32 results on '"Wolthers, Benjamin O."'
Search Results
2. Impact of acute lymphoblastic leukemia induction therapy: findings from metabolomics on non-fasted plasma samples from a biorepository
- Author
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Saito, Toshie, Wei, Yue, Wen, Li, Srinivasan, Chaitanya, Wolthers, Benjamin O., Tsai, Cheng-Yu, Harris, Marian H., Stevenson, Kristen, Byersdorfer, Craig, Oparaji, Judy-April, Fernandez, Christian, Mukherjee, Amitava, Abu-El-Haija, Maisam, Agnihotri, Sameer, Schmiegelow, Kjeld, Showalter, Megan R., Fogle, Paul W., McCulloch, Scott, Contrepois, Kevin, Silverman, Lewis B., Ding, Ying, and Husain, Sohail Z.
- Published
- 2021
- Full Text
- View/download PDF
3. Zuma-25: A Phase 2 Study of Brexucabtagene Autoleucel (KTE-X19) Chimeric Antigen Receptor T-Cell Therapy in Adult Patients with Relapsed/Refractory Rare B-Cell Malignancies
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Eichhorst, Barbara, primary, Dunleavy, Kieron, additional, Tiacci, Enrico, additional, Buske, Christian, additional, Jain, Nitin, additional, Castillo, Jorge J., additional, Rossi, Davide, additional, Woolven, Kate, additional, Masouleh, Behzad Kharabi, additional, Peng, Weimin, additional, Schuberth, Petra C., additional, Domper, Neus, additional, Wolthers, Benjamin O., additional, and Palomba, M. Lia, additional
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- 2023
- Full Text
- View/download PDF
4. Can Machine Learning Models Predict Asparaginase-associated Pancreatitis in Childhood Acute Lymphoblastic Leukemia
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Nielsen, Rikke L., Wolthers, Benjamin O., Helenius, Marianne, Albertsen, Birgitte K., Clemmensen, Line, Nielsen, Kasper, Kanerva, Jukka, Niinimäki, Riitta, Frandsen, Thomas L., Attarbaschi, Andishe, Barzilai, Shlomit, Colombini, Antonella, Escherich, Gabriele, Aytan-Aktug, Derya, Liu, Hsi Che, Möricke, Anja, Samarasinghe, Sujith, Van Der Sluis, Inge M., Stanulla, Martin, Tulstrup, Morten, Yadav, Rachita, Zapotocka, Ester, Schmiegelow, Kjeld, Gupta, Ramneek, Nielsen, Rikke L., Wolthers, Benjamin O., Helenius, Marianne, Albertsen, Birgitte K., Clemmensen, Line, Nielsen, Kasper, Kanerva, Jukka, Niinimäki, Riitta, Frandsen, Thomas L., Attarbaschi, Andishe, Barzilai, Shlomit, Colombini, Antonella, Escherich, Gabriele, Aytan-Aktug, Derya, Liu, Hsi Che, Möricke, Anja, Samarasinghe, Sujith, Van Der Sluis, Inge M., Stanulla, Martin, Tulstrup, Morten, Yadav, Rachita, Zapotocka, Ester, Schmiegelow, Kjeld, and Gupta, Ramneek
- Abstract
Asparaginase-associated pancreatitis (AAP) frequently affects children treated for acute lymphoblastic leukemia (ALL) causing severe acute and persisting complications. Known risk factors such as asparaginase dosing, older age and single nucleotide polymorphisms (SNPs) have insufficient odds ratios to allow personalized asparaginase therapy. In this study, we explored machine learning strategies for prediction of individual AAP risk. We integrated information on age, sex, and SNPs based on Illumina Omni2.5exome-8 arrays of patients with childhood ALL (N=1564, 244 with AAP aged 1.0 to 17.9 y) from 10 international ALL consortia into machine learning models including regression, random forest, AdaBoost and artificial neural networks. A model with only age and sex had area under the receiver operating characteristic curve (ROC-AUC) of 0.62. Inclusion of 6 pancreatitis candidate gene SNPs or 4 validated pancreatitis SNPs boosted ROC-AUC somewhat (0.67) while 30 SNPs, identified through our AAP genome-wide association study cohort, boosted performance (0.80). Most predictive features included rs10273639 (PRSS1-PRSS2), rs10436957 (CTRC), rs13228878 (PRSS1/PRSS2), rs1505495 (GALNTL6), rs4655107 (EPHB2) and age (1 to 7 y). Second AAP following asparaginase re-exposure was predicted with ROC-AUC: 0.65. The machine learning models assist individual-level risk assessment of AAP for future prevention trials, and may legitimize asparaginase re-exposure when AAP risk is predicted to be low.
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- 2022
5. Asparaginase enzyme activity levels and toxicity in childhood acute lymphoblastic leukemia:a NOPHO ALL2008 study
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Lynggaard, Line Stensig, Rank, Cecilie Utke, Hansen, Stefan Nygaard, Højfeldt, Sofie Gottschalk, Henriksen, Louise Tram, Jarvis, Kirsten Brunsvig, Ranta, Susanna, Niinimaki, Riitta, Harila-Saari, Arja, Wolthers, Benjamin O., Frandsen, Thomas L., Heyman, Mats, Schmiegelow, Kjeld, Albertsen, Birgitte Klug, Lynggaard, Line Stensig, Rank, Cecilie Utke, Hansen, Stefan Nygaard, Højfeldt, Sofie Gottschalk, Henriksen, Louise Tram, Jarvis, Kirsten Brunsvig, Ranta, Susanna, Niinimaki, Riitta, Harila-Saari, Arja, Wolthers, Benjamin O., Frandsen, Thomas L., Heyman, Mats, Schmiegelow, Kjeld, and Albertsen, Birgitte Klug
- Abstract
Asparaginase treatment is a mainstay in contemporary treatment of acute lymphoblastic leukemia (ALL), but substantial asparaginase-related toxicity may lead to jeopardized protocol compliance and compromises survival. We investigated the association between risk of asparaginase-associated toxicities (AspTox) and asparaginase enzyme activity (AEA) levels in 1155 children aged 1.0 to 17.9 years, diagnosed with ALL between July 2008 and March 2016, and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. Patients with $2 blood samples for AEA measurement drawn 14 6 2 days after asparaginase administration were included (6944 trough values). AEA was measurable (or .0 IU/L) in 955 patients, whereas 200 patients (17.3%) had asparaginase inactivation and few AspTox recorded. A time-dependent multiple Cox model of time to any first asparaginase-associated toxicity adjusted for sex and age was used. For patients with measurable AEA, we found a hazard ratio (HR) of 1.17 per 100 IU/L increase in median AEA (95% confidence interval [CI], 0.98-1.41; P 5 .09). For pancreatitis, thromboembolism, and osteonecrosis, the HRs were 1.40 (95% CI, 1.12-1.75; P 5 .002), 0.99 (95% CI, 0.70-1.40; P 5 .96), and 1.36 (95% CI, 1.04-1.77; P 5 .02) per 100 IU/L increase in median AEA, respectively. No significant decrease in the risk of leukemic relapse was found: HR 0.88 per 100 IU/L increase in AEA (95% CI, 0.66-1.16; P 5 .35). In conclusion, these results emphasize that overall AspTox and relapse are not associated with AEA levels, yet the risk of pancreatitis and osteonecrosis increases with increasing AEA levels.
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- 2022
6. Can Machine Learning Models Predict Asparaginase-associated Pancreatitis in Childhood Acute Lymphoblastic Leukemia
- Author
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Nielsen, Rikke L., primary, Wolthers, Benjamin O., additional, Helenius, Marianne, additional, Albertsen, Birgitte K., additional, Clemmensen, Line, additional, Nielsen, Kasper, additional, Kanerva, Jukka, additional, Niinimäki, Riitta, additional, Frandsen, Thomas L., additional, Attarbaschi, Andishe, additional, Barzilai, Shlomit, additional, Colombini, Antonella, additional, Escherich, Gabriele, additional, Aytan-Aktug, Derya, additional, Liu, Hsi-Che, additional, Möricke, Anja, additional, Samarasinghe, Sujith, additional, van der Sluis, Inge M., additional, Stanulla, Martin, additional, Tulstrup, Morten, additional, Yadav, Rachita, additional, Zapotocka, Ester, additional, Schmiegelow, Kjeld, additional, and Gupta, Ramneek, additional
- Published
- 2021
- Full Text
- View/download PDF
7. Pancreatitis-associated protein as an early marker of asparaginase-associated pancreatitis
- Author
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Lukes, Julius, primary, Wolthers, Benjamin O., additional, Altaf Raja, Raheel, additional, Uhrinova, Karolina, additional, Skvarova Kramarzova, Karolina, additional, Hermanova, Ivana, additional, Simcikova, Marketa, additional, Kicko, Peter, additional, Zaliova, Marketa, additional, Sramkova, Lucie, additional, Stary, Jan, additional, Trka, Jan, additional, Schmiegelow, Kjeld, additional, and Starkova, Julia, additional
- Published
- 2021
- Full Text
- View/download PDF
8. Impact of acute lymphoblastic leukemia induction therapy:findings from metabolomics on non-fasted plasma samples from a biorepository
- Author
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Saito, Toshie, Wei, Yue, Wen, Li, Srinivasan, Chaitanya, Wolthers, Benjamin O., Tsai, Cheng Yu, Harris, Marian H., Stevenson, Kristen, Byersdorfer, Craig, Oparaji, Judy April, Fernandez, Christian, Mukherjee, Amitava, Abu-El-Haija, Maisam, Agnihotri, Sameer, Schmiegelow, Kjeld, Showalter, Megan R., Fogle, Paul W., McCulloch, Scott, Contrepois, Kevin, Silverman, Lewis B., Ding, Ying, Husain, Sohail Z., Saito, Toshie, Wei, Yue, Wen, Li, Srinivasan, Chaitanya, Wolthers, Benjamin O., Tsai, Cheng Yu, Harris, Marian H., Stevenson, Kristen, Byersdorfer, Craig, Oparaji, Judy April, Fernandez, Christian, Mukherjee, Amitava, Abu-El-Haija, Maisam, Agnihotri, Sameer, Schmiegelow, Kjeld, Showalter, Megan R., Fogle, Paul W., McCulloch, Scott, Contrepois, Kevin, Silverman, Lewis B., Ding, Ying, and Husain, Sohail Z.
- Abstract
Introduction: Acute lymphoblastic leukemia (ALL) is among the most common cancers in children. With improvements in combination chemotherapy regimens, the overall survival has increased to over 90%. However, the current challenge is to mitigate adverse events resulting from the complex therapy. Several chemotherapies intercept cancer metabolism, but little is known about their collective role in altering host metabolism. Objectives: We profiled the metabolomic changes in plasma of ALL patients initial- and post- induction therapy. Methods: We exploited a biorepository of non-fasted plasma samples derived from the Dana Farber Cancer Institute ALL Consortium; these samples were obtained from 50 ALL patients initial- and post-induction therapy. Plasma metabolites and complex lipids were analyzed by high resolution tandem mass spectrometry and differential mobility tandem mass spectrometry. Data were analyzed using a covariate-adjusted regression model with multiplicity adjustment. Pathway enrichment analysis and co-expression network analysis were performed to identify unique clusters of molecules. Results: More than 1200 metabolites and complex lipids were identified in the total of global metabolomics and lipidomics platforms. Over 20% of those molecules were significantly altered. In the pathway enrichment analysis, lipids, particularly phosphatidylethanolamines (PEs), were identified. Network analysis indicated that the bioactive fatty acids, docosahexaenoic acid (DHA)-containing (22:6) triacylglycerols (TAGs), were decreased in the post-induction therapy. Conclusion: Metabolomic profiling in ALL patients revealed a large number of alterations following induction chemotherapy. In particular, lipid metabolism was substantially altered. The changes in metabolites and complex lipids following induction therapy could provide insight into the adverse events experienced by ALL patients.
- Published
- 2021
9. Pancreatitis-associated protein as an early marker of asparaginase-associated pancreatitis
- Author
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Lukes, Julius, Wolthers, Benjamin O., Altaf Raja, Raheel, Uhrinova, Karolina, Skvarova Kramarzova, Karolina, Hermanova, Ivana, Simcikova, Marketa, Kicko, Peter, Zaliova, Marketa, Sramkova, Lucie, Stary, Jan, Trka, Jan, Schmiegelow, Kjeld, Starkova, Julia, Lukes, Julius, Wolthers, Benjamin O., Altaf Raja, Raheel, Uhrinova, Karolina, Skvarova Kramarzova, Karolina, Hermanova, Ivana, Simcikova, Marketa, Kicko, Peter, Zaliova, Marketa, Sramkova, Lucie, Stary, Jan, Trka, Jan, Schmiegelow, Kjeld, and Starkova, Julia
- Published
- 2021
10. Relapse risk following truncation of pegylated asparaginase in childhood acute lymphoblastic leukemia
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Gottschalk Højfeldt, Sofie, primary, Grell, Kathrine, additional, Abrahamsson, Jonas, additional, Lund, Bendik, additional, Vettenranta, Kim, additional, Jónsson, Ólafur G., additional, Frandsen, Thomas L., additional, Wolthers, Benjamin O., additional, Marquart, Hanne Vibeke, additional, Vaitkeviciene, Goda, additional, Lepik, Kristi, additional, Heyman, Mats, additional, Schmiegelow, Kjeld, additional, and Albertsen, Birgitte Klug, additional
- Published
- 2021
- Full Text
- View/download PDF
11. International consensus definitions of clinical trial outcomes for kidney failure: 2020
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Anand, Shuchi, Argent, Nicholas, Babak, Elena, Banerjee, Debasish, Barratt, Jonathan, Bello, Aminu K., Bernardo, Angelito A., Blais, Jaime, Canovatchel, William, Caskey, Fergus J., Coresh, Josef, de Boer, Ian H., Eckardt, Kai-Uwe, Evans, Rhys DR., Feldman, Harold I., Fogo, Agnes B., Gudmundsdottir, Hrefna, Hamano, Takayuki, Harris, David C.H., Hauske, Sibylle J., Haynes, Richard, Herzog, Charles A., Hiemstra, Thomas, Idorn, Thomas, Inker, Lesley, Ishida, Julie H., Johnson, David W., Jones-Burton, Charlotte, Joseph, Amer, Koitka-Weber, Audrey, Kretzler, Matthias, Lawatscheck, Robert, Liew, Adrian, Moist, Louise, Naicker, Saraladevi, Nakashima, Reiko, Patel, Uptal, Filho, Roberto Pecoits, Rose, Jennifer B., Rosenberg, Noah L., Sinsakul, Marvin, Smoyer, William E., Sola, Laura, Sood, Amy R., Stengel, Benedicte, Taal, Maarten W., Tanaka, Mototsugu, Tonelli, Marcello, Tong, Allison, Toto, Robert, Trask, Michele, Ulasi, Ifeoma I., Wanner, Christoph, Wheeler, David C., Wolthers, Benjamin O., Wright, Harold M., Yamada, Yoshihisa, Zakharova, Elena, Levin, Adeera, Agarwal, Rajiv, Herrington, William G., Heerspink, Hiddo L., Mann, Johannes F.E., Shahinfar, Shahnaz, Tuttle, Katherine R., Donner, Jo-Ann, Jha, Vivekanand, Nangaku, Masaomi, de Zeeuw, Dick, Jardine, Meg J., Mahaffey, Kenneth W., Thompson, Aliza M., Beaucage, Mary, Chong, Kate, Roberts, Glenda V., Sunwold, Duane, Vorster, Hans, Warren, Madeleine, Damster, Sandrine, Malik, Charu, and Perkovic, Vlado
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- 2020
- Full Text
- View/download PDF
12. Asparaginase-Associated Pancreatitis in Acute Lymphoblastic Leukemia : Results From the NOPHO ALL2008 Treatment of Patients 1-45 Years of Age
- Author
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Rank, Cecilie U., Wolthers, Benjamin O., Grell, Kathrine, Albertsen, Birgitte K., Frandsen, Thomas L., Overgaard, Ulrik M., Toft, Nina, Nielsen, Ove J., Wehner, Peder S., Harila-Saari, Arja H., Heyman, Mats M., Malmros, Johan, Abrahamsson, Jonas, Norén-Nyström, Ulrika, Tomaszewska-Toporska, Beata, Lund, Bendik, Jarvis, Kirsten B., Quist-Paulsen, Petter, Vaitkeviciene, Goda E., Griskevicius, Laimonas, Taskinen, Mervi, Wartiovaara-Kautto, Ulla, Lepik, Kristi, Punab, Mari, Jonsson, Olafur G., Schmiegelow, Kjeld, Rank, Cecilie U., Wolthers, Benjamin O., Grell, Kathrine, Albertsen, Birgitte K., Frandsen, Thomas L., Overgaard, Ulrik M., Toft, Nina, Nielsen, Ove J., Wehner, Peder S., Harila-Saari, Arja H., Heyman, Mats M., Malmros, Johan, Abrahamsson, Jonas, Norén-Nyström, Ulrika, Tomaszewska-Toporska, Beata, Lund, Bendik, Jarvis, Kirsten B., Quist-Paulsen, Petter, Vaitkeviciene, Goda E., Griskevicius, Laimonas, Taskinen, Mervi, Wartiovaara-Kautto, Ulla, Lepik, Kristi, Punab, Mari, Jonsson, Olafur G., and Schmiegelow, Kjeld
- 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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- 2020
- Full Text
- View/download PDF
13. Genome-wide association meta-analysis of single-nucleotide polymorphisms and symptomatic venous thromboembolism during therapy for acute lymphoblastic leukemia and lymphoma in caucasian children
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Mateos, Marion K., Tulstrup, Morten, Quinn, Michael C.J., Tuckuviene, Ruta, Marshall, Glenn M., Gupta, Ramneek, Mayoh, Chelsea, Wolthers, Benjamin O., Barbaro, Pasquale M., Ruud, Ellen, Sutton, Rosemary, Huttunen, Pasi, Revesz, Tamas, Trakymiene, Sonata S., Barbaric, Draga, Tedgård, Ulf, Giles, Jodie E., Alvaro, Frank, Jonsson, Olafur G., Mechinaud, Françoise, Saks, Kadri, Catchpoole, Daniel, Kotecha, Rishi S., Dalla-Pozza, Luciano, Chenevix-Trench, Georgia, Trahair, Toby N., Macgregor, Stuart, Schmiegelow, Kjeld, Mateos, Marion K., Tulstrup, Morten, Quinn, Michael C.J., Tuckuviene, Ruta, Marshall, Glenn M., Gupta, Ramneek, Mayoh, Chelsea, Wolthers, Benjamin O., Barbaro, Pasquale M., Ruud, Ellen, Sutton, Rosemary, Huttunen, Pasi, Revesz, Tamas, Trakymiene, Sonata S., Barbaric, Draga, Tedgård, Ulf, Giles, Jodie E., Alvaro, Frank, Jonsson, Olafur G., Mechinaud, Françoise, Saks, Kadri, Catchpoole, Daniel, Kotecha, Rishi S., Dalla-Pozza, Luciano, Chenevix-Trench, Georgia, Trahair, Toby N., Macgregor, Stuart, and Schmiegelow, Kjeld
- Abstract
Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied. Methods: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included. Results: No SNPs reached genome-wide significance (p < 5 × 10−8) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p < 1 × 10−6), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 × 10−7) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 × 10−7) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease. Conclusion: This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.
- Published
- 2020
14. Asparaginase-Associated Pancreatitis in Acute Lymphoblastic Leukemia:Results From the NOPHO ALL2008 Treatment of Patients 1-45 Years of Age
- Author
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Rank, Cecilie U, Wolthers, Benjamin O, Grell, Kathrine, Albertsen, Birgitte K, Frandsen, Thomas L, Overgaard, Ulrik M, Toft, Nina, Nielsen, Ove J., Wehner, Peder S, Harila-Saari, Arja, Heyman, Mats M, Malmros, Johan, Abrahamsson, Jonas, Norén-Nyström, Ulrika, Tomaszewska-Toporska, Beata, Lund, Bendik, Jarvis, Kirsten B, Quist-Paulsen, Petter, Vaitkevičienė, Goda E, Griškevičius, Laimonas, Taskinen, Mervi, Wartiovaara-Kautto, Ulla, Lepik, Kristi, Punab, Mari, Jónsson, Ólafur G, Schmiegelow, Kjeld, Rank, Cecilie U, Wolthers, Benjamin O, Grell, Kathrine, Albertsen, Birgitte K, Frandsen, Thomas L, Overgaard, Ulrik M, Toft, Nina, Nielsen, Ove J., Wehner, Peder S, Harila-Saari, Arja, Heyman, Mats M, Malmros, Johan, Abrahamsson, Jonas, Norén-Nyström, Ulrika, Tomaszewska-Toporska, Beata, Lund, Bendik, Jarvis, Kirsten B, Quist-Paulsen, Petter, Vaitkevičienė, Goda E, Griškevičius, Laimonas, Taskinen, Mervi, Wartiovaara-Kautto, Ulla, Lepik, Kristi, Punab, Mari, Jónsson, Ólafur G, and Schmiegelow, Kjeld
- 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.
- Published
- 2020
15. International consensus definitions of clinical trial outcomes for kidney failure: 2020
- Author
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Levin, Adeera, primary, Agarwal, Rajiv, additional, Herrington, William G., additional, Heerspink, Hiddo L., additional, Mann, Johannes F.E., additional, Shahinfar, Shahnaz, additional, Tuttle, Katherine R., additional, Donner, Jo-Ann, additional, Jha, Vivekanand, additional, Nangaku, Masaomi, additional, de Zeeuw, Dick, additional, Jardine, Meg J., additional, Mahaffey, Kenneth W., additional, Thompson, Aliza M., additional, Beaucage, Mary, additional, Chong, Kate, additional, Roberts, Glenda V., additional, Sunwold, Duane, additional, Vorster, Hans, additional, Warren, Madeleine, additional, Damster, Sandrine, additional, Malik, Charu, additional, Perkovic, Vlado, additional, Anand, Shuchi, additional, Argent, Nicholas, additional, Babak, Elena, additional, Banerjee, Debasish, additional, Barratt, Jonathan, additional, Bello, Aminu K., additional, Bernardo, Angelito A., additional, Blais, Jaime, additional, Canovatchel, William, additional, Caskey, Fergus J., additional, Coresh, Josef, additional, de Boer, Ian H., additional, Eckardt, Kai-Uwe, additional, Evans, Rhys DR., additional, Feldman, Harold I., additional, Fogo, Agnes B., additional, Gudmundsdottir, Hrefna, additional, Hamano, Takayuki, additional, Harris, David C.H., additional, Hauske, Sibylle J., additional, Haynes, Richard, additional, Herzog, Charles A., additional, Hiemstra, Thomas, additional, Idorn, Thomas, additional, Inker, Lesley, additional, Ishida, Julie H., additional, Johnson, David W., additional, Jones-Burton, Charlotte, additional, Joseph, Amer, additional, Koitka-Weber, Audrey, additional, Kretzler, Matthias, additional, Lawatscheck, Robert, additional, Liew, Adrian, additional, Moist, Louise, additional, Naicker, Saraladevi, additional, Nakashima, Reiko, additional, Patel, Uptal, additional, Filho, Roberto Pecoits, additional, Rose, Jennifer B., additional, Rosenberg, Noah L., additional, Sinsakul, Marvin, additional, Smoyer, William E., additional, Sola, Laura, additional, Sood, Amy R., additional, Stengel, Benedicte, additional, Taal, Maarten W., additional, Tanaka, Mototsugu, additional, Tonelli, Marcello, additional, Tong, Allison, additional, Toto, Robert, additional, Trask, Michele, additional, Ulasi, Ifeoma I., additional, Wanner, Christoph, additional, Wheeler, David C., additional, Wolthers, Benjamin O., additional, Wright, Harold M., additional, Yamada, Yoshihisa, additional, and Zakharova, Elena, additional
- Published
- 2020
- Full Text
- View/download PDF
16. 521 - Zuma-25: A Phase 2 Study of Brexucabtagene Autoleucel (KTE-X19) Chimeric Antigen Receptor T-Cell Therapy in Adult Patients with Relapsed/Refractory Rare B-Cell Malignancies
- Author
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Eichhorst, Barbara, Dunleavy, Kieron, Tiacci, Enrico, Buske, Christian, Jain, Nitin, Castillo, Jorge J., Rossi, Davide, Woolven, Kate, Masouleh, Behzad Kharabi, Peng, Weimin, Schuberth, Petra C., Domper, Neus, Wolthers, Benjamin O., and Palomba, M. Lia
- Published
- 2023
- Full Text
- View/download PDF
17. Genome-Wide Association Meta-Analysis of Single-Nucleotide Polymorphisms and Symptomatic Venous Thromboembolism during Therapy for Acute Lymphoblastic Leukemia and Lymphoma in Caucasian Children
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Mateos, Marion K., primary, Tulstrup, Morten, additional, Quinn, Michael CJ, additional, Tuckuviene, Ruta, additional, Marshall, Glenn M., additional, Gupta, Ramneek, additional, Mayoh, Chelsea, additional, Wolthers, Benjamin O., additional, Barbaro, Pasquale M., additional, Ruud, Ellen, additional, Sutton, Rosemary, additional, Huttunen, Pasi, additional, Revesz, Tamas, additional, Trakymiene, Sonata S., additional, Barbaric, Draga, additional, Tedgård, Ulf, additional, Giles, Jodie E., additional, Alvaro, Frank, additional, Jonsson, Olafur G., additional, Mechinaud, Françoise, additional, Saks, Kadri, additional, Catchpoole, Daniel, additional, Kotecha, Rishi S., additional, Dalla-Pozza, Luciano, additional, Chenevix-Trench, Georgia, additional, Trahair, Toby N., additional, MacGregor, Stuart, additional, and Schmiegelow, Kjeld, additional
- Published
- 2020
- Full Text
- View/download PDF
18. Validation of distinct type 2 diabetes clusters and their association with diabetes complications in the DEVOTE, LEADER and SUSTAIN‐6 cardiovascular outcomes trials
- Author
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Kahkoska, Anna R., primary, Geybels, Milan S., additional, Klein, Klara R., additional, Kreiner, Frederik F., additional, Marx, Nikolaus, additional, Nauck, Michael A., additional, Pratley, Richard E., additional, Wolthers, Benjamin O., additional, and Buse, John B., additional
- Published
- 2020
- Full Text
- View/download PDF
19. Asparaginase-Associated Pancreatitis in Acute Lymphoblastic Leukemia: Results From the NOPHO ALL2008 Treatment of Patients 1-45 Years of Age
- Author
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Rank, Cecilie U., primary, Wolthers, Benjamin O., additional, Grell, Kathrine, additional, Albertsen, Birgitte K., additional, Frandsen, Thomas L., additional, Overgaard, Ulrik M., additional, Toft, Nina, additional, Nielsen, Ove J., additional, Wehner, Peder S., additional, Harila-Saari, Arja, additional, Heyman, Mats M., additional, Malmros, Johan, additional, Abrahamsson, Jonas, additional, Norén-Nyström, Ulrika, additional, Tomaszewska-Toporska, Beata, additional, Lund, Bendik, additional, Jarvis, Kirsten B., additional, Quist-Paulsen, Petter, additional, Vaitkevičienė, Goda E., additional, Griškevičius, Laimonas, additional, Taskinen, Mervi, additional, Wartiovaara-Kautto, Ulla, additional, Lepik, Kristi, additional, Punab, Mari, additional, Jónsson, Ólafur G., additional, and Schmiegelow, Kjeld, additional
- Published
- 2020
- Full Text
- View/download PDF
20. Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008
- Author
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Højfeldt, Sofie G., Wolthers, Benjamin O, Tulstrup, Morten, Abrahamsson, Jonas, Gupta, Ramneek, Harila-Saari, Arja H., Heyman, Mats, Henriksen, Louise T., Jónsson, Òlafur G., Lähteenmäki, Päivi M, Lund, Bendik, Pruunsild, Kaie, Vaitkeviciene, Goda, Schmiegelow, Kjeld, Albertsen, Birgitte K, Højfeldt, Sofie G., Wolthers, Benjamin O, Tulstrup, Morten, Abrahamsson, Jonas, Gupta, Ramneek, Harila-Saari, Arja H., Heyman, Mats, Henriksen, Louise T., Jónsson, Òlafur G., Lähteenmäki, Päivi M, Lund, Bendik, Pruunsild, Kaie, Vaitkeviciene, Goda, Schmiegelow, Kjeld, and Albertsen, Birgitte K
- Abstract
Asparaginase is essential in childhood acute lymphoblastic leukaemia (ALL) treatment, however hypersensitivity reactions to pegylated asparaginase (PEG-asparaginase) hampers anti-neoplastic efficacy. Patients with PEG-asparaginase hypersensitivity have been shown to possess zero asparaginase enzyme activity. Using this measurement to define the phenotype, we investigated genetic predisposition to PEG-asparaginase hypersensitivity in a genome-wide association study (GWAS). From July 2008 to March 2016, 1494 children were treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol. Cases were defined by clinical hypersensitivity and no enzyme activity, controls had enzyme activity ≥ 100 iu/l and no hypersensitivity symptoms. PEG-asparaginase hypersensitivity was reported in 13·8% (206/1494) of patients. Fifty-nine cases and 772 controls fulfilled GWAS inclusion criteria. The CNOT3 variant rs73062673 on 19q13.42, was associated with PEG-asparaginase allergy (P = 4·68 × 10-8 ). We further identified two signals on chromosome 6 in relation to HLA-DQA1 (P = 9·37 × 10-6 ) and TAP2 (P = 1·59 × 10-5 ). This study associated variants in CNOT3 and in the human leucocyte antigen (HLA) region with PEG-asparaginase hypersensitivity, suggesting that not only genetic variations in the HLA region, but also regulation of these genes are of importance in the biology of this toxicity. Furthermore, our study emphasizes the importance of using asparaginase enzyme activity measurements to identify PEG-asparaginase hypersensitivity.
- Published
- 2019
- Full Text
- View/download PDF
21. Intermittent Versus Continuous PEG-Asparaginase to Reduce Asparaginase-Associated Toxicities:A NOPHO ALL2008 Randomized Study
- Author
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Albertsen, Birgitte Klug, Grell, Kathrine, Abrahamsson, Jonas, Lund, Bendik, Vettenranta, Kim, Jónsson, Ólafur G, Frandsen, Thomas L, Wolthers, Benjamin O, Heyman, Mats, Schmiegelow, Kjeld, Albertsen, Birgitte Klug, Grell, Kathrine, Abrahamsson, Jonas, Lund, Bendik, Vettenranta, Kim, Jónsson, Ólafur G, Frandsen, Thomas L, Wolthers, Benjamin O, Heyman, Mats, and Schmiegelow, Kjeld
- Abstract
PURPOSE: Asparaginase is an essential drug in childhood acute lymphoblastic leukemia (ALL) therapy and is frequently given for months to obtain continuous asparagine depletion. We randomly assigned patients to continuous versus intermittent pegylated-asparaginase (PEG-asp) treatment, hypothesizing there would be decreased toxicity with unchanged efficacy.METHODS: Children (median age, 4.2 years) treated for non-high-risk ALL according to the Nordic Society for Pediatric Hematology and Oncology ALL2008 protocol received five intramuscular PEG-asp injections (1,000 IU/m2) every two weeks and were then randomly assigned to additional three doses (6-week intervals [experimental arm], n = 309) versus 10 doses (2-week intervals [standard arm], n = 316). The primary end point was noninferior (6% margin) disease-free survival. Toxicity reduction was a secondary end point. Occurrence of asparaginase-associated hypersensitivity, pancreatitis, osteonecrosis, and thromboembolism were prospectively registered.RESULTS: After a median follow-up of 4.1 years, the 5-year disease-free survival was 92.2% (95% CI, 88.6 to 95.8) and 90.8% (95% CI, 87.0 to 94.6) in the experimental and standard arms, respectively. The 3-year cumulative incidence of any first asparaginase-associated toxicity (hypersensitivity [n = 13]; osteonecrosis [n = 29]; pancreatitis [n = 24]; thromboembolism [n = 17]) was 9.3% in the experimental arm and 18.1% in the standard arm ( P = .001). Asparaginase-associated toxicity reduction was confirmed in sex- and risk-group-adjusted Cox regression analysis stratified by age (≥ 10 and < 10 years; hazard ratio, 0.48; P = .001). The experimental arm had the lowest incidences of all four toxicities, reaching significance for pancreatitis (6-month risk, 5.8% v 1.3%; P = .002).CONCLUSION: The excellent cure rates and reduced toxicity risk support the use of intermittent PEG-asp therapy after the first 10 weeks in future childhood ALL trials that ap
- Published
- 2019
22. Trypsin encoding PRSS1-PRSS2 variation influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report
- Author
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Wolthers, Benjamin O., Frandsen, Thomas L., Patel, Chirag J, Abaji, Rachid, Attarbaschi, Andishe, Barzilai, Shlomit, Colombini, Antonella, Escherich, Gabriele, Grosjean, Marie, Krajinovic, Maja, Larsen, Eric, Liang, Der-Cherng, Möricke, Anja, Rasmussen, Kirsten K., Samarasinghe, Sujith, Silverman, Lewis B., van der Sluis, Inge M., Stanulla, Martin, Tulstrup, Morten, Yadav, Rachita, Yang, Wenjian, Zapotocka, Ester, Gupta, Ramneek, Schmiegelow, Kjeld, Wolthers, Benjamin O., Frandsen, Thomas L., Patel, Chirag J, Abaji, Rachid, Attarbaschi, Andishe, Barzilai, Shlomit, Colombini, Antonella, Escherich, Gabriele, Grosjean, Marie, Krajinovic, Maja, Larsen, Eric, Liang, Der-Cherng, Möricke, Anja, Rasmussen, Kirsten K., Samarasinghe, Sujith, Silverman, Lewis B., van der Sluis, Inge M., Stanulla, Martin, Tulstrup, Morten, Yadav, Rachita, Yang, Wenjian, Zapotocka, Ester, Gupta, Ramneek, and Schmiegelow, Kjeld
- Abstract
Asparaginase-associated pancreatitis is a life-threatening toxicity to childhood acute lymphoblastic leukemia treatment. To elucidate genetic predisposition and asparaginase-associated pancreatitis pathogenesis, ten acute lymphoblastic leukemia trial groups contributed remission samples from patients aged 1.0-17.9 years and treated from 2000-2016. Cases were defined (n=244) by at least two of the following criteria: i) abdominal pain, ii) pancreatic enzymes >3 x upper normal limit, iii) imaging compatible with asparaginase-associated pancreatitis. Controls (n=1320) completed intended asparaginase therapy, 78% receiving ≥8 pegylated-asparaginase injections, without developing aparaginase-associated pancreatitis. rs62228256 on 20q13.2 showed the strongest association (OR=3.75; P=5.2x10-8). Moreover, rs13228878 (OR=0.61; P=7.1x10-6) and rs10273639 (OR=0.62; P=1.1x10-5) on 7q34 showed significant association. A Dana Farber Cancer Institute ALL Consortium cohort consisting of patients treated protocols from 1987-2004 (controls=285, cases=33), and the Children's Oncology Group AALL0232 cohort (controls=2653, cases=76) were available as replication cohorts for the 20q13.2 and 7q34 variants, respectively. While rs62228256 was not validated (P=0.86), both rs13228878 (P=0.03) and rs10273639 (P=0.04) were. rs13228878 and rs10273639 are in high linkage disequilibrium (r2=0.94) and associated with elevated expression of the trypsinogen encoding PRSS1 gene and are known risk variants for alcohol-associated and sporadic pancreatitis in adults. Intra-pancreatic trypsinogen cleavage to proteolytic trypsin induces autodigestion and pancreatitis. Asparaginase-associated pancreatitis and non-asparaginase associated pancreatitis shares genetic predisposition and targeting the trypsinogen activation pathway may enable identification of effective interventions towards asparaginase-associated pancreatitis.
- Published
- 2019
23. Intermittent Versus Continuous PEG-Asparaginase to Reduce Asparaginase-Associated Toxicities: A NOPHO ALL2008 Randomized Study
- Author
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Albertsen, Birgitte Klug, primary, Grell, Kathrine, additional, Abrahamsson, Jonas, additional, Lund, Bendik, additional, Vettenranta, Kim, additional, Jónsson, Ólafur G., additional, Frandsen, Thomas L., additional, Wolthers, Benjamin O., additional, Heyman, Mats, additional, and Schmiegelow, Kjeld, additional
- Published
- 2019
- Full Text
- View/download PDF
24. Trypsin-encoding PRSS1-PRSS2 variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report
- Author
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Wolthers, Benjamin O., primary, Frandsen, Thomas L., additional, Patel, Chirag J., additional, Abaji, Rachid, additional, Attarbaschi, Andishe, additional, Barzilai, Shlomit, additional, Colombini, Antonella, additional, Escherich, Gabriele, additional, Grosjean, Marie, additional, Krajinovic, Maja, additional, Larsen, Eric, additional, Liang, Der-Cherng, additional, Möricke, Anja, additional, Rasmussen, Kirsten K., additional, Samarasinghe, Sujith, additional, Silverman, Lewis B., additional, van der Sluis, Inge M., additional, Stanulla, Martin, additional, Tulstrup, Morten, additional, Yadav, Rachita, additional, Yang, Wenjian, additional, Zapotocka, Ester, additional, Gupta, Ramneek, additional, and Schmiegelow, Kjeld, additional
- Published
- 2018
- Full Text
- View/download PDF
25. Association between body mass index and pancreatitis in children with acute lymphoblastic leukemia
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Mogensen, Pernille R., Wolthers, Benjamin O., Grell, Kathrine, Schmiegelow, Kjeld, Frandsen, Thomas L., Mogensen, Pernille R., Wolthers, Benjamin O., Grell, Kathrine, Schmiegelow, Kjeld, and Frandsen, Thomas L.
- Published
- 2018
26. Association between body mass index and pancreatitis in children with acute lymphoblastic leukemia
- Author
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Mogensen, Pernille R., primary, Wolthers, Benjamin O., additional, Grell, Kathrine, additional, Schmiegelow, Kjeld, additional, and Frandsen, Thomas L., additional
- Published
- 2018
- Full Text
- View/download PDF
27. Intermittent Versus Continuous Asparaginase to Reduce Asparaginase-Associated Toxicities: A NOHPO ALL2008 Randomized Study
- Author
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Albertsen, Birgitte, primary, Grell, Kathrine, additional, Abrahamsson, Jonas, additional, Lund, Bendik, additional, Vettenranta, Kim, additional, Jónsson, Ólafur G., additional, Frandsen, Thomas L., additional, Wolthers, Benjamin O., additional, Heyman, Mats, additional, and Schmiegelow, Kjeld, additional
- Published
- 2018
- Full Text
- View/download PDF
28. Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia:an observational Ponte di Legno Toxicity Working Group study
- Author
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Wolthers, Benjamin O., Frandsen, Thomas L., Baruchel, André, Attarbaschi, Andishe, Barzilai, Shlomit, Colombini, Antonella, Escherich, Gabriele, Grell, Kathrine, Inaba, Hiroto, Kovacs, Gabor G., Liang, Der-Cherng, Mateos, Marion, Mondelaers, Veerle, Möricke, Anja, Ociepa, Tomasz, Samarasinghe, Sujith, Silverman, Lewis B., van der Sluis, Inge M., Stanulla, Martin, Vrooman, Lynda M., Yano, Michihiro, Zapotocka, Ester, Schmiegelow, Kjeld, Wolthers, Benjamin O., Frandsen, Thomas L., Baruchel, André, Attarbaschi, Andishe, Barzilai, Shlomit, Colombini, Antonella, Escherich, Gabriele, Grell, Kathrine, Inaba, Hiroto, Kovacs, Gabor G., Liang, Der-Cherng, Mateos, Marion, Mondelaers, Veerle, Möricke, Anja, Ociepa, Tomasz, Samarasinghe, Sujith, Silverman, Lewis B., van der Sluis, Inge M., Stanulla, Martin, Vrooman, Lynda M., Yano, Michihiro, Zapotocka, Ester, and Schmiegelow, Kjeld
- Abstract
BACKGROUND: Survival for childhood acute lymphoblastic leukaemia surpasses 90% with contemporary therapy; however, patients remain burdened by the severe toxic effects of treatment, including asparaginase-associated pancreatitis. To investigate the risk of complications and risk of re-exposing patients with asparaginase-associated pancreatitis to asparaginase, 18 acute lymphoblastic leukaemia trial groups merged data for this observational study.METHODS: Patient files from 26 trials run by 18 trial groups were reviewed on children (aged 1·0-17·9 years) diagnosed with t(9;22)-negative acute lymphoblastic leukaemia between June 1, 1996, and Jan 1, 2016, who within 50 days of asparaginase exposure developed asparaginase-associated pancreatitis. Asparaginase-associated pancreatitis was defined by at least two criteria: abdominal pain, pancreatic enzymes at least three times the upper limit of normal (ULN), and imaging compatible with pancreatitis. Patients without sufficient data for diagnostic criteria were excluded. Primary outcomes were defined as acute and persisting complications of asparaginase-associated pancreatitis and risk of re-exposing patients who suffered an episode of asparaginase-associated pancreatitis to asparaginase. Data were collected from Feb 2, 2015, to June 30, 2016, and analysed and stored in a common database at Rigshospitalet, Copenhagen, Denmark.FINDINGS: Of 465 patients with asparaginase-associated pancreatitis, 33 (8%) of 424 with available data needed mechanical ventilation, 109 (26%) of 422 developed pseudocysts, acute insulin therapy was needed in 81 (21%) of 393, and seven (2%) of 458 patients died. Risk of assisted mechanical ventilation, need for insulin, pseudocysts, or death was associated with older age (median age for patients with complications 10·5 years [IQR 6·4-13·8] vs without complications 6·1 years [IQR 3·6-12·2], p<0·0001), and having one or more affected vital signs (fever, hypotension, tachycardia, or
- Published
- 2017
29. Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia: an observational Ponte di Legno Toxicity Working Group study
- Author
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Wolthers, Benjamin O, primary, Frandsen, Thomas L, additional, Baruchel, André, additional, Attarbaschi, Andishe, additional, Barzilai, Shlomit, additional, Colombini, Antonella, additional, Escherich, Gabriele, additional, Grell, Kathrine, additional, Inaba, Hiroto, additional, Kovacs, Gábor, additional, Liang, Der-Cherng, additional, Mateos, Marion, additional, Mondelaers, Veerle, additional, Möricke, Anja, additional, Ociepa, Tomasz, additional, Samarasinghe, Sujith, additional, Silverman, Lewis B, additional, van der Sluis, Inge M, additional, Stanulla, Martin, additional, Vrooman, Lynda M, additional, Yano, Michihiro, additional, Zapotocka, Ester, additional, and Schmiegelow, Kjeld, additional
- Published
- 2017
- Full Text
- View/download PDF
30. Can Machine Learning Models Predict Asparaginase-associated Pancreatitis in Childhood Acute Lymphoblastic Leukemia.
- Author
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Nielsen RL, Wolthers BO, Helenius M, Albertsen BK, Clemmensen L, Nielsen K, Kanerva J, Niinimäki R, Frandsen TL, Attarbaschi A, Barzilai S, Colombini A, Escherich G, Aytan-Aktug D, Liu HC, Möricke A, Samarasinghe S, van der Sluis IM, Stanulla M, Tulstrup M, Yadav R, Zapotocka E, Schmiegelow K, and Gupta R
- Subjects
- Child, Genome-Wide Association Study, Humans, Machine Learning, Antineoplastic Agents adverse effects, Asparaginase adverse effects, Pancreatitis chemically induced, Pancreatitis genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Asparaginase-associated pancreatitis (AAP) frequently affects children treated for acute lymphoblastic leukemia (ALL) causing severe acute and persisting complications. Known risk factors such as asparaginase dosing, older age and single nucleotide polymorphisms (SNPs) have insufficient odds ratios to allow personalized asparaginase therapy. In this study, we explored machine learning strategies for prediction of individual AAP risk. We integrated information on age, sex, and SNPs based on Illumina Omni2.5exome-8 arrays of patients with childhood ALL (N=1564, 244 with AAP 1.0 to 17.9 yo) from 10 international ALL consortia into machine learning models including regression, random forest, AdaBoost and artificial neural networks. A model with only age and sex had area under the receiver operating characteristic curve (ROC-AUC) of 0.62. Inclusion of 6 pancreatitis candidate gene SNPs or 4 validated pancreatitis SNPs boosted ROC-AUC somewhat (0.67) while 30 SNPs, identified through our AAP genome-wide association study cohort, boosted performance (0.80). Most predictive features included rs10273639 (PRSS1-PRSS2), rs10436957 (CTRC), rs13228878 (PRSS1/PRSS2), rs1505495 (GALNTL6), rs4655107 (EPHB2) and age (1 to 7 y). Second AAP following asparaginase re-exposure was predicted with ROC-AUC: 0.65. The machine learning models assist individual-level risk assessment of AAP for future prevention trials, and may legitimize asparaginase re-exposure when AAP risk is predicted to be low., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2022
- Full Text
- View/download PDF
31. Trypsin-encoding PRSS1-PRSS2 variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report.
- Author
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Wolthers BO, Frandsen TL, Patel CJ, Abaji R, Attarbaschi A, Barzilai S, Colombini A, Escherich G, Grosjean M, Krajinovic M, Larsen E, Liang DC, Möricke A, Rasmussen KK, Samarasinghe S, Silverman LB, van der Sluis IM, Stanulla M, Tulstrup M, Yadav R, Yang W, Zapotocka E, Gupta R, and Schmiegelow K
- Subjects
- Adolescent, Alleles, Antineoplastic Agents administration & dosage, Asparaginase administration & dosage, Child, Child, Preschool, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Infant, Male, Models, Biological, Phenotype, Polyethylene Glycols administration & dosage, Polymorphism, Single Nucleotide, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Antineoplastic Agents adverse effects, Asparaginase adverse effects, Genetic Variation, Pancreatitis etiology, Polyethylene Glycols adverse effects, Precursor Cell Lymphoblastic Leukemia-Lymphoma complications, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Trypsin genetics, Trypsinogen genetics
- Abstract
Asparaginase-associated pancreatitis is a life-threatening toxicity to childhood acute lymphoblastic leukemia treatment. To elucidate genetic predisposition and asparaginase-associated pancreatitis pathogenesis, ten trial groups contributed remission samples from patients aged 1.0-17.9 years treated for acute lymphoblastic leukemia between 2000 and 2016. Cases (n=244) were defined by the presence of at least two of the following criteria: (i) abdominal pain; (ii) levels of pancreatic enzymes ≥3 × upper normal limit; and (iii) imaging compatible with pancreatitis. Controls (n=1320) completed intended asparaginase therapy, with 78% receiving ≥8 injections of pegylated-asparaginase, without developing asparaginase-associated pancreatitis. rs62228256 on 20q13.2 showed the strongest association with the development of asparaginase-associated pancreatitis (odds ratio=3.75; P =5.2×10
-8 ). Moreover, rs13228878 (OR=0.61; P =7.1×10-6 ) and rs10273639 (OR=0.62; P =1.1×10-5 ) on 7q34 showed significant association with the risk of asparaginase-associated pancreatitis. A Dana Farber Cancer Institute ALL Consortium cohort consisting of patients treated on protocols between 1987 and 2004 (controls=285, cases=33), and the Children's Oncology Group AALL0232 cohort (controls=2653, cases=76) were available as replication cohorts for the 20q13.2 and 7q34 variants, respectively. While rs62228256 was not validated as a risk factor ( P =0.77), both rs13228878 ( P =0.03) and rs10273639 ( P =0.04) were. rs13228878 and rs10273639 are in high linkage disequilibrium (r2 =0.94) and associated with elevated expression of the PRSS1 gene, which encodes for trypsinogen, and are known risk variants for alcohol-associated and sporadic pancreatitis in adults. Intra-pancreatic trypsinogen cleavage to proteolytic trypsin induces autodigestion and pancreatitis. In conclusion, this study finds a shared genetic predisposition between asparaginase-associated pancreatitis and non-asparaginase-associated pancreatitis, and targeting the trypsinogen activation pathway may enable identification of effective interventions for asparaginase-associated pancreatitis., (Copyright© 2019 Ferrata Storti Foundation.)- Published
- 2019
- Full Text
- View/download PDF
32. Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008.
- Author
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Højfeldt SG, Wolthers BO, Tulstrup M, Abrahamsson J, Gupta R, Harila-Saari A, Heyman M, Henriksen LT, Jónsson ÒG, Lähteenmäki PM, Lund B, Pruunsild K, Vaitkeviciene G, Schmiegelow K, and Albertsen BK
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 3 genetics, Adolescent, Asparaginase administration & dosage, Child, Child, Preschool, Chromosomes, Human, Pair 19 genetics, Chromosomes, Human, Pair 6 genetics, Female, Genome-Wide Association Study, HLA-DQ Antigens genetics, Humans, Infant, Male, Polyethylene Glycols administration & dosage, Transcription Factors genetics, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Drug Hypersensitivity genetics, Genetic Predisposition to Disease, Genetic Variation, Neoplasm Proteins genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
- Abstract
Asparaginase is essential in childhood acute lymphoblastic leukaemia (ALL) treatment, however hypersensitivity reactions to pegylated asparaginase (PEG-asparaginase) hampers anti-neoplastic efficacy. Patients with PEG-asparaginase hypersensitivity have been shown to possess zero asparaginase enzyme activity. Using this measurement to define the phenotype, we investigated genetic predisposition to PEG-asparaginase hypersensitivity in a genome-wide association study (GWAS). From July 2008 to March 2016, 1494 children were treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol. Cases were defined by clinical hypersensitivity and no enzyme activity, controls had enzyme activity ≥ 100 iu/l and no hypersensitivity symptoms. PEG-asparaginase hypersensitivity was reported in 13·8% (206/1494) of patients. Fifty-nine cases and 772 controls fulfilled GWAS inclusion criteria. The CNOT3 variant rs73062673 on 19q13.42, was associated with PEG-asparaginase allergy (P = 4·68 × 10
-8 ). We further identified two signals on chromosome 6 in relation to HLA-DQA1 (P = 9·37 × 10-6 ) and TAP2 (P = 1·59 × 10-5 ). This study associated variants in CNOT3 and in the human leucocyte antigen (HLA) region with PEG-asparaginase hypersensitivity, suggesting that not only genetic variations in the HLA region, but also regulation of these genes are of importance in the biology of this toxicity. Furthermore, our study emphasizes the importance of using asparaginase enzyme activity measurements to identify PEG-asparaginase hypersensitivity., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)- Published
- 2019
- Full Text
- View/download PDF
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