (95% CI = 2.6-8.2%), which is almost 10 times higher than the national prevalence of 0.5%. Only 12% of the Stockholm cohort were tested during the screening campaign in 2007-2010, while the test uptake using active tracing screening within this study was 40% (p

In patients with cancer, osteonecrosis (ON) lesions can affect multiple sites throughout the skeleton, including the long and short bones and the joints. The aims of this study were to explore the natural course of ON in patients treated for cancer by using radiological classification suitable for multisite ON lesions and to assess correlations between the ON grade and surgical procedures.Data were retrieved from hospital databases on 233 ON lesions in 54 patients (aged 2-73 years at cancer diagnosis; mean age: 25 years). ONs were graded according to the Niinimäki classification, based on magnetic resonance images. Medical records were reviewed to identify surgical procedures.A total of 14 different ON sites were detected; the hip was the most common site (n = 51), followed by the femur (n = 45), tibia (n = 41) and knee (n = 37). Among the 233 ON lesions, 78.1% did not require surgical procedures. The remaining lesions required total joint arthroplasty (TJA; 40/233, 17.2%), core decompression (3.4%) and arthroscopy (1.3%). Most TJAs (33/40, 82.5%) were performed on the hip. ONs of the knee required TJAs only once; grade 3 knee ONs frequently healed (58%, 11/19). None of the diaphyseal or metaphyseal (grade 1-2) ONs of the long bones required surgery, and no fractures of those bones were identified.In conclusion, the natural history of ONs varied by the grade and site. Based on our findings, we would not recommend routine radiological follow-ups for grades 1-2 ON lesions that do not affect the joints, because the clinical consequences of those lesions appear to be minimal, although pain relief would be warranted. In contrast, joint deformations (grade 5) require surgery; therefore, intervention studies should focus on grades 3-4 ON lesions.

BACKGROUND Children with central nervous system (CNS) toxicity during therapy for acute lymphoblastic leukaemia (ALL) are at risk for treatment modifications, long-term sequelae and even higher mortality. A better understanding of CNS symptoms and their complications improves the potential to prevent and treat them. METHODS Patient files from 649 children treated with Nordic Society of Pediatric Hematology and Oncology ALL92 and ALL2000 protocols in Finland were reviewed retrospectively for any acute CNS symptom. Detailed data on symptoms, examinations and treatment of the underlying CNS complications were collected from the medical records. Disease-related and outcome data were retrieved from the Nordic leukaemia registry. RESULTS Altogether, 13% (86) of patients with ALL had acute CNS symptoms. Most symptoms (64%) occurred during the first 2 months of therapy. Posterior reversible encephalopathy syndrome was the most frequent complication (4.5%). Cerebrovascular events were diagnosed in 10 cases (1.6%), while methotrexate-related stroke-like syndrome (SLS) was observed in only one patient (0.2%). CNS symptoms due to systemic or unclear conditions, especially sepsis, were important for differential diagnosis. CNS leukaemia was associated with CNS symptoms (hazard ratio [HR] = 4.03; P = .003), and epilepsy was a common sequel of CNS complications (19%). CONCLUSIONS Acute CNS symptoms are common during ALL therapy, occurring mainly during the first 2 months of treatment. Patients with CNS leukaemia at diagnosis are at a higher risk for CNS toxicity. Despite intensive CNS-directed methotrexate treatment, SLS was diagnosed extremely rarely in our series.

BACKGROUND Childhood brain tumor survivors have a high risk of early cerebrovascular disease, but currently its clinical significance is unknown. METHODS In a nation-wide study, we investigated 68 childhood brain tumor survivors treated with radiotherapy by using magnetic resonance imaging (MRI) and neuropsychological examination after median follow-up time of 20.6 years (range 5.0 – 33.1 years) since radiotherapy. Associations between imaging markers of cerebrovascular disease, white matter hyperintensities and the results of neuropsychological examination were investigated. RESULTS Majority (65 %) of the survivors was diagnosed with cerebrovascular disease at median age of 27.1 years (range16.2 – 43.8 years). The presence of imaging markers of cerebrovascular disease or white matter hyperintensities was associated with poorer performance in verbal (VIQ) and performance (PIQ) intelligent quotient, working and semantic memory, executive functions, visuospatial ability, and immediate and general auditive memory (P < 0.05). Survivors with microbleeds performed worse in PIQ, processing speed, executive functions, and visuospatial ability (P CONCLUSION The imaging markers of cerebrovascular disease and white matter hyperintensities were related to poorer cognitive performance in radiation-treated long-term survivors of childhood brain tumor. Longitudinal studies are urgently needed to investigate how cerebrovascular disease and related cognitive impairment progress in the survivors.

We investigated efficacy and toxicity of replacing conventional triple (cytarabine, methotrexate, and hydrocortisone) intrathecal therapy (TIT) with liposomal cytarabine during maintenance therapy among 40 acute lymphoblastic leukemia patients. Twenty-eight of 29 patients in the TIT arm received TIT and 9/11 in the liposomal cytarabine arm received liposomal cytarabine. Arachnoiditis occurred in all initial 5 patients given liposomal cytarabine and intrathecal prednisolone succinate. Subsequently liposomal cytarabine was given with systemic dexamethasone. Neurotoxicity occurred at 6/27 liposomal cytarabine administrations with concomitant dexamethasone (22%). More liposomal cytarabine-treated patients experienced neurotoxicity in relation to intrathecal therapy during at least 1 cycle compared with TIT-treated patients (6/9 [67%] vs. 3/28 [11%], P=0.002). Apart from intermittent lower extremity sensory pain in 1 liposomal cytarabine-treated patient, no permanent adverse neurological sequelae were observed. In intention-to-treat analysis, projected 5-year event-free survival (pEFS-5y) was borderline higher for patients in the liposomal cytarabine arm compared with the TIT arm (1.0 vs. 0.69, P=0.046). However, pEFS-5y and projected 5-year relapse-free survival did not differ signficantly between patients treated with liposomal cytarabine or TIT (1.0 vs. 0.73, P=0.10; 1.0 vs. 0.76, P=0.12). Larger prospective trials are needed to explore whether liposomal cytarabine should be used as first-line prevention of relapse.

In order to assess neurocognitive and social outcomes after childhood cancer, we explored the educational and vocational attainments of Finnish survivors in comparison to matched population controls. From national registries, we identified survivors (n = 3243) born from 1960 to 1992 and aged below 16 at cancer diagnosis (years 1964–2009) as well as their controls (n = 16,215). Data on educational achievements, yearly income, employment status, and retirement were retrieved from Statistics Finland. The median (range) age at study was 28 (17–50) years. The proportion of those with no education after comprehensive school was higher than controls for all the diagnostic groups: brain tumor (BT) (33.5 vs 23.0 %), solid tumor (ST) (25.0 vs 21.4 %), and leukemia/NHL (29.2 vs 23.1 %). Odds ratios (OR) for unemployment were not significantly elevated in any survivor group compared to controls, but OR for being retired was elevated in each survivor group (BT 14.8, ST 2.2, leukemia/NHL 4.0). Irradiation significantly increased that OR only in BT survivors. Leukemia/NHL survivors treated after 1992 had lower risk for early retirement (OR 0.6) compared to those diagnosed earlier. Survivors had higher frequencies than controls for lacking further education after comprehensive school. Unemployment was not common, but risk for early retirement was significantly increased in each three survivor group. Reassuring is that premature retirement was less common during the most recent treatment era. Screening and follow-up of psychosocial performance more effectively might be essential, and there is a need for studies on possibility for effective rehabilitation of the survivors.

Background Each year approximately 200 children and adolescents are diagnosed with acute lymphoblastic leukemia (ALL) in the five Nordic countries, and 3% of these have central nervous system (CNS) involvement confirmed by leukemic cells in the cerebrospinal fluid (CSF) or neurological symptoms. We sought to determine the significance of neuraxis imaging in such patients. Procedure Magnetic resonance images of children aged 1–17.9 with CNS leukemia at diagnosis of ALL were centrally reviewed and clinical data were retrieved from the medical records and the Nordic leukemia registry. Patients were diagnosed in the period 2000–2012 in Sweden, Finland, or Denmark. Results The cohort comprised 1,877 patients, and 66 (3.5%) had CNS involvement. Forty-five percent (30/66) had CNS related symptoms. Symptoms included vomiting, facial palsy, headache, visual symptoms, and impaired hearing. CNS imaging was performed in 32 of 66 children (48%), and confirmed CNS involvement in 6 of 21 patients with symptoms (29%) and 5 of 11 (45%) without (P = 0.44). There was no difference in the overall survival between CNS-positive patients with and without signs of leukemic involvement by imaging (P = 0.53). Conclusions Radiological imaging of asymptomatic children with CNS leukemia at diagnosis lacks clinical importance, but may be useful in patients with cranial nerve symptoms and negative CSF, as well as for follow-up. Imaging of symptomatic patients is warranted in order to exclude other causes underlying the symptoms.

Background Skeletal complications such as osteonecrosis (ON) are potential adverse events in patients treated for cancer, especially in those treated for hematologic and lymphatic malignancies (HLMs). ON may damage the hip or knee joints and may lead to arthrosis requiring total joint arthroplasty (TJA). The aim of this study was to address the risk of TJA in patients with cancer, especially those treated for HLM, in a nationwide population-based setting. Material and methods All patients who had undergone TJA after cancer diagnosis between the years 2000 and 2012 were identified by linking the Arthroplasty Register and the Cancer Registry. Standardized incidence ratios (SIRs) of TJAs were calculated to assess whether patients with any cancer, but especially HLM, have increased risk for TJA when compared with the general population. Results In patients with HLM or other cancer, the overall SIRs were similar compared with the general population. However, in HLM patients under 50 years of age, the SIR was 7.6, and in patients under 35 years of age, it was 45.5. The corresponding SIRs in patients with other cancers were 3.6 and 6.6, respectively. The highest SIRs, including all age groups, were among patients with acute lymphoblastic leukemia (SIR = 4.5) and acute myeloid leukemia (SIR = 1.9). Discussion HLMs imply an increased risk for TJA compared with the general population. The risk is especially high in patients younger than 50 years, regardless of the type of HLM. Young patients with HLM, as well as their healthcare providers, should be aware of the highly increased risk of skeletal complications requiring TJA.

The antileukaemic drug 6-mercaptopurine is converted into thioguanine nucleotides (TGN) and incorporated into DNA (DNA-TG), the active end metabolite. In a series of genome-wide association studies, we analysed time-weighted means (wm) of erythrocyte concentrations of TGN (Ery-TGN) and DNA-TG in 1009 patients undergoing maintenance therapy for acute lymphoblastic leukaemia (ALL). In discovery analyses (454 patients), the propensity for DNA-TG incorporation (wmDNA-TG/wmEry-TGN ratio) was significantly associated with three intronic SNPs in NT5C2 (top hit: rs72846714; P = 2.09 × 10−10, minor allele frequency 15%). In validation analyses (555 patients), this association remained significant during both early and late maintenance therapy (P = 8.4 × 10−6 and 1.3 × 10−3, respectively). The association was mostly driven by differences in wmEry-TGN, but in regression analyses adjusted for wmEry-TGN (P < 0.0001), rs72846714-A genotype was also associated with a higher wmDNA-TG (P = 0.029). Targeted sequencing of NT5C2 did not identify any missense variants associated with rs72846714 or wmEry-TGN/wmDNA-TG. rs72846714 was not associated with relapse risk, but in a separate cohort of 180 children with relapsed ALL, rs72846714-A genotype was associated with increased occurrence of relapse-specific NT5C2 gain-of-function mutations that reduce cytosol TGN levels (P = 0.03). These observations highlight the impact of both germline and acquired mutations in drug metabolism and disease trajectory.

The increase in the number of childhood brain tumor survivors warrants detailed research to increase our knowledge regarding the possible physical and psychosocial adverse outcomes of tumor and tumor therapy. The aim of this study was to evaluate the current bone health by measuring the bone mineral density (BMD) in irradiated, adult long-term survivors of childhood brain tumors.We studied a national cohort of 74 adult survivors of childhood brain tumors treated with irradiation in Finland between 1970 and 2008. Dual X-ray absorptiometry (DXA) was performed for the femoral necks, total hips, and lumbar spine. Laboratory tests were conducted for evaluating the pituitary, thyroid, and gonadal functions. The participants were interviewed, examined clinically, and the disease and treatment related data were retrieved from the patient files.One fourth of the patients (23.6%) had sex- and age-normalized z-scores below the expected range for age (z-score ≤ -2.0). Mean BMD scores were decreased in all the DXA measurement sites. Male sex was associated with low BMD (p .05), while body mass index (BMI) had a significant positive association with BMD (p .01). Mode of irradiation (with or without spinal irradiation) or inclusion of chemotherapy in the treatment did not affect BMD significantly. However, patients with a ventriculoperitoneal shunt had lower BMD than those without a shunt (p .05). Follicle stimulating hormone (FSH) and luteinizing hormone (LH) were negatively associated with BMD in women (p .05). However, a higher cumulative dose of glucocorticoids during treatment was not associated with lower BMD, while low BMD was significantly associated with previous fractures in long bones.Low BMD should be taken in consideration in treatment of irradiated childhood brain tumor survivors especially in those with previous fractures in long bones.

Background: Second malignant neoplasms and cardiotoxicity are among the most serious and frequent adverse health outcomes experienced by childhood and adolescent cancer survivors (CCSs) and contribute significantly to their increased risk of premature mortality. Owing to differences in health-care systems, language and culture across the continent, Europe has had limited success in establishing multi-country collaborations needed to assemble the numbers of survivors required to clarify the health issues arising after successful cancer treatment. PanCareSurFup (PCSF) is the first pan-European project to evaluate some of the serious long-term health risks faced by survivors. This article sets out the overall rationale, methods and preliminary results of PCSF. Methods: The PCSF consortium pooled data from 13 cancer registries and hospitals in 12 European countries to evaluate subsequent primary malignancies, cardiac disease and late mortality in survivors diagnosed between ages 0 and 20 years. In addition, PCSF integrated radiation dosimetry to sites of second malignancies and to the heart, developed evidence-based guidelines for long-term care and for transition services, and disseminated results to survivors and the public. Results: We identified 115,596 individuals diagnosed with cancer, of whom 83,333 were 5-year survivors and diagnosed from 1940 to 2011. This single data set forms the basis for cohort analyses of subsequent malignancies, cardiac disease and late mortality and case–control studies of subsequent malignancies and cardiac disease in 5-year survivors. Conclusions: PCSF delivered specific estimates of risk and comprehensive guidelines to help survivors and care-givers. The expected benefit is to provide every European CCS with improved access to care and better long-term health.

Posterior reversible encephalopathy syndrome (PRES) in children with acute lymphoblastic leukemia has been increasingly recognized as a clinicoradiological entity. Our aim was to describe the incidence of PRES in pediatric patients with ALL, identify its risk factors, and examine its prognostic importance. For this research, we conducted a systematic, retrospective review of the patient records in a population-based series of children with acute lymphoblastic leukemia (n=643) treated in Finland from 1992 to 2008. Of the patients with ALL, 4.5% (n=29) developed radiologically confirmed PRES, of which 28 cases occurred during induction. Hypertension (P=0.006; odds ratio [OR], 4.10, confidence interval [CI], 1.50-11.25), constipation (P=0.001; OR, 5.60; CI, 2.02-15.52), and >14 days of alkalinization (P=0.017; OR, 3.27; CI, 1.23-8.68) were significant independent risk factors for PRES. One-third of the patients developed epilepsy. Relapses occurred significantly more often in those patients with PRES (P=0.001), which was associated with worse overall survival (P=0.040; 5-year survival=75.9% [60.3%-91.4%] vs. 88.4% [85.8%-90.9%]). Using NOPHO-ALL 92/2000 protocols, PRES is a significant early complication of therapy in ALL, and was associated with a poorer prognosis and significant neurological morbidity.

Background: Therapy directed at the central nervous system (CNS) is an essential part of the treatment for childhood acute lymphoblastic leukemia (ALL). The current evaluation of CNS involvement ba ...

Osteonecrosis (ON) is usually considered treatment related in patients with acute lymphoblastic leukemia (ALL). We report two patients with presentation of ON at the time of ALL diagnosis. Both were females and diagnosed with ALL at age 8 and 14 years. In the latter, some symptoms and radiologically verified ON in both knees were still present after the end of ALL therapy. No pediatric patients have previously been reported with ON presenting before initiation of ALL therapy.

Hepatotoxicity is a known toxicity to treatment of childhood acute lymphoblastic leukemia. Hepatotoxicity occurs during maintenance therapy and is caused by metabolites of 6-Mercaptopurine (6 MP) and Methotrexate (MTX). Our objective was to investigate the association between alanine aminotransferases (ALAT) levels and relapse rate. We included 385 patients enrolled in the NOPHO ALL-92 protocol. Data on ALAT levels, 6 MP and MTX doses, cytotoxic MTX/6 MP metabolites, and thiopurine methyltransferase (TPMT) activity were prospectively registered. In total, 91% of the patients had a mean ALAT (mALAT) level above upper normal limit (40 IU/L) and ALAT levels were positively correlated to 6 MP doses (rs=0.31; P

Background L-Asparaginase is an effective drug in the treatment of childhood acute lymphoblastic leukemia (ALL). The use of L-asparaginase may be limited by serious adverse events of which allergy is the most frequent. The objective of this study was to describe the clinical aspects of PEG-asparaginase allergy in children treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol. Procedure Children (1–17 years) enrolled in the NOPHO ALL2008 protocol between July 2008 and August 2011, who developed PEG-asparaginase allergy were identified through the NOPHO ALL2008 toxicity registry. In the NOPHO ALL2008 protocol, patients are randomized to 8 or 15 doses of intramuscular PEG-asparaginase (Oncaspar®) 1,000 IU/m2/dose administered at 2 or 6 weeks intervals during a total period of 30 weeks. (Clinical trials.gov no: NCT00819351). Results Of 615 evaluable patients, 79 patients developed clinical PEG-asparaginase allergy (cumulative risk; 13.2%) and discontinued PEG-asparaginase therapy for that reason. PEG-asparaginase allergy occurred after a median of two doses (75% range 2–4, max 14). In 58% of PEG-asparaginase hypersensitive patients, the clinical allergic reactions appeared within 2 hr after PEG-asparaginase administration and ranged from mild symptoms to systemic anaphylaxis. Nine patients experienced an anaphylactic reaction within 1 hr and 50 min from asparaginase administration; none were fatal. Four of 68 patients (6%) who subsequently received Erwinase therapy also reacted allergic to Erwinase. Conclusion Clinical allergy to PEG-asparaginase occurred early in treatment, was in general moderate in severity, and mostly developed within 2 hr after PEG-asparaginase administration. The risk of subsequent Erwinase allergic reactions was low. Pediatr Blood Cancer 2015;62:427–433. © 2014 Wiley Periodicals, Inc.

Osteonecrosis is a well-recognized complication in patients with childhood leukemia. Its clinical relevance is highly dependent on the size and location of the lesion. Therefore, the diagnosis, description of the affected site and the classification of the disease, must be precise. We conducted an extensive literature review to assess the quality of studies reporting the incidence of osteonecrosis in patients with childhood leukemia. Of the 31 included studies, one-third (32% [n = 10]) did not describe the diagnostic method that was used to assess osteonecrosis. In almost two-third (61% [n = 19]) of the studies, the osteonecrosis classification system was not used. We conclude that the quality of most published studies on the incidence of osteonecrosis in patients with childhood leukemia is relatively poor because many studies did not describe the radiological method used to diagnose osteonecrosis and/or did not use a validated osteonecrosis classification system. To compare the incidence of osteonecrosis, and to assess the severity and clinical consequences of osteonecrosis in patients with childhood leukemia, there is a need for a robust and widely recognized classification system to grade all cases of osteonecrosis despite the site of lesion. Pediatr Blood Cancer 2015;62:198-203. © 2014 Wiley Periodicals, Inc.

Background Despite major treatment attempts, the prognosis for pediatric diffuse intrinsic pontine gliomas (DIPGs) remains dismal. Gliomas are highly vascularized tumors, suggesting that the prevention of vessel formation by anti-angiogenic treatment might be effective. Procedure Forty-one pediatric patients with DIPG were treated according to the Angiocomb protocol, starting with radiotherapy combined with topotecan and followed by anti-angiogenic triple medication consisting of thalidomide, etoposide, and celecoxib. Overall survival, radiological response, quality of life, requirement of corticosteroids, and adverse effects were monitored. Eight patients treated with only radiotherapy were used as controls. Results For study patients, the 12 and 24 months overall survival was 61% and 17%, respectively. The median overall survival was 12 months (range 4–60 months). Four radiological complete responses were seen, of which two were transient. Radiologically, 56% of the tumors reduced in size and 78% in signal intensity. Study patients were able to visit school or daycare and walk for a significantly longer time compared to controls (Log Rank 0.036 and 0.008, respectively). Adverse effects were generally minor. Conclusions The Angiocomb protocol created a noticeable share of long-term survivors and was well tolerated, suggesting that anti-angiogenic therapy for patients with DIPG should be studied more in the future. Pediatr Blood Cancer 2014;61:1603–1609. © 2014 Wiley Periodicals, Inc.

Background Central nervous system (CNS) involvement in childhood acute lymphoblastic leukemia (ALL) remains a therapeutic challenge. Procedure To explore leukemia characteristics of patients with C ...

Background Previous studies have indicated that patients with thiopurine methyltransferase (TPMT) low activity (TPMTLA) have reduced risk of relapse but increased risk of second malignant neoplasm (SMN) compared to patients with TPMT wild-type (TPMTWT) when treated with 6MP maintenance therapy starting doses of 75 mg/m2/day. To reduce SMN risk, 6MP starting doses were reduced to 50 mg/m2/day for patients with TPMT heterozygosity in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2000 protocol. Procedure We explored the pattern of SMN and relapse in the NOPHO ALL2000 protocol (n = 674) and NOPHO ALL92 protocol (n = 601) in relation to TPMT pheno- and/or genotype. Results The overall risk of any event did not differ significantly between the two protocols. However, in event pattern analyses considering only the patients with TPMTLA who experienced relapse or SMN, the risk of SMN versus leukemia relapse was significantly lower in the ALL2000 cohort for patients with a 6MP starting dose

Purpose: The population-based incidence of severe osteonecrosis (ON) necessitating total joint arthroplasty (TJA) in patients with hematological cancer is unknown. This study assessed the incidence of ON requiring primary TJA in children and young adults treated for leukemia or lymphoma. Methods: Patients diagnosed with leukemia or lymphoma before 31 years of age were identified from the Finnish and Danish Cancer Registries. These data were combined with those from the National Hospital Discharge and the Finnish Arthroplasty Registers. Data on the orthopedic procedures performed and the appropriate diagnosis codes given before the age of 40 were also retrieved. Results: The estimated cumulative incidence of TJA was 4.5% at 20 years for patients treated for chronic myeloid leukemia, followed by 2.1% for patients treated for acute myeloid leukemia. It was considerably lower in patients with acute lymphoblastic leukemia (ALL; 0.4%). Multivariate analysis revealed that allogeneic stem cell transplantation (allo-SCT) increased the risk of TJA (hazard ratio [HR]=9.4; 95% CI: 5.3-16.9). The risk of TJA was higher in patients diagnosed with cancer at 10-19 and 20-30 years of age than in those diagnosed before the age of 10 (HR=24; 95% CI: 3.1-176 and HR=26; 95% CI: 3.6-192 respectively). Conclusion: The incidence of ON requiring TJA was highest among patients with myeloid leukemias and lowest in patients treated for ALL. Allo-SCT and age ≥10 years at diagnosis were the most important risk factors for ON requiring TJA in hematological malignancies.

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.

Background The event-free survival of childhood acute lymphoblastic leukemia (ALL) has been reported to be superior when oral methotrexate (MTX) and 6-mercaptopurine (6MP) maintenance therapy (MT) is administered in the evening compared to the morning. Procedure In the ALL92 MT study we prospectively registered the intake of MTX/6MP. The registration was done when blood samples for erythrocyte MTX/6MP metabolite measurements were collected, and referred to the time of intake in the period since last registration. Nine thousand one hundred ninety-five registrations in total. The administration of MTX/6MP was scored as morning, midday, or evening. Results Of 532 patients, 296 took their medication consistently in the evening, 129 in the evening 50.0–99.9% of the time, and 101 in the evening

Early morbidity and mortality in childhood acute lymphoblastic leukemia with very high white blood cell count

BackgroundCarboxypeptidase G2 (CPDG(2)) can be used as rescue treatment in cases of delayed methotrexate elimination (DME) and Mtx-induced nephrotoxicity.ProcedureBetween July 2008 and December 2014, all children (1.0-17.9 years) in the Nordic countries diagnosed with Philadelphia chromosome negative acute lymphoblastic leukemia (ALL) were treated according to the Nordic Organization for Pediatric Hematology and Oncology (NOPHO) ALL 2008 protocol, including administration of six to eight high-dose (5 g/m(2)/24 hr) Mtx (HDMtx) courses. The protocol includes recommendations for CPDG(2) administration in cases of DME (clinicaltrials.gov NCT01305655).ResultsForty-seven of the 1,286 children (3.6%) received CPDG(2) during 50 HDMtx courses at a median dose of 50 IU/kg. In 49% of the cases, CPDG(2) was used during the first HDMtx course. Within a median of 6 hr from CPDG(2) administration, the Mtx concentration decreased by 75% when measured with immune-based methods, and by 100% when measured with high-performance liquid chromatography. The median time from the start of Mtx infusion to plasma levels 0.2 M was 228 hr (range: 48-438). The maximum increase in plasma creatinine was 375% (range: 100-1,310). Creatinine peaked after a median of 48 hr (range: 36-86). Mtx elimination time was shorter in patients with body surface area ConclusionsCPDG(2) administration is highly effective as rescue in case of delayed Mtx clearance. Subsequent HDMtx courses could be administered without events in most of the patients.

Leukemic cells from 230 children with newly diagnosed B-cell precursor ALL were tested for in vitro drug resistance to a panel of anti-cancer drugs. Minimal residual disease (MRD) was measured by RQ-PCR. During follow-up, 24 relapses occurred in the 159 children with MRD

Cancer remains the leading cause of disease-related mortality among children aged 1-14 years in developed countries. Acute lymphoblastic leukaemia (ALL) is the most common malignancy in childhood and accounts for about 25% of all childhood cancers. In Norway about 30-40 children are diagnosed with ALL each year. Treatment comprises of a combination of 6-12 different chemotherapy drugs administered over a period of 2.5 years with additional supportive care. Side effects remain a great challenge for both patients and physicians. One of the most common side effects is immunosuppression which increases the risk of infection. Today, the overall survival rate in childhood ALL is 80-85%. About 75% of deaths related to ALL are caused by the disease itself, most after relapse, but about 25% of deaths are caused by treatment and are classified as treatment-related deaths (TRDs). In this study, the incidence, risk factors and causes of death were investigated for 88 TRDs among 2,700 patients in the Nordic countries Sweden, Denmark, Finland, Iceland and Norway. The incidence of TRD was 3.2%, which was stable in the two protocols, the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL 1992 and ALL 2000 protocols. The risk factors identified were female gender, treatment risk-group, T-cell disease, Down syndrome and stem cell transplantation. Seventy-five percent of the deaths were related to infection, 10% to bleeding or thrombosis, 10% to organ failure and 5% to the tumour burden. We have no good explanation as to why some patients experience more severe infections than others, even when receiving the same drugs, drug dosage and supportive care. It is reasonable to believe that genetic factors play a role. In accordance with the increasing understanding of host genetic variation the past 10 years, we investigated 34,000 single nucleotide polymorphisms (SNPs) relevant in childhood ALL in a Danish ALL cohort including 69 children and detected 24 SNPs which associated with infections during induction treatment. Through CART-analysis (classification and regression tree) a four-SNP risk profile were identified as highly predictive of risk of infections during the 50 days induction treatment. The four SNPs belong to the genes R51F1, CBR1, POLDIP3 and CCL11 which regulate drug metabolism, cell-growth and inflammation. If these findings are replicated in larger studies, such knowledge may be useful for developing personalized medicine with more tailored therapy and supportive care, which will hopefully reduce the severity of side effects and increase overall survival. Studies involving multiple biological markers, such as SNPs and short tandem repeats (STRs), often use high-quality DNA extracted from blood samples. However, blood samples are not always easy to obtain from study participants, especially if the patient has died. Archival bone marrow samples from patients with leukaemia are available and represent a potential DNA source. We were interested in exploring whether such archival material is usable for the analysis and identification of multiple markers. DNA from 21 bone marrow smears and 13 bone marrow biopsies were extracted and quantified. Because of small amounts of DNA from each sample whole genome amplification (WGA) was applied. Ten different STR-markers and 34,000 SNPs were analysed and compared with corresponding blood samples. For the STR markers 90% detection rates were obtained. Shorter markers (107bp-242bp) from samples stored 0-3 years gave better results compared with longer markers (219bp-317bp) stored 4-10 years. Multiple SNP analysis was more complicated and only seven of 34 archival samples gave acceptable results (SNP call-rates above 50%). However, in two samples, nearly 100% of SNP-markers were detected. Although increasing the total amount of DNA, WGA reduced the analysis quality. In conclusion, DNA from archival bone-marrow samples might be used in multiple marker analysis, but adjustments of the laboratory set-up are essential to optimize this method.

Background: Central nervous system (CNS) involvement is common in childhood acute lymphoblastic leukemia (ALL). Today all patients receive intensive prophylactic CNS-directed therapy, which is associated with short- and long-term neurotoxicity. The conventional method for diagnosing CNS leukemia is by microscopic examination of cytospin preparations of cerebrospinal fluid (CSF). Both high (CNS3: ≥5 x 109 cells/L) and low level CNS disease (CNS2: Methods: Cytospin results were collected from local oncology clinics for patients treated according to the Nordic Society of Pediatric Hematology (NOPHO) ALL2008 protocol from July 2008 to December 2017 (N=1841). CSF samples for FCM were obtained from patients enrolled from September 2012 to December 2017 at 17 participating centers (N=669). CSF samples were collected into Transfix® tubes (Intermedico Ltd., Hellerup, Denmark) and shipped to Rigshospitalet, Copenhagen, Denmark for centralized analysis as previously described (Levinsen at al., Pediatr Blood Cancer 2016). FCM positivity required detection of ≥10 cells with a leukemia-associated phenotype. CSF FCM results were blinded to the treating physician. Time to relapse was analyzed using Cox proportional hazards models with delayed entry at remission and with death and second malignant neoplasm as competing events. Results: At diagnosis, 241 of 1841 (13.1%; CNS2: 8.9% and CNS3: 4.2%) patients were positive by cytospin, whereas 167 of 669 (25.0%) patients were positive by FCM. FCM positivity was not associated with shipment duration (median: 2 days). In total, 191 of the 669 patients (28.6%) were CNS positive by cytospin and/or FCM. CNS positivity was associated with higher white blood cell (WBC) count at diagnosis, T-cell ALL, lack of t(12;21), and traumatic lumbar puncture (TLP) (all comparisons: p < 0.001). However, patients with CNS positivity did not differ in their end of induction bone-marrow minimal residual disease (MRD) levels compared to the remaining patients (cytospin: median MRD 1.2 x 10-4 vs. 0.9 x 10-4, p = 0.058; FCM: median MRD 2.0 x 10-4 vs. 1.7 x 10-4, p = 0.62). During follow-up, 30 patients relapsed with nine of the relapses involving the CNS and 16 relapses isolated to the bone-marrow. The 4-year cumulative incidence of any relapse was higher for patients who were CNS positive by cytospin (16.1% vs. 8.9%), FCM (18.6% vs. 6.0%), and combined cytospin/FCM (19.0% vs. 5.5%) (Figure 1a). Simple Cox regressions yielded relapse hazard ratio (HR) estimates of CNS positivity at diagnosis of 2.4 for cytospin (95% CI 1.0-5.7, p = 0.04), 3.5 for FCM (95% CI 1.7-7.2, p < 0.001), and 4.1 for combined cytospin/FCM (95% CI 2.0-8.7, p < 0.001). Cytospin and/or FCM was associated with increased risk of both isolated bone-marrow relapse (16 events, HR 3.1, 95% CI 1.2-8.4, p = 0.024) and of any CNS relapse (9 events, HR 4.9, 95% CI 1.2-19.5, p = 0.025). In a multiple Cox model stratified by immunophenotype and risk group, predictors of relapse were age (per year: HR 1.1, 95% CI 1.0-1.2, p = 0.003), WBC at diagnosis (per doubling: HR 1.3, 95% CI 1.1-1.6, p = 0.005), and cytospin and/or FCM (HR 3.2, 95% CI 1.4-7.2, p = 0.006) (Figure 1b). Cytospin and/or FCM was associated with a significantly higher risk of relapse for BCP-ALL (N=581; 23 relapses; HR 4.5, 95% CI 1.9-10.4, p = < 0.001). For T-cell ALL no significant association was observed (N=85; 7 relapses; HR 1.6, 95% CI 0.3-8.2, p = 0.58), however the number of T-cell ALL was too small to allow reliable conclusions. In a simple Cox model, TLP was associated with a significantly higher risk of relapse than no TLP (HR 2.7, 95% CI 1.3-5.9, p = 0.011), but this was only the case for patients who were positive by FCM (FCM pos: HR 2.7, 95% CI 1.0-7.0, p = 0.043; FCM neg: 0.7, 95% CI 0.1-5.0, p = 0.68). Conclusion: FCM markedly increases the detection rate for CNS involvement at diagnosis, and distinguish between patients at high and low risk of relapse. Diagnosis of CNS leukemia by combined cytospin and FCM analysis should be the standard for accurate classification of CNS status, which will enable better stratification of CNS-directed and systemic therapy. Disclosures No relevant conflicts of interest to declare.

BACKGROUND Treatment-related osteonecrosis (ON) is a serious complication of treatment of acute lymphoblastic leukemia (ALL). PROCEDURE This study included 1,489 patients with ALL, aged 1-45 years, treated according to the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol, using alternate-week dexamethasone during delayed intensification, with prospective registration of symptomatic ON. We aimed at comparing risk factors, timing, and clinical characteristics of ON in children and young adults. RESULTS ON was diagnosed in 67 patients, yielding a 5-year cumulative incidence of 6.3%, but 28% in female adolescents. Median age at ALL diagnosis was 12.1 years and 14.9 years for females and males, respectively. At ON diagnosis, 59 patients had bone pain (91%) and 30 (46%) had multiple-joint involvement. The median interval between ALL and ON diagnosis was significantly shorter in children aged 1.0-9.9 years (0.7 years [range: 0.2-2.1]) compared with adolescents (1.8 years [range: 0.3-3.7, P