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Methotrexate/6-mercaptopurine maintenance therapy improves acute lymphoblastic leukemia (ALL) outcome. Cytotoxicity is mediated by DNA incorporation of thioguanine nucleotides (DNA-TG). We investigated the association of DNA-TG to relapse risk in 1 910 children and young adults with non-high risk ALL. In a cohort-stratified Cox regression analysis adjusted for sex, age, and white cell count at diagnosis, the relapse-specific hazard ratio (HRa) per 100 fmol/μg increase in weighted mean DNA-TG (wmDNA-TG) was 0.87 (95% CI 0.78-0.97; p = 0.013) in the 839 patients who were minimal residual disease (MRD) positive at end of induction therapy (EOI), whereas this was not the case in EOI MRD-negative patients (p = 0.76). Validation analysis excluding the previously published Nordic NOPHO ALL2008 pediatric cohort yielded a HRa of 0.92 (95% CI 0.82-1.03; p = 0.15) per 100 fmol/μg increase in wmDNA-TG in EOI MRD-positive patients. If also excluding the United Kingdom cohort, in which samples were taken non-randomly in selected patients, the HRa for the EOI MRD-positive patients was 0.82 (95% CI 0.68-0.99; p = 0.044) per 100 fmol/μg increase in wmDNA-TG. The importance of DNA-TG as a biomarker for maintenance therapy intensity calls for novel strategies to increase DNA-TG, although its clinical value may vary by protocol backbone.

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.

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.

Endothelial dysfunction has not previously been investigated as a thrombogenic risk factor among patients with acute lymphoblastic leukemia (ALL), known to be at high risk of thromboembolism. We retrospectively explored the association between three circulating biomarkers of endothelial dysfunction (thrombomodulin, syndecan-1, VEGFR-1) measured in prospectively collected blood samples and risk of thromboembolism in 55 cases and 165 time-matched controls, treated according to the NOPHO ALL2008 protocol. In age-, sex-, and risk group-adjusted analysis, increasing levels of thrombomodulin and VEGFR-1 were independently associated with increased odds of developing thromboembolism (OR 1.37 per 1 ng/mL [95% CI 1.20‒1.56, P 30 days before thromboembolic diagnosis. Thrombomodulin levels were on average 3.2 ng/mL (95% CI 2.6-8.2 ng/mL) higher in samples with measurable asparaginase activity (P

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.

The NOPHO ALL2008 is a population-based study using an unmodified pediatric protocol in patients 1-45 years of age with acute lymphoblastic leukemia. Patients with T-ALL were given a traditional pediatric scheme if fast responding (minimal residual disease (MRD) 0.1% day 29), or intensive block-based chemotherapy if slow responding (MRD 0.1% day 29). Both treatment arms included pediatric doses of high-dose methotrexate and asparaginase. If MRD ≥ 5% on day 29 or ≥0.1% after consolidation, patients were assigned to allogeneic hematopoietic stem cell transplantation. The 5-year overall survival of the 278 T-ALL patients was 0.75 (95% CI 0.69-0.81), being 0.82 (0.74-0.88) for patients 1.0-9.9 years, 0.76 (0.66-0.86) for those 10.0-17.9 years, and 0.65 (0.55-0.75) for the older patients. The risk of death in first remission was significantly higher in adults (12%) compared with the 1-9 years group (4%). The MRD responses in the three age groups were similar, and only a nonsignificant increase in relapse risk was found in adults. In conclusion, an unmodified pediatric protocol in patients 1-45 years is effective in all age groups. The traditional pediatric treatment schedule was safe for all patients, but the intensive block therapy led to a high toxic death rate in adults.

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 10 years, 14.9% (95% CI 9.7-20.2%) for patients aged 10.0-17.9 years, and 14.4% (95% CI 8.0-20.8%) for patients aged ≥ 18 years. The median time from diagnosis of ALL to diagnosis of osteonecrosis in these age groups was 1.0 year (IQR 0.7-2.0), 2.0 years (IQR 1.1-2.4), and 2.2 years (IQR 1.8-2.8), respectively (p = 0.001). With 17,854 blood samples available for MTX and 6MP metabolite analysis, neither erythrocyte levels of 6-thioguanine (TG) nucleotides (p 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.

Endothelial dysfunction has not previously been investigated as a thrombogenic risk factor among patients with acute lymphoblastic leukemia (ALL), known to be at high risk of thromboembolism. We retrospectively explored the association between three circulating biomarkers of endothelial dysfunction (thrombomodulin, syndecan-1, VEGFR-1) measured in prospectively collected blood samples and risk of thromboembolism in 55 cases and 165 time-matched controls, treated according to the NOPHO ALL2008 protocol. In age-, sex-, and risk group-adjusted analysis, increasing levels of thrombomodulin and VEGFR-1 were independently associated with increased odds of developing thromboembolism (OR 1.37 per 1 ng/mL [95% CI 1.20‒1.56, P 0.0001] and OR 1.21 per 100 pg/mL [95% CI 1.02‒1.21, P = 0.005], respectively). These associations remained significant when including only samples drawn30 days before thromboembolic diagnosis. Thrombomodulin levels were on average 3.2 ng/mL (95% CI 2.6-8.2 ng/mL) higher in samples with measurable asparaginase activity (P 0.0001). Among single nucleotide variants located in or neighboring coding genes for the three biomarkers, none were significantly associated with odds of thromboembolism. If results are validated in another cohort, thrombomodulin and VEGFR-1 could serve as predictive biomarkers, identifying patients in need of preemptive antithrombotic prophylaxis.

Introduction The direct oral anti-coagulants (DOAC) edoxaban and rivaroxaban are suggested treatment alternatives for cancer-associated venous thromboembolism (VTE) together with low molecular-weight heparins. New studies indicate that the DOAC apixaban also is an option for cancer-associated VTE. The current study assessed recurrent VTE, arterial thrombosis, bleedings and adverse events in a cohort of apixaban treated cancer patients with VTE. Materials and methods Single-arm, interventional study of apixaban as treatment of cancer-associated VTE. Inclusion criteria were cancer with objectively verified VTE. Patients received apixaban 10 mg bid for seven days, then 5 mg bid for six months. Primary efficacy and safety outcomes were recurrent VTE and bleeding respectively. This trial is registered with ClinicalTrials.gov identifier NCT02581176 . Results We recruited 298 cancer patients with VTE. During six months treatment, recurrent VTE or death related to VTE occurred in 12 patients (4.0%, 95% confidence interval (CI) 2.1–6.9%). Major bleeding occurred in 16 patients (5.4%, 95% CI 2.8–7.9), most frequently gastrointestinal bleeding. There were no overrepresentation of major bleedings among patients with gastrointestinal cancer (7/126, 5.5%, 95% CI 2.3–11%). Twenty-six patients experienced one or more clinically relevant non-major bleedings (8.9%, 95% CI 5.5–12%). Twelve patients had arterial thrombosis (4.0%, 95% CI 2.1–6.9%), of which the majority were strokes in patients with pancreatic cancer. Death occurred in 35 patients (12%, 95% CI 8.3–16%). Conclusion The frequency of recurrent VTE and major bleedings are in line with other studies on apixaban in cancer-associated VTE. Arterial thrombosis was a frequent serious adverse event.

Background: Apixaban is a treatment option for venous thromboembolism (VTE) in cancer patients. There are no data on the effect of low dose apixaban after 6 months treatment. We wanted to assess the efficacy and safety of apixaban 2.5 mg twice daily as prophylaxis for recurrent VTE after 6 months initial treatment with full-dose apixaban. Patients and methods: We included 298 patients with cancer and any type of VTE. All patients were treated with full dose apixaban for the first 6 months. After 6 months, all patients with active cancer continued with apixaban 2.5 mg twice daily and were followed for the next 30 months. The primary endpoint of efficacy was recurrent VTE, the primary safety endpoint was major bleedings. Clinically relevant non-major bleedings was a secondary endpoint. The endpoints are reported as incidence rates or fractions with 95% confidence intervals, and as Kaplan-Meier plots. Results: During the first 6 months of full-dose anticoagulation 12 of 298 patients had recurrent VTE (4.0%, 95% confidence interval 2.1-6.9), 16 experienced major bleeding (5.4%, 95% CI 2.8-7.9%), and 26 patients experienced one or more episodes of CRNMB (8.9%, 95% CI 5.5-12) as previously reported. 1 Of the 298 patients included, 196 continued with apixaban 2.5 mg twice daily after 6 months. During treatment from 6 to 36 months with low-dose apixaban 15 of 196 (7.6%, 95% CI: 4.4-12) patients had recurrent VTE, 7 (3.6%, CI: 1.5-7.2) patients experienced major bleeding and 16 (8.2%, 95% CI: 4.7-13) patients experienced CRNMB. The highest incidence rate of both recurrent VTE and major bleedings were seen during the first month of full-dose apixaban (Table 1). After the dose reduction of apixaban, the incidence rate of recurrent VTE increased slightly during 6 to 12 months while the incidence rate of major bleeding decreased during the same time-period. After 12 months the incidence rate of both recurrent VTE and major bleeding was low and remained low during the entire 30 months follow-up (Table 1 and Figure 1). The Kaplan-Meier plot of the composite endpoint of recurrent VTE or major bleeding did not change after dose-reduction. After about 9 months treatment (i.e. 3 months on low dose apixaban) the Kaplan-Meier curve of the composite endpoint flattened out. Conclusion: Dose reduction of apixaban to 2.5 mg twice daily after 6 months of full dose anticoagulation resulted in a small increase in recurrent VTE, but a marked decrease in major bleedings during the 6-12 months period. After approximately 9 months the frequency of recurrent VTE and major bleedings remained low compared with the first 6 months of full-dose treatment. Reducing the dose of apixaban to 2.5 mg twice daily after 6 months of full-dose treatment appears safe and effective. References 1. Hannevik TL, Brekke J, Enden T, et al: Thrombosis and bleedings in a cohort of cancer patients treated with apixaban for venous thromboembolism. Thromb Res, 2020 Figure 1 Figure 1. Disclosures Hannevik: Pfizer/Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Garresori: Pfizer: Honoraria; Amgen: Honoraria; Bayer: Honoraria. Froen: Bristol-Myers Squibb: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees. Porojnicu: Bristol-Myers Squibb: Honoraria. Ghanima: Bayer, BMS/Pfizer: Research Funding; Amgen, Novartis, Pfizer, Bristol Myers Squibb, SOBI, Griffols, Sanofi: Honoraria; Amgen, Novartis, Pfizer, Principia Biopharma Inc- a Sanofi Company, Sanofi, SOBI, Griffols, UCB, Argenx: Consultancy. Dahm: Pfizer: Honoraria; Novartis: Honoraria; Pfizer/Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

Extracorporeal photopheresis (ECP), an immunomodulatory therapy for the treatment of chronic graft-versus-host disease (cGvHD), exposes isolated white blood cells to photoactivatable 8-methoxypsoralen (8-MOP) and UVA light to induce the apoptosis of T-cells and, hence, to modulate immune responses. However, 8-MOP-ECP kills diseased and healthy cells with no selectivity and has limited efficacy in many cases. The use of 5-aminolevulinic acid (ALA) and light (ALA-based photodynamic therapy) may be an alternative, as ex vivo investigations show that ALA-ECP kills T-cells from cGvHD patients more selectively and efficiently than those treated with 8-MOP-ECP. The purpose of this phase I-(II) study was to evaluate the safety and tolerability of ALA-ECP in cGvHD patients. The study included 82 treatments in five patients. One patient was discharged due to the progression of the haematological disease. No significant persistent changes in vital signs or laboratory values were detected. In total, 62 adverse events were reported. Two events were severe, 17 were moderate, and 43 were mild symptoms. None of the adverse events evaluated by the internal safety review committee were considered to be likely related to the study medication. The results indicate that ALA-ECP is safe and is mainly tolerated well by cGvHD patients.

Premature discontinuation of asparaginase reduces cure rate in contemporary acute lymphoblastic leukemia (ALL) treatment. One of the commonest causes of asparaginase truncation is asparaginase-associated pancreatitis (AAP). We prospectively registered AAP during treatment of 2,448 consecutive Nordic/Baltic ALL patients aged 1.0-45.9 years treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol (7/2008-10/2018). The Day 280 cumulative incidence of first-time AAP (including 99% (167/168) of AAP events at this time point) was 8.3% (95% confidence interval (CI) 7.0-9.9) with a median time of 104 days (interquartile range (IQR) 70-145) from ALL diagnosis to AAP, with a median of 10 days (IQR 6-13) from last asparaginase exposure, and after a median number of five asparaginase doses (IQR 3-7, max 14 doses). All patients received polyethylene glycol conjugated Escherichia coli-derived asparaginase as standard treatment. Eighty-five percent (140/164, unknown in N=4) of AAP events were severe (AAP-associated symptoms and/or pancreatic enzymes >3x upper normal limit lasting >72 hours or with hemorrhagic pancreatitis, pancreatic abscess, or pseudocyst). Four age groups were defined: 1.0-4.9, 5.0-8.9, 9.0-16.9, and 17.0-45.9 years-each containing approximately 25% of the AAP events. Compared with patients aged 1.0-4.9 years, adjusted (sex, immunophenotype, and white blood cell count) hazard ratios (HR) of AAP were associated with higher age (5.0-8.9 years: HR 2.3, 95% CI 1.5-3.6, P Of 168 AAP patients, 34 (20%) were re-challenged with asparaginase. Fifty percent (17/34) developed a second episode of AAP-41% being severe (7/17). The median time to a second AAP event from asparaginase re-exposure was 29 days (IQR 16-94) and occurred after a median of two asparaginase doses (range 0-7). Neither age group nor severity of the first AAP was associated with increased hazard of a second AAP event. None of the patients with a second AAP were further re-exposed to asparaginase, and none died of the second AAP. Among a total of 196 ALL relapses, 21 patients have had AAP including 17 patients with asparaginase truncation. However, the hazard of relapse (age- and sex-adjusted) was not increased among AAP patients with asparaginase truncation versus AAP patients with asparaginase re-exposure (5.0-year cumulative incidence of relapse: 13.2% versus 14.2%) (HR 1.0, 95% CI 0.3-3.1, P=1.0). When analyzing time to relapse among AAP patients versus non-AAP patients, no difference in hazard of relapse was found (HR 2.0, 95% CI 0.8-4.9, P=.2). In conclusion, adolescents and young adults tolerated asparaginase treatment as well as children; however, the risk of AAP was higher for patients older than 5.0 years of age with no difference with increasing age. Despite a low AAP-related mortality, the morbidity was considerable and most profound for patients aged 9.0-16.9 years. Since asparaginase re-exposure was associated with a high risk of a second AAP event and neither AAP development nor AAP-related asparaginase truncation was associated with increased relapse risk, asparaginase re-exposure should be attempted only in patients with a high risk of leukemic relapse. Finally, there is an unmet need for preventive strategies toward AAP. Disclosures Wolthers: Novo Nordisk: Employment.

Background Congenital thrombotic thrombocytopenic purpura (TTP) is a rare, hereditary disorder. Clinically it presents as episodic microangiopathic haemolytic anaemia and thrombocytopenia with varying degrees of damage to internal organs. The condition may present in neonates, but can also present for the first time in adulthood. The prevalence of congenital TTP is particularly high in Norway, and it is therefore important for Norwegian doctors to be aware of the condition. In this article we review the main characteristics of the disease, including its diagnosis and management, and introduce potential new treatments for the future. Method The article is based on a literature search in PubMed as well as the authors’ own research and clinical experience. Results There was great variation in the severity of congenital TTP: from neonatal mortality to disease-free intervals of several years. Episodes are generally precipitated by a trigger. Acute episodes are treated with plasma infusions, and approximately half of all patients experience frequent episodes and require prophylactic infusions to avoid organ damage. The risk of episodes is greatest in neonates, during pregnancy and in association with infections. Interpretation There is little research-based evidence regarding long-term prognosis in congenital TTP. There is also a need for guidelines to help identify candidates for prophylactic treatment. An international patient registry would provide useful information and form the basis for better guidelines on the monitoring and treatment of these patients.

Essentials The population prevalence of hereditary thrombotic thrombocytopenic purpura (TTP) is unknown. We studied the prevalence of hereditary TTP and population frequencies of two ADAMTS-13 mutations. A high frequency of hereditary TTP related to ADAMTS-13 mutation c.4143_4144dupA was found. Vicinity of ABO blood group and ADAMTS-13 loci may facilitate screening of ADAMTS-13 mutations.Background Hereditary thrombotic thrombocytopenic purpura (TTP) caused by ADAMTS-13 mutations is a rare, but serious condition. The prevalence is unknown, but it seems to be high in Norway. Objectives To identify all patients with hereditary TTP in central Norway and to investigate the prevalence of hereditary TTP and the population frequencies of two common ADAMTS-13 mutations. Patients/Methods Patients were identified in a cross-sectional study within the Central Norway Health Region by means of three different search strategies. Frequencies of ADAMTS-13 mutations, c.4143_4144dupA and c.3178 CT (p.R1060W), were investigated in a population-based cohort (500 alleles) and in healthy blood donors (2104 alleles) by taking advantage of the close neighborhood of the ADAMTS-13 and ABO blood group gene loci. The observed prevalence of hereditary TTP was compared with the rates of ADAMTS-13 mutation carriers in different geographical regions. Results We identified 11 families with hereditary TTP in central Norway during the 10-year study period. The prevalence of hereditary TTP in central Norway was 16.7 × 10(-6) persons. The most prevalent mutation was c.4143_4144dupA, accounting for two-thirds of disease causing alleles among patients and having an allelic frequency of 0.33% in the central, 0.10% in the western, and 0.04% in the southeastern Norwegian population. The allelic frequency of c.3178 CT (p.R1060W) in the population was even higher (0.3-1%), but this mutation was infrequent among patients, with no homozygous cases. Conclusions We found a high prevalence of hereditary TTP in central Norway and an apparently different penetrance of ADAMTS-13 mutations.

Thromboembolism frequently occurs during acute lymphoblastic leukemia (ALL) therapy. We prospectively registered thromboembolic events during the treatment of 1772 consecutive Nordic/Baltic patients with ALL aged 1 to 45 years who were treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol (July 2008-April 2017). The 2.5-year cumulative incidence of thromboembolism (N = 137) was 7.9% (95% confidence interval [CI], 6.6-9.1); it was higher in patients aged at least 10 years (P < .0001). Adjusted hazard ratios (HRas) were associated with greater age (range, 10.0-17.9 years: HRa, 4.9 [95% CI, 3.1-7.8; P < .0001]; 18.0-45.9 years: HRa, 6.06 [95% CI, 3.65-10.1; P < .0001]) and mediastinal mass at ALL diagnosis (HRa, 2.1; 95% CI, 1.0-4.3; P = .04). In a multiple absolute risk regression model addressing 3 thromboembolism risk factors, age at least 10 years had the largest absolute risk ratio (RRage, 4.7 [95% CI, 3.1-7.1]; RRenlarged lymph nodes, 2.0 [95% CI, 1.2-3.1]; RRmediastinal mass, 1.6 [95% CI, 1.0-2.6]). Patients aged 18.0 to 45.9 years had an increased hazard of pulmonary embolism (HRa, 11.6; 95% CI, 4.02-33.7; P < .0001), and patients aged 10.0 to 17.9 years had an increased hazard of cerebral sinus venous thrombosis (HRa, 3.3; 95% CI, 1.5-7.3; P = .003) compared with children younger than 10.0 years. Asparaginase was truncated in 38/128 patients with thromboembolism, whereas thromboembolism diagnosis was unassociated with increased hazard of relapse (P = .6). Five deaths were attributable to thromboembolism, and patients younger than 18.0 years with thromboembolism had increased hazard of dying compared with same-aged patients without thromboembolism (both P ≤ .01). In conclusion, patients aged at least 10 years could be candidates for preemptive antithrombotic prophylaxis. However, the predictive value of age 10 years or older, enlarged lymph nodes, and mediastinal mass remain to be validated in another cohort.

Adults with acute lymphoblastic leukemia (ALL) do worse than children. From 7/2008 to 12/2014, Nordic and Baltic centers treated 1509 consecutive patients aged 1-45 years with Philadelphia chromosome-negative ALL according to the NOPHO ALL2008 without cranial irradiation. Overall, 1022 patients were of age 1-9 years (A), 266 were 10-17 years (B) and 221 were 18-45 years (C). Sixteen patients (three adults) died during induction. All others achieved remission after induction or 1-3 intensive blocks. Subsequently, 45 patients (12 adults) died, 122 patients relapsed (32 adults) with a median time to relapse of 1.6 years and 13 (no adult) developed a second malignancy. Median follow-up time was 4.6 years. Among the three age groups, older patients more often had higher risk ALL due to T-ALL (32%/25%/9%, P

Introduction Known genetic variants with reference to preeclampsia only explain a proportion of the heritable contribution to the development of this condition. The association between preeclampsia and the risk of cardiovascular disease later in life has encouraged the study of genetic variants important in thrombosis and vascular inflammation also in relation to preeclampsia. The von Willebrand factor-cleaving protease, ADAMTS13, plays an important role in micro vascular thrombosis, and partial deficiencies of this enzyme have been observed in association with cardiovascular disease and preeclampsia. However, it remains unknown whether decreased ADAMTS13 levels represent a cause or an effect of the event in placental and cardiovascular disease. Methods We studied the distribution of three functional genetic variants of ADAMTS13 , c.1852C > G (rs28647808), c.4143_4144dupA (rs387906343), and c.3178C > T (rs142572218) in women with preeclampsia and their controls in a nested case–control study from the second Nord-Trondelag Health Study (HUNT2). We also studied the association between ADAMTS13 activity and preeclampsia, in serum samples procured unrelated in time of the preeclamptic pregnancy. Results No differences were observed in genotype, allele or haplotype frequencies of the different ADAMTS13 variants when comparing cases and controls, and no association to preeclampsia was found with lower levels of ADAMTS13 activity. Conclusion Our findings indicate that ADAMTS13 variants and ADAMTS13 activity do not contribute to an increased risk of preeclampsia in the general population.

The European Clinical Trials Directive of 2004 has increased the amount of paper work and reduced the number of initiated clinical trials. Particularly multinational trials have been delayed. To meet this challenge we developed a novel, simplified, fast and easy strategy for on-line toxicity registration for patients treated according to the Nordic/Baltic acute lymphoblastic leukaemia protocol, NOPHO ALL 2008, for children and young adults, including three randomisations. We used a risk-assessment based approach, avoiding reporting of expected adverse events and instead concentrating on 20 well-known serious, but rarer events with focus on changes in therapy introduced in the treatment protocol. This toxicity registration strategy was approved by the relevant regulatory authorities in all seven countries involved, as compliant within the EU directive of 2004. The centre compliance to registration was excellent with 98.9% of all patients being registered within 5 weeks from the requested quarterly registration. Currently, four toxicities (thrombosis, fungal infections, pancreatitis and allergic reactions) have been chosen for further detailed exploration due to the cumulative fraction of patients with positive registrations exceeding 5%. This toxicity registration offers real-time toxicity profiles of the total study cohort and provides early warnings of specific toxicities that require further investigation.

Congenital thrombotic thrombocytopenic purpura (TTP) is a rare, hereditary disorder. Clinically it presents as episodic microangiopathic haemolytic anaemia and thrombocytopenia with varying degrees of damage to internal organs. The condition may present in neonates, but can also present for the first time in adulthood. The prevalence of congenital TTP is particularly high in Norway, and it is therefore important for Norwegian doctors to be aware of the condition. In this article we review the main characteristics of the disease, including its diagnosis and management, and introduce potential new treatments for the future.The article is based on a literature search in PubMed as well as the authors’ own research and clinical experience.There was great variation in the severity of congenital TTP: from neonatal mortality to disease-free intervals of several years. Episodes are generally precipitated by a trigger. Acute episodes are treated with plasma infusions, and approximately half of all patients experience frequent episodes and require prophylactic infusions to avoid organ damage. The risk of episodes is greatest in neonates, during pregnancy and in association with infections.There is little research-based evidence regarding long-term prognosis in congenital TTP. There is also a need for guidelines to help identify candidates for prophylactic treatment. An international patient registry would provide useful information and form the basis for better guidelines on the monitoring and treatment of these patients.

A 29-year-old woman developed progressive dysarthria and coordination problems from the age of 15. Examination showed dysarthria, facial dystonia, bibrachial dystonia, hyperreflexia, ataxia, and emotional incontinence. Downward supranuclear gaze palsy was prominent with a “Round the Houses” sign. Magnetic resonance imaging of the brain and medulla, electroneurography, and cerebrospinal fluid were normal. A computed tomography scan showed hepatosplenomegaly. This combination of progressive neurological symptoms together with hepatosplenomegaly was suggestive of inborn error of metabolism. A bone marrow biopsy showed an increased number of macrophages with foamy content, highly suggestive of lysosomal disease. Plasmatic chitotriosidase activity and CCL18 were increased. Genetic testing showed heterozygosis for the variation c.1070C→T (p.Ser357Leu) and c.1843→T (Arg615Cys), confirming the diagnosis of Niemann-Pick type C (NPC). The “Round the Houses” sign has only been described in patients with progressive supranuclear palsy (PSP). This sign is described as an inability to produce pure vertical saccades along the midline and instead moving the eyes in a lateral arc to accomplish the movement. The observation of this sign in a patient with NPC indicates that this bedside finding is not specific for PSP, but a sign of medial longitudinal fasciculus dysfunction. The presence of facial dystonia with facial grimacing together with supranuclear gaze palsy is highly characteristic and useful for the diagnosis of NPC. NPC is an important underdiagnosed condition, given the availability of treatment and a mean diagnostic delay of 6 years. © 2015 Taylor & Francis. This is the authors’ accepted and refereed manuscript to the article.

Introduction: Congenital thrombotic thrombocytopenic purpura (cTTP) is an autosomal recessive disease characterised by acute episodes of thrombotic microangiopathy. cTTP has a clinically heterogeneous course. Currently there are more than 150 disease-causing ADAMTS13 gene mutations reported, though a genotype-phenotype correlation of this ultra-rare disease remains incompletely understood. Characterization of mutations of the ADAMTS13 gene will be useful for carrier detection and genetic counselling. In 2006, the Hereditary TTP Registry (ClinicalTrials.gov NCT01257269; www.ttpregistry.net) was initiated in order to achieve this objective by identifying possible triggers of acute episodes of TTP and to document individual clinical courses and treatment requirements. Methods: The Hereditary TTP Registry is an international cohort study. Individual data were analysed from 121 cTTP patients, who were enrolled between 2006 and the end of 2017. Diagnosis of cTTP was confirmed by a severely deficient ADAMTS13 activity Results: The cTTP cohort consists of 54 and 52 patients from Europe and Asia (90% from Japan), respectively, 13 patients from the Americas and 2 patients from Africa. For 69% of the patients regular treatment was reported, which consisted predominantly of fresh frozen plasma infusion (84%). More compound heterozygous (n=76) than homozygous mutation carriers (n=45) were included. The female to male ratio was 1:1, and the median age at first diagnosis was 25.8 years (range from 0 to 81.3 years). Prior arterial thromboembolic events (mainly myocardial infarction, stroke, TIA) were present in 27% of patients at enrolment and at the age of 50 years more than half of the patients had experienced at least one such event. In the 121 patients, we identified 98 different ADAMTS13 mutations (missense 57; nonsense 12; frameshift due to deletions or insertions 21; splice site 8). The most frequent observed mutations were c.4143_4144dupA (exon 29; p.Glu1382Argfs*6; n=58 alleles), c.3178C>T (exon 24; p.Arg1060Trp; n=13), and c.577C>T (exon 6; p.Arg193Trp; n=11). Nineteen mutations have not been previously reported (8 missense, 3 splice site, 2 nonsense, and 6 frameshift mutations). Mutations are located across the whole ADAMTS13 gene and affect all domains (there was no "hotspot"). We did not find a correlation of the mutations with clinical or laboratory features, except for ADAMTS13 c.4143_4144dupA. For this mutation, the age at initial diagnosis was younger (median age 4.1 years, range 1.8 - 52.1) in compound heterozygous compared to homozygous patients (median 23.3 years, range 0.7 - 47.5,) (p=0.040). Patient numbers were equally distributed (p = 0.51); 16 patients were compound heterozygotes and 21 were homozygotes. All patients were of Scandinavian or Central European ancestry. For the other assessed clinical parameters, no significant difference between compound heterozygotes and homozygotes was observed. Conclusion: At present, the Hereditary TTP Registry is the largest cohort on cTTP, to our knowledge. The large number of different mutations as well as confounding factors, including multi-ethnic and geographical factors in our internationally compiled patient cohort make unravelling the genotype-phenotype correlation in cTTP challenging. Yet, for c.4143_4144dupA, we can conclude that homozygous patients with ADAMTS13 c.4143_4144dupA are clinically less severely affected than compound heterozygotes due to the later onset of the disease in homozygotes, whereas the clinical characteristics are similar between compound heterozygotes and homozygotes. Why homozygous carriers of c.4143_4144dupA, despite having no ADAMTS13 activity in plasma, may have a rather late onset of acute TTP remains to be further elucidated. Disclosures Friedman: Shire: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees. Knöbl:Ablynx: Consultancy, Other: Member of Advisory Board. Schneppenheim:CSL Behring: Consultancy; SHIRE: Consultancy. Kremer Hovinga Strebel:Ablynx: Other: Advisory Board; SHIRE: Other: Advisory Board, Research Funding.

Introduction: Approximately one-third of the adult population in industrial countries and 70% in several Asian countries are daily smokers. Tobacco is now regarded as the world's leading cause of death. Approximately two-thirds of lifelong smokers eventually die because of smoking. Smoking cessation is the most effective action to reduce mortality in patients with chronic obstructive pulmonary disease (COPD) and coronary heart disease. Objective: The aim of this study was to determine the effectiveness of smoking cessation programmes in patients with smoking-related disorders. Methods: Medline was searched for studies of interventions for smoking cessation in patients. Results: In patients with cardiovascular diseases and COPD, smoking cessation programmes with behavioural support over several months significantly increase quit rates. The intensity of the programmes seems to be proportional to the effect. A long follow-up period is probably the most important element in the programmes. Even the most intensive programmes are very cost-effective in terms of cost per life-year gained. Effective programmes can be delivered by personnel without special education in smoking cessation using simple intervention principles. Conclusions: In patients with smoking-related disorders, smoking cessation interventions with several months of follow-up are effective and easily applicable in clinical practice. Wider implementation of such programmes would be a cost-effective way of saving lives. Please cite this paper as: Quist-Paulsen P. Cessation in the use of tobacco – pharmacologic and non-pharmacologic routines in patients. The Clinical Respiratory Journal 2008; 2: 4–10.

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

Extracorporeal photopheresis (ECP) is an immunomodulatory alternative for treatment of graft versus host disease (GVHD). The blood is then separated into its various components through apheresis; buffy coat cells are thereafter treated with 8-methoxypsoralen before exposure to ultraviolet light and finally reinfused into the patient. There is a general agreement that this treatment has an anti-GVHD effect, but the mechanisms of action behind this effect are only partly understood. However, altered maturation of dendritic cells (DC) and thereby indirect modulation of T-cell reactivity seems to be one important mechanism together with DC-presentation of antigens derived from apoptotic donor T cells and induction of regulatory T cells. The treatment has been best studied in patients with chronic GVHD (both pediatric and adult patients), but most studies are not randomized and it is difficult to know whether the treatment is more effective than the alternatives. The clinical studies of ECP in adults with acute GVHD are few and not randomized; it is not possible to judge whether this treatment should be a preferred second- or third-line treatment. There is no evidence for increased risk of leukemia relapse or suppression of specific graft versus leukemia reactivity by this treatment, so specific antileukemic immunotherapy may still be possible. Thus, even though the treatment seems effective in patients with GVHD, further clinical (especially randomized) as well as biological studies with careful standardization of the treatment are needed before it is possible to conclude how ECP should be used in acute and chronic GVHD.

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.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.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%; P0.0001) or high-risk chemotherapy with transplantation (4%, 13%, 19%; P0.0001). This age-dependent skewing of risk grouping reflected more T-ALL (11%, 27%, 33%, P0.0001), poorer MRD response day 29 (MRD0.1%: 75%, 61%, 52%; P0.0001), and more MLL gene rearrangements (3%, 3%, 10%; P = 0.005) in older patients.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.

Randomized trials have suggested that the beneficial effects of statins could extend to mechanisms beyond cholesterol reduction. Investigations have shown that statins are associated with reduced plasma markers of inflammation, reduced T-cell and monocyte activation, and reduced blood clotting. These effects could be explained by the inhibition of L-mevalonic acid synthesis, thus affecting cell-signalling pathways. However, it has been difficult to evaluate whether the nonlipid effects of statins translate into clinically meaningful outcomes.Inflammation, as measured by C-reactive protein (CRP), has been established as an independent cardiovascular risk factor, even in persons with low-density lipoprotein (LDL)-cholesterol. Statins have anti-inflammatory effects, and lower CRP. Reducing both LDL-cholesterol and CRP is important in order to decrease the risk of cardiovascular events. Statins significantly reduce the risk of venous thrombosis. It is probable that this effect goes beyond lipid lowering. The clinical benefit of statin therapy in infectious diseases remains to be determined by randomized controlled trials.Statins have anti-inflammatory properties that are clinically important in lowering cardiovascular risk. It is probable, but not definitely proven, that some of the benefits of statins are due to their nonlipid effects.

Smoking cessation is probably the most important action to reduce mortality after a coronary event. Smoking cessation programs are not widely implemented in patients with coronary heart disease, however, possibly because they are thought not to be worth their costs. Our objectives were to estimate the cost effectiveness of a smoking cessation program, and to compare it with other treatment modalities in cardiovascular medicine.A cost-effectiveness analysis was performed on the basis of a recently conducted randomized smoking cessation intervention trial in patients admitted for coronary heart disease. The cost per life year gained by the smoking cessation program was derived from the resources necessary to implement the program, the number needed to treat to get one additional quitter from the program, and the years of life gained if quitting smoking. The cost effectiveness was estimated in a low-risk group (i.e. patients with stable coronary heart disease) and a high-risk group (i.e. patients after myocardial infarction or unstable angina), using survival data from previously published investigations, and with life-time extrapolation of the survival curves by survival function modeling.In a lifetime perspective, the incremental cost per year of life gained by the smoking cessation program was euro 280 and euro 110 in the low and high-risk group, respectively (2000 prices). These costs compare favorably to other treatment modalities in patients with coronary heart disease, being approximately 1/25 the cost of both statins in the low-risk group and angiotensin-converting enzyme inhibitors in the high-risk group. In a sensitivity analysis, the costs remained low in a wide range of assumptions.A nurse-led smoking cessation program with several months of intervention is very cost-effective compared with other treatment modalities in patients with coronary heart disease.

To evaluate whether smoking cessation after a coronary event improves quality of life, and to assess whether quality of life is a predictor of smoking cessation.Health-related quality of life at baseline and at 12 months follow up were measured in a randomised smoking cessation trial of 240 smokers aged under 76 years admitted for myocardial infarction, unstable angina or coronary bypass surgery. At 12 months follow up 101 had managed to give up smoking (quitters), and 117 were smokers (sustained smokers).The quitters and sustained smokers had similar improvements in all quality of life domains from baseline to 12 months follow up. Further, after adjustment for differences in baseline characteristics, the quality of life was not significantly different in the quitters compared to the sustained smokers neither at baseline nor at 12 months follow up.Smoking cessation did not improve quality of life compared to sustained smoking after a coronary event in a 12 month follow up. Quality of life was not a significant predictor of smoking cessation.

Background Smoking cessation is probably the most important single action after a coronary event. In order to increase the effectiveness of smoking cessation programs, it is important to have knowledge of the predictors of smoking cessation. Further, it is unknown whether smoking cessation programs have impact on these predictors. Methods Data were obtained from a randomized controlled trial of smoking cessation intervention in 240 smokers aged less than 76 years admitted for myocardial infarction, unstable angina, or cardiac bypass surgery. Baseline characteristics were prospectively recorded. Smoking cessation was determined by self report and biochemical verification at 12 months follow-up. Results In multivariate logistic regression analysis, a high level of nicotine addiction, low level of self-confidence in quitting and having previous coronary heart disease were significant negative predictors of smoking cessation at 12 months follow-up. Having previous coronary heart disease and a diagnosis other than acute myocardial infarction as a reason for admission were important negative predictors of abstinence in the usual care group, in contrast to the intervention group, although this did not reach a level of significance in the subgroup interaction analyses. A high level of nicotine addiction was a strong negative predictor in both groups. Conclusion A high level of nicotine addiction is an important negative predictor of smoking cessation, even within an individualized smoking cessation program. Smoking cessation intervention seems to be especially effective in patients with previous coronary heart disease and in patients with unstable angina or coronary artery bypass surgery, compared to usual care.

Objective To determine whether a nurse led smoking cessation intervention affects smoking cessation rates in patients admitted for coronary heart disease. Design Randomised controlled trial. Setting Cardiac ward of a general hospital, Norway. Participants 240 smokers aged under 76 years admitted for myocardial infarction, unstable angina, or cardiac bypass surgery. 118 were randomly assigned to the intervention and 122 to usual care (control group). Intervention The intervention was based on a booklet and focused on fear arousal and prevention of relapses. The intervention was delivered by cardiac nurses without special training. The intervention was initiated in hospital, and the participants were contacted regularly for at least five months. Main outcome measure Smoking cessation rates at 12 months determined by self report and biochemical verification. Results 12 months after admission to hospital, 57% (n = 57/100) of patients in the intervention group and 37% (n = 44/118) in the control group had quit smoking (absolute risk reduction 20%, 95% confidence interval 6% to 33%). The number needed to treat to get one additional person who would quit was 5 (95% confidence interval, 3 to 16). Assuming all dropouts relapsed at 12 months, the smoking cessation rates were 50% in the intervention group and 37% in the control group (absolute risk reduction 13%, 0% to 26%). Conclusion A smoking cessation programme delivered by cardiac nurses without special training, significantly reduced smoking rates in patients 12 months after admission to hospital for coronary heart disease.

Abstract 4654 Background: Hereditary TTP, also known as Upshaw-Schulman syndrome (USS), is a rare disorder and the result of recessively inherited ADAMTS13 gene (located on chromosome 9q34) mutations. The clinical presentation is variable and may vary from mild isolated thrombocytopenia to recurrent severe TTP episodes leading to organ damage or even death. The first acute TTP episode may occur during the neonatal period up to older age. The same variety applies to the treatment requirements as some patients need regular plasma infusion every two to three weeks to prevent recurrent episodes while others only need plasma therapy in situations of increased risk, such as pregnancy or during infections. Due to the rareness of USS evidence based guidelines are lacking as are knowledge of long-term outcome which emphasizes the need of a multicenter cooperation. Aim: We have established a long-term observational study with an electronic database system for hereditary TTP patients (www.ttpregistry.net, ClinicalTrials.gov NCT01257269) to gather as much information as possible about the clinical courses and laboratory investigations performed. We aim at the identification of triggers that set about acute TTP bouts and of factors influencing the clinical course with the goal to possibly elucidated the underlying causes of the variable clinical presentation of this rare monogenic disorder eventually leading to optimization of therapy and evidence based recommendations. The study is open to any patient diagnosed with hereditary TTP and his/her interested family members. Eligibility criteria are as follows: • ADAMTS13 activity ≤10% on two separate occasions at least 1 month apart; and • Absence of a functional ADAMTS13 inhibitor and • ≥2 ADAMTS13 gene mutations and/or full recovery and normal half-life of infused plasma ADAMTS13); or • Being a family members of a confirmed patient Clinical information and laboratory investigations are collected retrospectively up to enrollment as well as prospectively every 12 months following enrollment. Analysis of ADAMTS13 related parameters including molecular analysis of ADAMTS13 gene are offered free of charge to patients and all family members. Conclusion: Our long-term goal is to establish an international network and knowledge platform to exchange information and experience on USS, that helps to improve diagnosis, treatment and prevention of acute episodes with risk of permanent organ damage for affected patients. Physicians treating USS patients are invited to contact us for diagnostics of suspected patients or enroll their confirmed patients. Disclosures: Fujimura: Baxter BioScience: Membership on an entity's Board of Directors or advisory committees; Alexion Pharma: Membership on an entity's Board of Directors or advisory committees. George:Baxter, Inc.: Consultancy; Alexion, Inc.: Consultancy; Amgen, Inc.: Consultancy, PI for clinical trial involving romiplostim, PI for clinical trial involving romiplostim Other, Research Funding. Kremer Hovinga Strebel:Baxter: Consultancy, Research Funding.