| 1. |
- Mishra, A., et al.
(author)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Journal article (peer-reviewed)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 2. |
- Lynggaard, L. S., et al.
(author)
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Asparaginase encapsulated in erythrocytes as second-line treatment in hypersensitive patients with acute lymphoblastic leukaemia
- 2022
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In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 197:6, s. 745-754
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Journal article (peer-reviewed)abstract
- Asparaginase is essential in treating acute lymphoblastic leukaemia (ALL). Asparaginase-related hypersensitivity causes treatment discontinuation, which is associated with decreased event-free survival. To continue asparaginase treatment after hypersensitivity, a formulation of asparaginase encapsulated in erythrocytes (eryaspase) was developed. In NOR-GRASPALL 2016 (NCT03267030) the safety and efficacy of eryaspase was evaluated in 55 patients (aged 1-45 years; median: 6.1 years) with non-high-risk ALL and hypersensitivity to asparaginase conjugated with polyethylene glycol (PEG-asparaginase). Eryaspase (150 u/kg) was scheduled to complete the intended course of asparaginase (1-7 doses) in two Nordic/Baltic treatment protocols. Forty-nine (96.1%) patients had asparaginase enzyme activity (AEA) >= 100 iu/l 14 +/- 2 days after the first eryaspase infusion [median AEA 511 iu/l; interquartile range (IQR), 291-780], whereas six of nine (66.7%) patients had AEA >= 100 iu/l 14 +/- 2 days after the fourth infusion (median AEA 932 iu/l; IQR, 496-163). The mean terminal half-life of eryaspase following the first infusion was 15.3 +/- 15.5 days. Few asparaginase-related adverse events were reported; five patients (9.1%) developed clinical allergy associated with enzyme inactivation. Replacement therapy was successfully completed in 50 patients (90.9%). Eryaspase was well tolerated, and most patients had AEA levels above the therapeutic target after the first infusion. The half-life of eryaspase confirmed that a 2-week schedule is appropriate.
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| 3. |
- Porcu, E, et al.
(author)
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Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3300-
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits.
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| 4. |
- Rank, CU, et al.
(author)
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Asparaginase-Associated Pancreatitis in ALL: Results from the NOPHO ALL2008 Treatment of Patients 1-45 Years
- 2019
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In: Blood. 134 (Suppl. 1), 3820.. - : American Society of Hematology. - 0006-4971 .- 1528-0020.
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Conference paper (peer-reviewed)abstract
- 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<.0001; 9.0-16.9 years: HR 2.5, 95% CI 1.6-3.8, P<.0001; and 17.0-45.9 years: HR 2.5, 95% CI 1.6-3.8, P<.0001). When analyzing the odds of developing any AAP-related complication among patients with ≥100 days of follow-up after the AAP diagnosis, older children (≥5.0 years) and adolescents had increased odds of developing any complication compared with younger children aged 1.0-4.9 years, notably a more than six-fold increase among adolescents (5.0-8.9 years: odds ratio (OR) 2.67, 95% CI 1.07-6.68, P=.04 and 9.0-16.9 years: OR 6.52, 95% CI 2.35-18.1, P=.0003)-including acute and permanent insulin need; intensive care unit admission; pancreatic pseudocyst development; recurrent abdominal pain; elevated pancreatic enzymes at last-follow-up; imaging compatible with pancreatitis (pancreatic inflammation/edema/pseudocysts/hemorrhage) at last follow-up; and AAP-related death. Adult age was not associated with development of any AAP-related complication (17.0-45.9 years: OR 2.3, 95% CI 0.9-5.9, P=.07). Three patients aged 8.6, 17.3, and 18.6 years died of first-time AAP within 0-29 days from AAP diagnosis. 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
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| 5. |
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| 6. |
- Toksvang, LN, et al.
(author)
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Thiopurine Enhanced ALL Maintenance (TEAM): study protocol for a randomized study to evaluate the improvement in disease-free survival by adding very low dose 6-thioguanine to 6-mercaptopurine/methotrexate-based maintenance therapy in pediatric and adult patients (0-45 years) with newly diagnosed B-cell precursor or T-cell acute lymphoblastic leukemia treated according to the intermediate risk-high group of the ALLTogether1 protocol
- 2022
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In: BMC cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 22:1, s. 483-
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Journal article (peer-reviewed)abstract
- BackgroundA critical challenge in current acute lymphoblastic leukemia (ALL) therapy is treatment intensification in order to reduce the relapse rate in the subset of patients at the highest risk of relapse. The year-long maintenance phase is essential in relapse prevention. The Thiopurine Enhanced ALL Maintenance (TEAM) trial investigates a novel strategy for ALL maintenance.MethodsTEAM is a randomized phase 3 sub-protocol to the ALLTogether1 trial, which includes patients 0–45 years of age with newly diagnosed B-cell precursor or T-cell ALL, and stratified to the intermediate risk-high (IR-high) group, in 13 European countries. In the TEAM trial, the traditional methotrexate (MTX)/6-mercaptopurine (6MP) maintenance backbone (control arm) is supplemented with low dose (2.5–12.5 mg/m2/day) oral 6-thioguanine (6TG) (experimental arm), while the starting dose of 6MP is reduced from 75 to 50 mg/m2/day. A total of 778 patients will be included in TEAM during ~ 5 years. The study will close when the last included patient has been followed for 5 years from the end of induction therapy. The primary objective of the study is to significantly improve the disease-free survival (DFS) of IR-high ALL patients by adding 6TG to 6MP/MTX-based maintenance therapy. TEAM has 80% power to detect a 7% increase in 5-year DFS through a 50% reduction in relapse rate. DFS will be evaluated by intention-to-treat analysis. In addition to reducing relapse, TEAM may also reduce hepatotoxicity and hypoglycemia caused by high levels of methylated 6MP metabolites. Methotrexate/6MP metabolites will be monitored and low levels will be reported back to clinicians to identify potentially non-adherent patients.DiscussionTEAM provides a novel strategy for maintenance therapy in ALL with the potential of improving DFS through reducing relapse rate. Potential risk factors that have been considered include hepatic sinusoidal obstruction syndrome/nodular regenerative hyperplasia, second cancer, infection, and osteonecrosis. Metabolite monitoring can potentially increase treatment adherence in both treatment arms.Trial registrationEudraCT, 2018–001795-38. Registered 2020-05-15,Clinicaltrials.gov,NCT04307576. Registered 2020-03-13,https://clinicaltrials.gov/ct2/show/NCT04307576
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| 7. |
- Rank, Cecilie U., et al.
(author)
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Asparaginase-Associated Pancreatitis in Acute Lymphoblastic Leukemia : Results From the NOPHO ALL2008 Treatment of Patients 1-45 Years of Age
- 2020
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In: Journal of Clinical Oncology. - Alexandria : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 38:2, s. 145-154
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Journal article (peer-reviewed)abstract
- 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.
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