Asparaginase-Associated Pancreatitis in Acute Lymphoblastic Leukemia : Results From the NOPHO ALL2008 Treatment of Patients 1-45 Years of Age

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. (C) 2019 by American Society of Clinical OncologyPeer reviewe

Stroke genetics informs drug discovery and risk prediction across ancestries

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.</p

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. 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 analysis3, 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 approach4, 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 ancestry5. 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

Relapse risk following truncation of pegylated asparaginase in childhood acute lymphoblastic leukemia

Truncation of asparaginase treatment due to asparaginase-related toxicities or silent inactivation (SI) is common and may increase relapse risk in acute lymphoblastic leukemia (ALL). We investigated relapse risk following suboptimal asparaginase exposure among 1401 children aged 1 to 17 years, diagnosed with ALL between July 2008 and February 2016, treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol (including extended asparaginase exposure [1000 IU/m(2) intramuscularly weeks 5-33]). Patients were included with delayed entry at their last administered asparaginase treatment, or detection of SI, and followed until relapse, death, secondary malignancy, or end of follow-up (median, 5.71 years; interquartile range, 4.02-7.64). In a multiple Cox model comparing patients with (n = 358) and without (n = 1043) truncated asparaginase treatment due to clinical toxicity, the adjusted relapse-specific hazard ratio (HR; aHR) was 1.33 (95% confidence interval [CI], 0.86-2.06; P = .20). In a substudy including only patients with information on enzymeactivity (n = 1115), the 7-year cumulative incidence of relapse for the 301 patients with truncation of asparaginase treatment or SI (157 hypersensitivity, 53 pancreatitis, 14 thrombosis, 31 other, 46 SI) was 11.1%(95% CI, 6.9-15.4) vs 6.7%(95% CI, 4.7-8.6) for the 814 remaining patients. The relapse-specific aHR was 1.69 (95% CI, 1.05-2.74, P=.03). The unadjusted bone marrow relapse-specific HR was 1.83 (95% CI, 1.07-3.14, P=.03) and 1.86 (95% CI, 0.90- 3.87, P=.095) for any central nervous system relapse. These results emphasize the importance of therapeutic drug monitoring and appropriate adjustment of asparaginase therapy when feasible.Peer reviewe

Obesity as a predictor of treatment-related toxicity in children with acute lymphoblastic leukaemia

Abstract Obesity is associated with poor outcomes in childhood acute lymphoblastic leukaemia (ALL). We explored whether severe treatment-related toxicity and treatment delays could explain this observation. This study included 1 443 children aged 2·0–17·9 years with ALL treated with the Nordic Society of Pediatric Haematology and Oncology (NOPHO) ALL2008 non-high-risk protocol. Prospective treatment-related toxicities registered every three-month interval were used. Patients were classified according to sex- and age-adjusted international childhood cut-off values, corresponding to adult body mass index: underweight, &lt;17 kg/m²; healthy weight, 17 to &lt;25 kg/m² overweight 25 to &lt;30 kg/m²; and obese, ≥30 kg/m². Obese children had a higher incidence rate ratio (IRR) for severe toxic events {IRR: 1·55 [95% confidence interval (CI) 1·07–2·50]}, liver and kidney failures, bleeding, abdominal complication, suspected unexpected severe adverse reactions and hyperlipidaemia compared with healthy-weight children. Obese children aged ≥10 years had increased IRRs for asparaginase-related toxicities compared with healthy-weight older children: thromboses [IRR 2·87 (95% CI 1·00–8·21)] and anaphylactic reactions [IRR 7·95 (95% CI 2·15–29·37)] as well as higher risk for truncation of asparaginase [IRR 3·54 (95% CI 1·67–7·50)]. The high prevalence of toxicity and a higher risk of truncation of asparaginase may play a role in the poor prognosis of obese children aged ≥10 years with ALL

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

Abstract Background: A 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. Methods: TEAM 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. Discussion: TEAM 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 registration: EudraCT, 2018–001795-38. Registered 2020-05-15

Stroke genetics informs drug discovery and risk prediction across ancestries.

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. 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 analysis3, 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 approach4, 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 ancestry5. 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