Publications by authors named "Olafur Gisli Jonsson"

31 Publications

No association between relapse hazard and thiopurine methyltransferase geno- or phenotypes in non-high risk acute lymphoblastic leukemia: a NOPHO ALL2008 sub-study.

Cancer Chemother Pharmacol 2021 Apr 29. Epub 2021 Apr 29.

Department of Pediatrics and Adolescent Medicine, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark.

Purpose: 6-mercaptopurine(6MP)/methotrexate maintenance therapy is essential to reduce relapse of childhood acute lymphoblastic leukemia (ALL). Common germline variants in TPMT cause low activity of thiopurine methyltransferase (TPMT) and higher 6MP metabolite (TGN) levels. Higher levels of TGNs incorporated into DNA (DNA-TG) and low TPMT activity have previously been associated with a lower relapse risk. We explored if TPMT geno- or phenotype was associated with DNA-TG levels and relapse rate in NOPHO ALL2008.

Methods: TPMT genotype, repeated phenotyping, and DNA-TG measurements were collected in 918 children with non-high risk ALL (NOPHO ALL2008 maintenance therapy study). Maintenance therapy started with 6MP at 50 and 75 mg/m for TPMT heterozygous and wildtype patients and was adjusted to a target WBC of 1.5 - 3.0 × 10/L.

Results: Of 918 patients, 78 (8.5%) were TPMT heterozygous and 903 had at least one TPMT measurement (total 3063). Mean TPMT activities were higher with wildtype than heterozygous TPMT (N = 752, 16.6 versus 9.6 U/mL ery., p < 0.001). The 5-year cumulative incidence of relapse was 6.4% and 6.0% for TPMT heterozygous and wildtype patients, and there was no association between genotype and relapse rate (N = 918, hazard ratio = 1.01, 95% confidence interval [CI] 0.40 - 2.54, p = 0.98). Although TPMT heterozygous patients had higher DNA-TG (N = 548, median 760.9 [interquartile range (IQR) 568.7 - 890.3] versus 492.7 [IQR 382.1 - 634.6] fmol/µg, p < 0.001), TPMT activity was not associated with relapse rate (N = 813; hazard ratio = 0.98 per one U/mL ery. increase in TPMT activity, 95% CI 0.91 - 1.06, p = 0.67).

Conclusion: TPMT geno- and phenotype were not associated with relapse in non-high risk NOPHO ALL2008.
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http://dx.doi.org/10.1007/s00280-021-04281-7DOI Listing
April 2021

polymorphisms and minimal residual disease after 6-mercaptopurine post-remission consolidation therapy of childhood acute lymphoblastic leukaemia.

Pediatr Hematol Oncol 2021 Apr 18;38(3):227-238. Epub 2020 Nov 18.

Pediatric Oncology research laboratory, The University Hospital Rigshospitalet, Copenhagen, Denmark.

Bone marrow minimal residual disease (MRD) is the strongest predictor of relapse in children with acute lymphoblastic leukemia (ALL). 6-mercaptopurine (6MP) in ALL therapy has wide inter-individual variation in disposition and is strongly influenced by polymorphisms in the thiopurine methyltransferase () gene. In 952 patients treated according to the NOPHO ALL2008 protocol, we explored the association between thiopurine disposition, genotypes and MRD levels after consolidation therapy with 6MP, high-dose methotrexate (HD-MTX), asparaginase, and vincristine. The levels of the cytotoxic DNA-incorporated thioguanine were significantly higher on day 70-79 in G460A/A719G heterozygous () compared to wild type () patients (mean: 230.7 vs. 149.7 fmol/µg DNA, p = 0.002). In contrast, genotype did not associate with the end of consolidation MRD levels irrespective of randomization of the patients to fixed dose (25 mg/m/day) or 6MP escalation (up to 50 or 75 mg/m/day) during consolidation therapy.
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http://dx.doi.org/10.1080/08880018.2020.1842570DOI Listing
April 2021

Polygenic risk score-analysis of thromboembolism in patients with acute lymphoblastic leukemia.

Thromb Res 2020 12 12;196:15-20. Epub 2020 Aug 12.

Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Postboks 4950 Nydalen, 0424 Oslo, Norway.

Introduction: Thromboembolism (TE) is a common and serious toxicity of acute lymphoblastic leukemia (ALL) treatment, but studies of genetic predisposition have been underpowered with conflicting results. We tested whether TE in ALL and TE in the general adult population have a shared genetic etiology.

Materials And Methods: We prospectively registered TE events and collected germline DNA in patients 1.0-45.9 years in the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 study (7/2008-7/2016). Based on summary statistics from two large genome-wide association studies (GWAS) on venous TE in adults (the International Network of VENous Thromboembolism Clinical Research Networks (INVENT) consortium and the UK Biobank), we performed polygenic risk score (PRS) analysis on TE development in the NOPHO cohort, progressively expanding the PRS by increasing the p-value threshold of single nucleotide polymorphism (SNP) inclusion.

Results And Conclusion: Eighty-nine of 1252 patients with ALL developed TE, 2.5 year cumulative incidence 7.2%. PRS of genome-wide significant SNPs from the INVENT and UK Biobank data were not significantly associated with TE, HR 1.16 (p 0.14) and 1.02 (p 0.86), respectively. Expanding PRS by increasing p-value threshold did not reveal polygenic overlap. However, subgroup analysis of adolescents 10.0-17.9 years (n = 231), revealed significant polygenic overlap with the INVENT GWAS. The best fit PRS, including 16,144 SNPs, was associated with TE with HR 1.76 (95% CI 1.23-2.52, empirical p-value 0.02). Our results support an underlying genetic predisposition for TE in adolescents with ALL and should be explored further in future TE risk prediction models.
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http://dx.doi.org/10.1016/j.thromres.2020.08.015DOI Listing
December 2020

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

Res Pract Thromb Haemost 2020 Jul 21;4(5):866-871. Epub 2020 Jun 21.

Department of Pediatric Hematology and Oncology Unit for Pediatric and Adolescent Medicine Oslo University Hospital Oslo Norway.

Background: Pulmonary embolism (PE) is a serious complication of acute lymphoblastic leukemia (ALL). We examined the cumulative incidence and clinical presentation of PE in a well-defined cohort of patients with ALL aged 1-45 years treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol.

Methods: As part of the mandatory toxicity reporting of NOPHO ALL2008, thromboembolism including PE was reported consecutively. The cumulative incidence of first-time PE was calculated using the Aalen-Johansen estimator during a 2.5-year period from ALL diagnosis. We used Fisher's exact test to examine categorical variables and Cox logistic regression to estimate hazard ratios (HRs) for PE.

Results: PE was diagnosed in 32 of 1685 patients. The 2.5-year cumulative incidence of first-time PE increased with age: 0.43% (95% CI, 0.18-1.03) in children aged 1-9 years, 3.28% (95% CI, 1.72-6.22) in children aged 10-17 years, and 7.22% (95% CI, 4.61-11.21) in adults aged 18-45 years. The majority of PEs, 78% (25/32), occurred during asparaginase treatment. HRs adjusted for age and sex were associated with male sex (HR, 2.4; 95% CI, 1.0-5.6) and older age (10-17 years: HR 7.5; 95% CI, 2.5-22.2), 18-45 years: HR, 16.5; 95% CI, 6.1-44.5). In two-thirds of the patients (63%; 17/27), PE and its treatment had no impact on the administered doses of asparaginase. PE-associated 30-day mortality was 9.4% (95% CI, 1.9-25.0).

Conclusions: Awareness of PE is warranted during ALL treatment. Larger multicenter studies are needed to examine predictors of PE in ALL.
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http://dx.doi.org/10.1002/rth2.12356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354408PMC
July 2020

Effects of germline DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia.

Blood 2020 09;136(10):1161-1168

Department of Pediatrics and Adolescent Medicine and.

Methotrexate (MTX) during maintenance therapy is essential for curing acute lymphoblastic leukemia (ALL), but dosing strategies aiming at adequate treatment intensity are challenged by interindividual differences in drug disposition. To evaluate genetic factors associated with MTX metabolism, we performed a genome-wide association study in 447 ALL cases from the Nordic Society for Pediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic single-nucleotide polymorphism rs1382539, located in a regulatory element of DHFR, was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 × 10-8) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P = 5.6 × 10-9) was associated with decreased levels of long-chain MTX polyglutamates through reduced catalytic activity. Furthermore, the FPGS variant was linked with increased relapse risk (P = .044). These findings show a genetic basis for interpatient variability in MTX response and could be used to improve future dosing algorithms.
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http://dx.doi.org/10.1182/blood.2020005064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472715PMC
September 2020

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

Eur J Paediatr Neurol 2020 Jul 18;27:72-77. Epub 2020 Apr 18.

University of Uppsala, Department of Women's and Children's Health, Uppsala, Sweden.

Background: Seizures are common in children with acute lymphoblastic leukemia (ALL). As ALL survival rates are improving, the challenge to minimize treatment related side effects and late sequelae rises. Here, we studied the frequency, timing, etiology and risk factors of seizures in ALL patients.

Methods: The study included children aged 1-17.9 years at diagnosis of B-cell-precursor and T cell ALL who were treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol between 2008 and 2015. Detailed patient data were acquired from the NOPHO ALL2008 registry and by review of medical records.

Results: Seizures occurred in 81/1464 (5.5%) patients. The cumulative incidence of seizures at one months was 1.7% (95% CI: 1.2-2.5) and at one year 5.3% (95% CI 4.2-6.5%). Patients aged 10-17.9 years, those with T cell immunophenotype, CNS involvement, or high-risk induction with dexamethasone had higher risk for seizures in univariable analyses. Only age remained a risk factor in multivariable analyses (the cumulative incidence of seizures for patients 10-17.9 years old at one year was 9.0% (95% CI: 6.2-12.9)). Of the 81 patients with seizures, 43 had posterior reversible encephalopathy syndrome (PRES), 15 had isolated seizures, nine had sinus venous thrombosis (SVT), three had stroke-like syndrome, and 11 had other neurotoxicities. Epilepsy diagnosis was reported in totally 11 ALL survivors at last follow up.

Conclusion: Seizures are relatively common in ALL patients and occur most often in patients with PRES, SVT, or as an isolated symptom. Older children have higher risk of seizures.
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http://dx.doi.org/10.1016/j.ejpn.2020.04.004DOI Listing
July 2020

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

Thromb Res 2019 Dec 7;184:92-98. Epub 2019 Nov 7.

Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University Hospital of Copenhagen, Belgdamsvej 9, 2100 Copenhagen, Denmark; Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Nørregade 10, 1165 Copenhagen, Denmark.

Introduction: Thromboembolism is a serious toxicity of acute lymphoblastic leukemia treatment, and contributes to substantial morbidity and mortality. Several single nucleotide polymorphisms have been associated with thromboembolism in the general population; however, their impact in patients with acute lymphoblastic leukemia, particularly in children, remains uncertain.

Materials And Methods: We collected constitutional DNA and prospectively registered thromboembolic events in 1252 patients, 1-45 years, with acute lymphoblastic leukemia included in the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol in the Nordic and Baltic countries (7/2008-7/2016). Based on previously published data and a priori power calculations, we selected four single nucleotide polymorphisms: F5 rs6025, F11 rs2036914, FGG rs2066865, and ABO rs8176719.

Results: The 2.5 year cumulative incidence of thromboembolism was 7.1% (95% confidence interval (CI) 5.6-8.5). F11 rs2036914 was associated with thromboembolism (hazard ratio (HR) 1.52, 95%CI 1.11-2.07) and there was a borderline significant association for FGG rs2066865 (HR 1.37, 95%CI 0.99-1.91), but no association for ABO rs8176719 or F5 rs6025 in multiple cox regression. A genetic risk score based on F11 rs2036914 and FGG rs2066865 was associated with thromboembolism (HR 1.45 per risk allele, 95%CI 1.15-1.81), the association was strongest in adolescents 10.0-17.9 years (HR 1.64).

Conclusion: If validated, a F11 rs2036914/FGG rs2066865 risk prediction model should be tested as a stratification tool for prevention of thromboembolism in patients with acute lymphoblastic leukemia.
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http://dx.doi.org/10.1016/j.thromres.2019.11.002DOI Listing
December 2019

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

Pediatr Blood Cancer 2019 05 27;66(5):e27594. Epub 2018 Dec 27.

Department of Women's and Children's Health, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1002/pbc.27594DOI Listing
May 2019

Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy.

Cancer Chemother Pharmacol 2019 01 15;83(1):53-60. Epub 2018 Oct 15.

Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark.

Purpose: Methotrexate polyglutamates (MTXpg) facilitate incorporation of thioguanine nucleotides into DNA (DNA-TG, the primary cytotoxic thiopurine metabolite and outcome determinant in MTX/6-mercaptopurine treatment of childhood ALL). We hypothesized that mapping erythrocyte levels of MTXpg with 1-6 glutamates and their associations with DNA-TG formation would facilitate future guidelines for maintenance therapy dosing.

Methods And Results: Summed MTX with 1-6 glutamates resolved by LCMS [median (interquartile): 5.47 (3.58-7.69) nmol/mmol hemoglobin] was in agreement with total MTX by radio ligand assay. In 16,389 blood samples from 1426 ALL maintenance therapy patients, MTXpg3 21.0 (15.2-27.4)% was the predominant metabolite, and MTXpg1 (the maternal drug) constituted 38.6 (27.2-50.2)% of MTXpg1-6. All subsets correlated; the strongest associations were between metabolites with similar polyglutamate lengths. Correlations of MTXpg1 with MTXpg2 and MTXpg3,4,5,6 were r = 0.68 and r = 0.25-0.42, respectively. Intercorrelations of MTXpg3,4,5,6 were all r ≥ 0.51. MTXpg4 accounted for 29.8 (24.7-33.3)% of MTXpg3-6, yet explained 96% of the summed MTXpg3-6 variation. MTXpg1-4, MTXpg1-6, MTXpg2-6 and MTXpg3 were all associated with DNA-TG levels (p < 0.00001), but collinearity precluded identification of the most informative subset.

Conclusions: Measuring erythrocyte MTXpg4 simplifies and can replace longer chain MTXpg monitoring. Resolving individual MTXpg identifies samples that are unsuitable for dose guidance due to high levels of MTXpg1 remaining in the plasma fraction because of recent MTX intake. All tested MTXpg subsets correlated with DNA-TG and may be used for ALL maintenance therapy dose adjustments, but the most informative subset remains to be identified.
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http://dx.doi.org/10.1007/s00280-018-3704-7DOI Listing
January 2019

NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia.

Leukemia 2018 12 10;32(12):2527-2535. Epub 2018 Sep 10.

Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.

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 () 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 (DNA-TG/Ery-TGN ratio) was significantly associated with three intronic SNPs in NT5C2 (top hit: rs72846714; P = 2.09 × 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 and 1.3 × 10, respectively). The association was mostly driven by differences in Ery-TGN, but in regression analyses adjusted for Ery-TGN (P < 0.0001), rs72846714-A genotype was also associated with a higher DNA-TG (P = 0.029). Targeted sequencing of NT5C2 did not identify any missense variants associated with rs72846714 or Ery-TGN/DNA-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.
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http://dx.doi.org/10.1038/s41375-018-0245-3DOI Listing
December 2018

Thromboembolism in acute lymphoblastic leukemia: results of NOPHO ALL2008 protocol treatment in patients aged 1 to 45 years.

Blood 2018 05 16;131(22):2475-2484. Epub 2018 Apr 16.

Pediatric Oncology Research Laboratory and.

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 ( < .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; < .0001]; 18.0-45.9 years: HRa, 6.06 [95% CI, 3.65-10.1; < .0001]) and mediastinal mass at ALL diagnosis (HRa, 2.1; 95% CI, 1.0-4.3; = .04). In a multiple absolute risk regression model addressing 3 thromboembolism risk factors, age at least 10 years had the largest absolute risk ratio (RR, 4.7 [95% CI, 3.1-7.1]; RR, 2.0 [95% CI, 1.2-3.1]; RR, 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; < .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; = .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 ( = .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 ≤ .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.
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http://dx.doi.org/10.1182/blood-2018-01-827949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5981169PMC
May 2018

DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia.

Clin Epigenetics 2018 5;10:31. Epub 2018 Mar 5.

1Department of Medical Biosciences, Umeå University, Blg 6M, 2nd floor, SE-90185 Umeå, Sweden.

Background: Few biological markers are associated with survival after relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In pediatric T-cell ALL, we have identified promoter-associated methylation alterations that correlate with prognosis. Here, the prognostic relevance of CpG island methylation phenotype (CIMP) classification was investigated in pediatric BCP-ALL patients.

Methods: Six hundred and one BCP-ALL samples from Nordic pediatric patients (age 1-18) were CIMP classified at initial diagnosis and analyzed in relation to clinical data.

Results: Among the 137 patients that later relapsed, patients with a CIMP- profile ( = 42) at initial diagnosis had an inferior overall survival (pOS 33%) compared to CIMP+ patients ( = 95, pOS 65%) ( = 0.001), which remained significant in a Cox proportional hazards model including previously defined risk factors.

Conclusion: CIMP classification is a strong candidate for improved risk stratification of relapsed BCP-ALL.
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http://dx.doi.org/10.1186/s13148-018-0466-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836434PMC
February 2019

Individualized 6-mercaptopurine increments in consolidation treatment of childhood acute lymphoblastic leukemia: A NOPHO randomized controlled trial.

Eur J Haematol 2018 Jan 9;100(1):53-60. Epub 2017 Nov 9.

Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.

Objectives: This randomized controlled trial tested the hypothesis that children with non-high-risk acute lymphoblastic leukemia could benefit from individualized 6-mercaptopurine increments during consolidation therapy (NCT00816049). Primary and secondary end points were end of consolidation minimal residual disease (MRD) positivity and event-free survival.

Methods: 392 patients were randomized to experimental and 396 to standard therapy. Patients allocated to standard therapy received oral 6-mercaptopurine (25 mg/m /day) from days 30 to 85, while the experimental arm received stepwise increments of additional 25 mg/m /day beginning on days 50 and/or 71 unless dose-limiting myelosuppression had occurred.

Results: In the experimental arm, 166 patients (42%) received one dose increment, and 62 (16%) received two. Fifty-seven of 387 (15%) patients in the experimental arm were MRD positive at end of consolidation vs 77 of 389 (20%) in the control arm (P = .08). Five-year probability of event-free survival was 0.89 (95% CI: 0.85-0.93) in the experimental arm vs 0.93 (0.90-0.96) in the control arm (P = .13). The median accumulated length of 6-mercaptopurine treatment interruptions was 7 (IQR 2-12) in the experimental arm vs 4 (IQR 0-10) in the control arm (P = .002).

Conclusion: This study found no benefit from individualized 6-mercaptopurine increments compared to standard therapy.
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http://dx.doi.org/10.1111/ejh.12979DOI Listing
January 2018

DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial.

Lancet Oncol 2017 04 1;18(4):515-524. Epub 2017 Mar 1.

Department of Pediatrics and Adolescent Medicine, University Hospital, Rigshospitalet, Copenhagen, Denmark; Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Background: Adjustment of mercaptopurine and methotrexate maintenance therapy of acute lymphoblastic leukaemia by leucocyte count is confounded by natural variations. Cytotoxicity is primarily mediated by DNA-incorporated thioguanine nucleotides (DNA-TGN). The aim of this study was to establish whether DNA-TGN concentrations in blood leucocytes during maintenance therapy are associated with relapse-free survival.

Methods: In this substudy of the NOPHO ALL2008 phase 3 trial done in 23 hospitals in seven European countries (Denmark, Estonia, Finland, Iceland, Lithuania, Norway, and Sweden), we analysed data from centralised and blinded analyses of 6-mercaptopurine and methotrexate metabolites in blood samples from patients with non-high-risk childhood acute lymphoblastic leukaemia. Eligible patients were aged 1·0-17·9 years; had been diagnosed with non-high-risk precursor B-cell or T-cell leukaemia; had been treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol; and had reached maintenance therapy in first remission. Maintenance therapy was (mercaptopurine 75 mg/m once per day and methotrexate 20 mg/m once per week, targeted to a leucocyte count of 1·5-3·0 × 10 cells per L). We measured DNA-TGN and erythrocyte concentrations of TGN nucleotides, methylated mercaptopurine metabolites, and methotrexate polyglutamates. The primary objective was the association of DNA-TGN concentrations and 6-mercaptopurine and methotrexate metabolites with relapse-free survival. The secondary endpoint was the assessment of DNA-TGN concentration and 6-mercaptopurine and methotrexate metabolites during maintenance therapy phase 2.

Findings: Between Nov 26, 2008 and June 14, 2016, 1509 patients from the NOPHO ALL2008 study were assessed for eligibility in the DNA-TGN substudy, of which 918 (89%) of 1026 eligible patients had at least one DNA-TGN measurement and were included in the analyses. Median follow-up was 4·6 years (IQR 3·1-6·1). Relapse-free survival was significantly associated with DNA-TGN concentration (adjusted hazard ratio 0·81 per 100 fmol/μg DNA increase, 95% CI 0·67-0·98; p=0·029). In patients with at least five blood samples, erythrocyte concentrations of TGN, methylated mercaptopurine metabolites, and methotrexate polyglutamates were associated with DNA-TGN concentration (all p<0·0001).

Interpretation: Our results suggest the need for intervention trials to identify clinically applicable strategies for individualised drug dosing to increase DNA-TGN concentration, and randomised studies to investigate whether such strategies improve cure rates compared with current dose adjustments based on white blood cell counts.

Funding: Danish Cancer Society, Childhood Cancer Foundation (Denmark), Childhood Cancer Foundation (Sweden), Nordic Cancer Union, Otto Christensen Foundation, University Hospital Rigshospitalet, and Novo Nordic Foundation.
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http://dx.doi.org/10.1016/S1470-2045(17)30154-7DOI Listing
April 2017

Efficacy and Toxicity of Intrathecal Liposomal Cytarabine in First-line Therapy of Childhood Acute Lymphoblastic Leukemia.

J Pediatr Hematol Oncol 2016 11;38(8):602-609

*Department of Paediatrics and Adolescent Medicine, The University Hospital Rigshospitalet ‡Section of Biostatistics, Department of Public Health ‡‡The Institute of Clinical medicine, The Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark †Department of Pediatrics, Astrid Lindgrens Hospital, Stockholm ¶Department of Pediatrics, Institution of Clinical Sciences, Sahlgrenska University Hospital, Gothenburg ††Department of Pediatrics, Skåne University Hospital, Lund, Sweden §Department of Pediatrics, Landspitali University Hospital, Reykjavík, Iceland ∥Division of Hematology-Oncology and Stem Cell Transplantation, Children and Adolescents, Helsinki **Department of Clinical Chemistry, Institute of Diagnostics, University of Oulu, Oulu, Finland #Department of Pediatrics, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway, NY.

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.
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http://dx.doi.org/10.1097/MPH.0000000000000642DOI Listing
November 2016

The effect of central nervous system involvement and irradiation in childhood acute lymphoblastic leukemia: Lessons from the NOPHO ALL-92 and ALL-2000 protocols.

Pediatr Blood Cancer 2017 02 17;64(2):242-249. Epub 2016 Oct 17.

Department of Pediatric Oncology, Astrid Lindgren Children's Hospital, Stockholm, Sweden.

Background: Central nervous system irradiation (CNS-RT) has played a central role in the cure of acute lymphoblastic leukemia (ALL), but due to the risk of long-term toxicity, it is now considered a less-favorable method of CNS-directed therapy.

Procedures: Retrospectively, we estimated the effect of CNS involvement and CNS-RT on events and overall survival (OS) in 835 children treated for high-risk ALL in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-92 and ALL-2000 trials.

Results: We did not observe a statistically significant difference in the OS or event-free survival (EFS) in patients with CNS involvement at diagnosis, but the risk of isolated CNS relapse was higher (hazard ratio [HR] 7.09, P < 0.001). CNS-RT was given to 169 of the 783 patients in first complete remission, of which 16 had CNS involvement at diagnosis. In general, CNS-RT improved EFS (HR 0.58, P < 0.05) but not OS (HR 0.69, P = n.s.). The adjusted HRs for all relapses, isolated bone marrow relapse, CNS-involving relapse, and isolated CNS relapse, were 0.47 (P < 0.01), 0.50 (P < 0.05), 0.34 (P < 0.01), and 0.12 (P < 0.01), respectively, in irradiated patients.

Conclusions: CNS-RT was associated with an advantage in EFS by decreasing the risk of relapse but without improving OS.
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http://dx.doi.org/10.1002/pbc.26191DOI Listing
February 2017

Parents' and Adolescents' Preferences for Intensified or Reduced Treatment in Randomized Lymphoblastic Leukemia Trials.

Pediatr Blood Cancer 2016 May 31;63(5):865-71. Epub 2015 Dec 31.

Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.

Background: When offered participation in clinical trials, families of children with cancer face a delicate balance between cure and toxicity. Since parents and children may perceive this balance differently, this paper explores whether adolescent patients have different enrollment patterns compared to younger children in trials with different toxicity profiles.

Procedure: Age-dependent participation rates in three consecutive, randomized childhood leukemia trials conducted by the Nordic Society of Paediatric Haematology and Oncology were evaluated. The ALL2000 dexamethasone/vincristine (Dx/VCR) trial tested treatment intensifications to improve cure, and the back-to-back ALL2008 6-mercaptopurine (6MP) and ALL2008 PEG-asparaginase (ASP) trials tested treatment intensifications (6MP) and toxicity reduction without compromising survival (ASP). Patient randomization and toxicity data were prospectively registered by the treating physicians.

Results: Parents of young children favored treatment intensifications (Dx/VCR: 12% refusal; 6MP: 14%; ASP: 21%), whereas parents of adolescents favored treatment reductions (Dx/VCR: 52% refusal; 6MP: 30%; ASP: 8%). Adolescents were more likely to refuse intensification trials than young children (adjusted ORs 6.3; P < 0.01 [Dx/VCR] and 2.1; P = 0.04 [6MP]). Adolescents were less likely to refuse the ASP trial, with varying effect size depending on the length of the preceding consolidation treatment (adjusted OR for median consolidation length 0.15; P = 0.01). Younger children participated more frequently in only 6MP than in only ASP (14% vs. 5%), and adolescents vice versa (2% vs. 17%; P = 0.001).

Conclusions: Parents' and adolescents' divergent inclinations toward intensified or reduced therapy emphasize the necessity of actively involving adolescents in the informed consent process, which should also address motives for trial participation.
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http://dx.doi.org/10.1002/pbc.25887DOI Listing
May 2016

Acute Myeloid Leukemia in Adolescents and Young Adults Treated in Pediatric and Adult Departments in the Nordic Countries.

Pediatr Blood Cancer 2016 Jan 18;63(1):83-92. Epub 2015 Aug 18.

Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.

Background: Studies on adolescents and young adults with acute lymphoblastic leukemia suggest better results when using pediatric protocols for adult patients, while corresponding data for acute myeloid leukemia (AML) are limited.

Procedure: We investigated disease characteristics and outcome for de novo AML patients 10-30 years old treated in pediatric or adult departments. We included 166 patients 10-18 years of age with AML treated according to the pediatric NOPHO-protocols (1993-2009) compared with 253 patients aged 15-30 years treated in hematology departments (1996-2009) in the Nordic countries.

Results: The incidence of AML was 4.9/million/year for the age group 10-14 years, 6.5 for 15-18 years, and 6.9 for 19-30 years. Acute promyelocytic leukemia (APL) was more frequent in adults and in females of all ages. Pediatric patients with APL had similar overall survival as pediatric patients without APL. Overall survival at 5 years was 60% (52-68%) for pediatric patients compared to 65% (58-70%) for adult patients. Cytogenetics and presenting white blood cell count were the only independent prognostic factors for overall survival. Age was not an independent prognostic factor.

Conclusions: No difference was found in outcome for AML patients age 10-30 years treated according to pediatric as compared to adult protocols.
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http://dx.doi.org/10.1002/pbc.25713DOI Listing
January 2016

Toxicity profile and treatment delays in NOPHO ALL2008-comparing adults and children with Philadelphia chromosome-negative acute lymphoblastic leukemia.

Eur J Haematol 2016 Feb 24;96(2):160-9. Epub 2015 Apr 24.

Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark.

Objectives: Cure rates improve when adolescents and young adults with acute lymphoblastic leukemia (ALL) are treated according to pediatric protocols. Assumed risks of toxicities and associated delays in treatment have played a role in setting upper age limits. The aim of this study was to examine the toxicity profile and treatment delays in NOPHO ALL2008 comparing children and adults.

Methods: We collected information on 19 treatment-related toxicities, systematically captured at 3-month intervals throughout therapy, and time intervals between 12 consecutive treatment phases for 1076 patients aged 1-45 yrs treated according to the Nordic/Baltic ALL2008 protocol.

Results: No adults died during induction. The duration of induction therapy and postinduction treatment phases did not differ between children and adults, except for patients 18-45 yrs being significantly delayed during two of nine high-risk blocks (median number of days for patients 1-9, 10-17, and 18-45 yrs; the glucocorticosteroid/antimetabolite-based block B1: 24, 26, and 29 d, respectively, P = 0.001, and Block 5 (in most cases also a B block): 29, 29, and 37 d, respectively, P = 0.02). A higher incidence of thrombosis with increasing age was found; highest odds ratio 5.4 (95% CI: (2.6;11.0)) for patients 15-17 yrs compared with children 1-9 yrs (P < 0.0001). Risk of avascular osteonecrosis was related to age with the highest OR for patients 10-14 yrs (OR = 10.4 (95% CI: (4.4;24.9)), P < 0.0001).

Conclusion: Adults followed and tolerated the NOPHO ALL2008 protocol virtually as well as children, although thrombosis and avascular osteonecrosis was most common among adolescents.
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http://dx.doi.org/10.1111/ejh.12562DOI Listing
February 2016

PEG-asparaginase allergy in children with acute lymphoblastic leukemia in the NOPHO ALL2008 protocol.

Pediatr Blood Cancer 2015 Mar 21;62(3):427-33. Epub 2014 Nov 21.

Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.

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/m(2) /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.
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http://dx.doi.org/10.1002/pbc.25319DOI Listing
March 2015

Pharmacogenetically based dosing of thiopurines in childhood acute lymphoblastic leukemia: influence on cure rates and risk of second cancer.

Pediatr Blood Cancer 2014 May 3;61(5):797-802. Epub 2014 Jan 3.

Department of Pediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, Copenhagen, Denmark.

Background: Previous studies have indicated that patients with thiopurine methyltransferase (TPMT) low activity (TPMT(LA)) have reduced risk of relapse but increased risk of second malignant neoplasm (SMN) compared to patients with TPMT wild-type (TPMT(WT)) when treated with 6 MP maintenance therapy starting doses of 75 mg/m(2)/day. To reduce SMN risk, 6MP starting doses were reduced to 50 mg/m(2)/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 TPMT(LA) 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 <75 mg/m(2)/day when compared to the patients in ALL92 (relapse (n = 11) and SMN (n = 0) in ALL2000 versus relapse (n = 5) and SMN (n = 4) in ALL92, P = 0.03). Furthermore, the 8-year cumulative incidence of relapse for patients with TPMT(LA) was significantly higher in the ALL2000 compared to the ALL92 cohort (19.7% (11.6-33.3%) vs. 6.7% (2.9-15.5%), P = 0.03).

Conclusion: This study indicates that reducing 6MP starting dose for patients with TPMT(LA) may reduce SMN risk but lead to a relapse risk similar to that of patients with TPMT(WT).
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http://dx.doi.org/10.1002/pbc.24921DOI Listing
May 2014

Risk group assignment differs for children and adults 1-45 yr with acute lymphoblastic leukemia treated by the NOPHO ALL-2008 protocol.

Eur J Haematol 2013 May 2;90(5):404-12. Epub 2013 Apr 2.

Department of Hematology, Herlev University Hospital, University of Copenhagen, Herlev, Denmark.

Background: The prognosis of acute lymphoblastic leukemia is poorer in adults than in children. Studies have indicated that young adults benefit from pediatric treatment, although no upper age limit has been defined.

Design And Methods: We analyzed 749 patients aged 1-45 yr treated by the NOPHO ALL-2008 protocol. Minimal residual disease (MRD) on days 29 and 79, immunophenotype, white blood cell count (WBC), and cytogenetics were used to stratify patients to standard-, intermediate-, or high-risk treatment with or without hematopoietic stem cell transplantation.

Results: Adults aged 18-45 had significantly lower WBCs at diagnosis compared with children aged 1-9 and 10-17 yr, but significantly more adults were stratified to high-risk chemotherapy (8%, 14%, 17%; P < 0.0001) or high-risk chemotherapy with transplantation (4%, 13%, 19%; P < 0.0001). This age-dependent skewing of risk grouping reflected more T-ALL (11%, 27%, 33%, P < 0.0001), poorer MRD response day 29 (MRD < 0.1%: 75%, 61%, 52%; P < 0.0001), and more MLL gene rearrangements (3%, 3%, 10%; P = 0.005) in older patients.

Conclusions: Even if identical diagnostics, treatment, and risk stratification are implemented, more adults will be stratified to high-risk therapy, which should be considered when comparing pediatric and adult outcomes.
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http://dx.doi.org/10.1111/ejh.12097DOI Listing
May 2013

Gemtuzumab ozogamicin as postconsolidation therapy does not prevent relapse in children with AML: results from NOPHO-AML 2004.

Blood 2012 Aug 22;120(5):978-84. Epub 2012 Jun 22.

Department of Pediatrics, Aarhus University Hospital, Skejby, Denmark.

There are no data on the role of postconsolidation therapy with gemtuzumab ozogamicin (GO; Mylotarg) in children with acute myeloid leukemia (AML). The NOPHO-AML 2004 protocol studied postconsolidation randomization to GO or no further therapy. GO was administered at 5 mg/m(2) and repeated after 3 weeks. We randomized 120 patients; 59 to receive GO. Survival was analyzed on an intention-to-treat basis. The median follow-up for patients who were alive was 4.2 years. Children who received GO showed modest elevation of transaminase and bilirubin without signs of veno-occlusive disease. Severe neutropenia followed 95% and febrile neutropenia 40% of the GO courses. Only a moderate decline in platelet count and a minor decrease in hemoglobin occurred. Relapse occurred in 24 and 25 of those randomized to GO or no further therapy. The median time to relapse was 16 months versus 10 months (nonsignificant). The 5-year event-free survival and overall survival was 55% versus 51% and 74% versus 80% in those randomized to receive GO or no further therapy, respectively. Results were similar in all subgroups. In conclusion, GO therapy postconsolidation as given in this trial was well tolerated, showed a nonsignificant delay in time to relapse, but did not change the rate of relapse or survival (clinicaltrials.gov identifier NCT00476541).
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http://dx.doi.org/10.1182/blood-2012-03-416701DOI Listing
August 2012

Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia.

Pediatr Blood Cancer 2011 Apr 8;56(4):551-9. Epub 2010 Dec 8.

Department of Pediatrics, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.

Background: In spite of major improvements in the cure rate of childhood acute lymphoblastic leukaemia (ALL), 2-4% of patients still die from treatment related complications.

Procedure: We investigated the pattern of treatment related deaths (TRDs) and possible risk factors in the NOPHO ALL-92 and ALL-2000 protocols. Fifty-five TRDs were identified among the 1,645 ALL-92 patients and 33 among the 1,090 ALL-2000 patients.

Results: There was no significant difference in the incidence of TRDs between the two protocols (3.4% vs. 3.2%). Five patients died before initiation of therapy (0.2%), and the overall subsequent risk of induction death and death in first complete remission (CR1) was 1.2% and 1.8%, respectively. Infections were the major cause of death comprising 72% of all cases including 9 deaths from Pseudomonas aeruginosa and 11 deaths from fungal infections. Other causes of death included bleeding or thrombosis (eight patients), tumour burden related toxicities (seven patients) and organ toxicity (seven patients). Female gender (hazard ratio (HR): 2.2, 95% confidence interval (95% CI): 1.4-3.4), high white blood cell count (≥ 200 × 10(9) /L) at diagnosis (HR: 3.5, 95% CI: 1.7-7.1), T-cell disease (HR: 1.9, 95% CI: 1.01-3.7), Down syndrome (HR: 7.3, 95% CI: 3.6-14.9) and haematopoietic stem cell transplantation in CR1 (HR: 8.0, 95% CI: 3.3-19.5) were identified as independent risk factors for TRD.

Conclusion: Several TRDs were potentially preventable and future efforts should be directed towards patients at risk.
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http://dx.doi.org/10.1002/pbc.22719DOI Listing
April 2011

[Survival and causes of death in children diagnosed with cancer in Iceland 1981-2006].

Laeknabladid 2010 11;96(11):675-80

Barnaspítali Hringsins, Reykjavík.

Objective: Of children diagnosed with cancer, approximately one fourth die of the disease or disease related complications. The aim of this study was to investigate survival and causes of death in children with cancer in Iceland.

Methods: This study is retrospective; population based and includes all children, less than 18 years of age, diagnosed with cancer in Iceland from 1981 to 2006. Information was extracted from the Icelandic Cancer Registry, patients hospital records and data from Statistics Iceland.

Results: Of 279 children diagnosed with cancer in the research period 215 were alive at the end of 2008. The overall 5-year survival was 81.2% and 10-year survival was 76.7%. There was not a significant survival difference with respect to age at diagnosis, year of diagnosis, gender or geographical residence. The small cohort size could be the explanation. Eleven individuals developed secondary neoplasm, eight of whom died. Sixteen of the 64 nonsurvivors were treated with curative intent until death, 12 of them died of therapy related complications.

Conclusions: Survival rate in childhood cancer in Iceland is comparable to other Western countries. As previously reported, prognosis of patients with secondary neoplasm is unfavorable. Therapy related complications are the most common cause of death in patients treated with curative intent.
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http://dx.doi.org/10.17992/lbl.2010.11.325DOI Listing
November 2010

In vitro cellular drug resistance adds prognostic information to other known risk-factors in childhood acute lymphoblastic leukemia.

Leuk Res 2011 Apr 18;35(4):472-8. Epub 2010 Oct 18.

Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.

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 <0.1% day 29. The risk of any relapse was correlated to vincristine and doxorubicin resistance, with a relative risk of 3.7 (95% CI 1.3-10.5; p=0.016) for patients resistant to both drugs. There was a significant correlation also for the subgroup with extra-medullary relapses. Our findings indicate that analysis of drug resistance can add prognostic information to other known risk-factors including MRD.
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http://dx.doi.org/10.1016/j.leukres.2010.09.001DOI Listing
April 2011

[Childhood cancer in Iceland 1981-2006].

Laeknabladid 2010 01;96(1):21-6

Barnaspitali hringsins, Landspitala Hringbraut, Reykjavik.

Background: Childhood cancer is the second most common cause of death in children. The aim of this study was to gather epidemiological information on childhood cancer in Iceland.

Methods: The study was population based and included all children younger than 18 years of age, diagnosed with cancer in Iceland from 1981 to 2006. Information was extracted from the Icelandic Cancer Registry and patient hospital records.

Results: During the study period 288 cancer cases were diagnosed in 279 children, 10 cases were secondary neoplasms. Age standardized incidence was 16.1 per 100.000 (95% CI 13,6-18,6) for boys and 12.8 per 100.000 (95% CI 10,5-15,0) for girls. There was no significant difference in the incidence rate between the first and second half of the study period. For children aged 0-14 years, the age standardized incidence was 13.6 per 100.000. The incidence was highest in the 0-4 year age group (17.3 per 100.000) and in the 15-17 year age group (19.6 per 100.000). Brain tumors (27.1%) and leukemia (25.0%) were the most common cancer groups diagnosed. Lymphoid leukemia was the most common cancer type (17.9%) and astrocytoma (13.1%) came second.

Conclusions: The incidence of childhood cancer in Iceland is similar to other Western countries. Long-term follow-up is very important in childhood cancer survivors.
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http://dx.doi.org/10.17992/lbl.2010.01.04DOI Listing
January 2010

Suspected infections in children treated for ALL.

Acta Paediatr 2009 Jul 16;98(7):1149-55. Epub 2009 Apr 16.

Children's Hospital Iceland, Landspítali - University Hospital, Reykjavík, Iceland.

Aim: The aim of our study was to get epidemiological information on bacterial infections in children treated for ALL and to analyse which patients have an enhanced infection risk.

Methods: Episodes of suspected or confirmed infections were evaluated during the first 12 months of treatment for childhood acute lymphoblastic leukaemia (ALL).

Results: The number of patients was 73 (43 boys). The median age was 4.6 years. A total of 179 episodes occurred, varying from none in six patients to eight in one. Bacteria were cultured in 57 episodes (31.8%), the most common being coagulase-negative staphylococci. The number of episodes fell significantly with increasing age for suspected and confirmed infections (p < 0.001 and p = 0.03). The proportion of confirmed infections was significantly higher (p < 0.001) in the first episodes. The average number of suspected infections was higher in girls than in boys (p = 0.03), but confirmed infections were not.

Conclusion: Most of the serious infections occur early in the treatment and the number of suspected and confirmed infections falls with age. Suspicion of infection is more likely in girls, but the number of confirmed infections is equal in both sexes. Coagulase-negative staphylococcus was most commonly isolated, highlighting the importance of careful handling of central venous devices.
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http://dx.doi.org/10.1111/j.1651-2227.2009.01286.xDOI Listing
July 2009

[Bacteremia in children with tumors or malignant diseases 1991-2000].

Laeknabladid 2008 Jul;94(7-8):531-9

Introduction: Ten to twelve children with tumors or malignant diseases are diagnosed annually in Iceland. Cancer treatment can cause severe immune suppression, which makes the patients susceptible to serious infections. The aim of the current study was to evaluate sepsis in children with tumors or haematological malignancies, describe the types of bacteria cultured and their antibiotic susceptibilities, and collect information on associated risk factors.

Materials And Methods: This was a retrospective study on all children 0-15 years of age in Iceland who were diagnosed with a tumor or malignant disease between 1991 and 2000. Information was gathered on diagnosis, treatment, blood cultures, blood tests, antibiotic use, presence of foreign bodies (such as CVC) and survival.

Results: Hundred-and-eighteen children were diagnosed with cancer or benign central nervous system (CNS) tumors in Iceland during the period 1991-2000. Central nervous system tumors were most common (N=28, 23.7%), leukemia (N=21, 17.8%) and lymphoma (N=17, 14%) were the second and third. The mean age at diagnosis was 5.9 years. Sufficient data was found in the hospital records on 99 children who were included in the study. Five hundred and twenty two blood cultures were drawn from 51 of the 99 children during the period. The mean number of blood cultures per patient was 14.8 for children with leukemia, but 2.6 for children with solid tumors. Of all blood cultures, 63.6% were from a central venous catheter or a Port-A Catheter , 5% from a peripheral site, but 30% were undisclosed. Of the 522 blood cultures, 90 grew bacteria (17.2%). Coagulase-negative staphylococci were isolated from 53 blood cultures (60%) and Staphylococcus aureus from 12 (13%). Positive cultures were regarded as a definite or possible infection in 47 blood cultures (52%), contamination in 17 (18.9% ), but uncertain in 26 (27.7%). Over 60 percent of the blood cultures (N=302) were drawn when a child was neutropenic (ANC < or =1.0 *109/L). The mean length of neutropenic episodes was 9.0 days. The mean CRP level was 63.9 mg/L. The mean temperature was 38.8 degrees C. In 138 instances the child was receiving antibiotics at the time of culture (35.1%). Children with positive blood cultures had similar clinical and laboratory tests results as children with negative cultures.

Conclusion: Gram-positive bacteria, especially coagulase-negative staphylococci, are much more common in children undergoing cancer therapy than Gram-negative bacteria. Results of blood tests appear to have low predictive values for blood culture results. No child died of a proven bacterial sepsis during the study period. Empiric antibiotic treatment at the Children s Hospital Iceland for children with malignant diseases is still effective.
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July 2008

[Central nervous system tumours in Icelandic children; diagnoses, treatment results and late effects.].

Laeknabladid 2002 Jan;88(1):21-7

Children's Hospital, Landspitali University Hospital, Hringbraut, 101 Reykjavík, Iceland.

Objective: Tumours in the central nervous system are the second most common malignant diseases in children. With improved treatment, the number of survivors is increasing. Therefore, better knowledge of the long-term effects of the disease and the therapy is needed. The aim of the current study was to find the incidence of central nervous system tumours in Iceland, evaluate the treatment results and study the long-term effects on the individuals.

Material And Methods: Data on diagnosis and treatment as well as demographic data were gathered from hospital records from the Reykjavik City Hospital and The University Hospital and operating lists at the Department of Neurosurgery were reviewed. On survivors, physical examination was carried out, blood tests and urine-analysis were done and hearing was tested. Social adaptation, school performance, memory, concentration and general well being were studied by a questionnaire.

Results: In the years 1970-1995, 57 children, aged 16 and younger, were diagnosed in Iceland with central nervous system tumours, 30 girls and 27 boys. Two children with brain metastases were excluded. Of the 55 individuals, 38 are alive today, 19 girls and 19 boys. Seventeen children had astrocytoma, grade 1 or 2 and seven had astrocytoma of grade 3 or 4. Seven children had medulloblastoma, other tumours were less common. Four patients with benign tumours in the spine were excluded from the study; three are living abroad and three refused participation. Therefore, 28 patients were included in the further study, 15 males and 13 females. The mean age at diagnoses was 7 years and 8 months (7:8) (median 6:7 years, span 0:0-15:11), the mean age at study was 21:4 years (median 20:2 years, span 7:6-39:9) and the mean time from diagnosis until study was 12:8 years (median 11:5 years, span 2:5-26:3). The mean standard deviation score for height (SDS) was -0.63 at the time of study, five of the patients had SDS below two. Five individuals need hormone replacement therapy and one patient has scoliosis. Three patients have disabilities; two of those are incapable of activities of daily life. Three patients have hearing impairment; one of them is also blind. Of five patients who had seizures when diagnosed, two still have convulsions. Of 28 patients, twelve (43%) had learning difficulties in school and ten (36%) needed remedial teaching.

Conclusions: The incidence of central nervous tumours in Icelandic children is comparable to what has been reported in other countries. The results of the treatment are similar to what has been found in the other Nordic countries which maybe better than in other countries. The most prominent long-term effects among the survivors are endocrine dysfunctions and specific learning disabilities. Other, severe long-term complications are rare but have considerable effect on the individuals. We emphazise that organised, long-term follow-up is essential for these individuals, paying special attention to learning difficulties and endocrine dysfunction.
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January 2002