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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.

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: 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 ...

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

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

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.

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 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

Background Health-related quality of life (HRQoL) was assessed in a cohort of long-term childhood acute lymphoblastic leukemia (ALL) survivors. Procedure Rand-36-Item health Survey (RAND-36) was used to assess subjective HRQoL in 74 survivors of ALL an average of 20 years after the diagnosis. Cranial irradiation had been administered to 46 of the survivors, while 28 survivors had solely been treated with chemotherapy. The control group consisted of 146 healthy young adults selected from local population registry. Survivors were examined by a physician and late effects were graded using the Common Terminology Criteria for Adverse Events (CTCAEv3). Results ALL survivors achieved significantly higher scores than the controls on three of the eight HRQoL subscales; role limitations due to emotional problems (P = 0.030), mental health (P = 0.030) and vitality (P = 0.004). In comparison to controls, survivors with a follow-up of more than 20 years had significantly higher scores on vitality (P = 0.006) and mental health (P = 0.011). Survivors with severe (grade 3 and 4) late effects scored significantly better than controls on vitality (P = 0.043) and mental health (P = 0.040). Patients who had been treated for an ALL relapse and had received the most intensive chemo- and radiotherapy had significantly higher scores on mental health (P = 0.004) and vitality (P = 0.004) than the controls. Conclusions Long-term survivors of childhood ALL reported equal or better HRQoL in RAND-36. Higher HRQoL scores were associated with more severe late effects and intensive therapy. Our findings support the idea of response bias. Pediatr Blood Cancer. 2010;55:331–336. © 2010 Wiley–Liss, Inc.

Background Despite the extensive literature on neuropsychological sequelae after treatment of childhood acute lymphoblastic leukemia (ALL), the very-long-term neurocognitive outcome of the survivors is poorly studied. We assessed neuropsychological functioning in a population-based cohort of young adult childhood ALL survivors. Procedure Neuropsychological testing was performed on 64 survivors an average of 20 years after the diagnosis. The test battery included verbal intelligence quotient (VIQ) and performance intelligence quotient (PIQ), memory function, orientation and attention as well as motor performance. Cranial irradiation had been administered to 44 survivors as part of ALL treatment, whereas 20 survivors had been treated solely with chemotherapy. A control group consisted of 45 healthy young adults. Earlier neuropsychological test results of 45 of the survivors were available for comparison. Results The ALL survivors attained significantly lower test scores than the controls in all the neuropsychological function areas. The mean VIQ test scores were 91, 100, and 109 (P

Central nervous system (CNS) involvement in childhood acute myeloid leukemia (AML) can manifest as leukemic cells in the cerebrospinal fluid, a solid CNS tumor, or as neurological symptoms. We evaluated the presenting symptoms and neuroimaging findings in 33 of 34 children with AML and CNS involvement at diagnosis in the period 2000-2012 in Sweden, Finland, and Denmark. Imaging was performed in 22 patients, of whom 16 had CNS-related symptoms. Seven patients, including all but two with facial palsy, had mastoid cell opacification, considered an incidental finding. The frequent involvement of the mastoid bone with facial palsy warrants evaluation in larger series.