10 results on '"Griskevicius L"'
Search Results
2. The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries
- Author
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Hoffmann, V S, Baccarani, M, Hasford, J, Lindoerfer, D, Burgstaller, S, Sertic, D, Costeas, P, Mayer, J, Indrak, K, Everaus, H, Koskenvesa, P, Guilhot, J, Schubert-Fritschle, G, Castagnetti, F, Di Raimondo, F, Lejniece, S, Griskevicius, L, Thielen, N, Sacha, T, Hellmann, A, Turkina, A G, Zaritskey, A, Bogdanovic, A, Sninska, Z, Zupan, I, Steegmann, J-L, Simonsson, B, Clark, R E, Covelli, A, Guidi, G, and Hehlmann, R
- Published
- 2015
- Full Text
- View/download PDF
3. Frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the European ENEST1st study
- Author
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Hochhaus, A, Rosti, G, Cross, N CP, Steegmann, J L, le Coutre, P, Ossenkoppele, G, Petrov, L, Masszi, T, Hellmann, A, Griskevicius, L, Wiktor-Jedrzejczak, W, Rea, D, Coriu, D, Brümmendorf, T H, Porkka, K, Saglio, G, Gastl, G, Müller, M C, Schuld, P, Di Matteo, P, Pellegrino, A, Dezzani, L, Mahon, F-X, Baccarani, M, and Giles, F J
- Published
- 2016
- Full Text
- View/download PDF
4. The proportion of different BCR-ABL1 transcript types in chronic myeloid leukemia. An international overview
- Author
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Baccarani, M, Castagnetti, F, Gugliotta, G, Rosti, G, Soverini, S, Albeer, A, Pfirrmann, M, Bekadja, Ma, Entasoltan, B, Nachi, M, Elghandour, A, El Sorady, M, Abdelfattah, R, El Nahass, Y, Samra, M, Azzazi, M, Elsobki, E, Moussa, M, Fahmy, O, Mattar, M, Shehata, Azmy, Se, (Azmy, E, 9 ), Emad), Bolarinwa, (Bolarinwa, Ra, ( 10 ), Rahman A., Eid, (Eid, S, Samir)( 11, ), Khelif, (Khelif, A, Abderrhaim)( 11, ), Hached, (Hached, F, Farhat)( 11, ), Menif, (Menif, S, Samia)( 12, ), Rahman, (Rahman, H, Hafizur)( 13, ), Huang, (Huang, Xj, Xiaojun)(, 14, 15, ), Jiang, (Jiang, Q, Qian)(, 14, (Ye, Yx, Yuanxin)( 16, ), Zhu, (Zhu, Hl, Huanling)( 16, ), Chen, (Chen, Sn, Suning)( 17, ), Varma, (Varma, N, Neelam)( 18, ), Ganesan, (Ganesan, P, Prasanth)( 19, ), Gundeti, (Gundeti, S, Sadashivudu)( 20, ), Malhotra, (Malhotra, H, Hemant)( 21, ), Radhakrishnan, (Radhakrishnan, Vs, ( 22 ), Vivek S., Kumar, (Kumar, L, Lalit)( 23, ), Sharawat, (Sharawat, Sk, Surender Kumar)( 23, ), Seth, (Seth, T, Tulika)( 24, ), Ausekar, (Ausekar, Bv, ( 25 ), B. V., Balasubramanian, (Balasubramanian, P, Poonkuzhali)( 26, ), Poopak, (Poopak, B, Behzad)(, 27, 28, ), Inokuchi, (Inokuchi, K, Koiti)( 29, ), Kim, (Kim, Dw, Dong-Wook)( 30, ), Kindi, Al, S (Al Kindi, Salam)( 31, ), Mirasol, (Mirasol, A, Angelina)( 32, ), Qari, (Qari, M, Mohammed)( 33, ), Goh, (Goh, Yt, Yeow Tee)( 34, ), Shih, (Shih, Ly, Lee-Yung)(, 35, 36, ), Branford, (Branford, S, Susan)(, 37, 38, ), Lion, (Lion, T, Thomas)( 39, ), Valent, (Valent, P, Peter)( 40, ), Burgstaller, (Burgstaller, S, Sonja)( 41, ), Thaler, (Thaler, J, Joseph)( 41, ), Labar, (Labar, B, Boris)( 42, ), Zadro, (Zadro, R, Renata)( 42, ), Mayer, (Mayer, J, Jiri)(, 43, 44, ), Zackova, (Zackova, D, Daniela)(, 43, Faber, (Faber, E, Edgar)( 45, ), Pallisgaard, (Pallisgaard, N, Niels)( 46, ), Xavier-Mahon, (Xavier-Mahon, F, Francois)( 47, ), Lippert, (Lippert, E, Eric)( 48, ), Cayuela, (Cayuela, Jm, Jean Michel)( 49, ), Rea, (Rea, D, Delphine)( 49, ), Millot, (Millot, F, Frederic)( 50, ), Suttorp, (Suttorp, M, Meinolf)( 51, ), Hochhaus, (Hochhaus, A, Andreas)( 52, ), Niederwieser, (Niederwieser, D, Dietger)( 53, ), Saussele, (Saussele, S, Susanne)( 54, ), Haferlach, (Haferlach, T, Torsten)( 55, ), Jeromine, (Jeromine, S, Sabine)( 55, ), Panayiotidis, (Panayiotidis, P, Panayiotis)(, 56, 57, ), Conneally, (Conneally, E, Eibhlin)( 58, ), Langabeer, (Langabeer, S, Steve)( 58, ), Nagler, (Nagler, A, Arnon)(, 59, 60, ), Rupoli, (Rupoli, S, Serena)( 61, ), Santoro, (Santoro, N, Nicola)( 62, ), Albano, (Albano, F, Francesco)( 63, ), Castagnetti, (Castagnetti, F, Fausto), Ottaviani, (Ottaviani, E, Emanuela)(, 64, 65, ), Rambaldi, (Rambaldi, A, Alessandro)(, 66, 67, ), Stagno, (Stagno, F, Fabio)( 68, ), Molica, (Molica, S, Stefano)( 69, ), Biagiotti, (Biagiotti, C, Caterina)( 70, ), Scappini, (Scappini, B, Barbara)( 70, ), Lemoli, (Lemoli, R, Roberto)( 71, ), Iurlo, (Iurlo, A, Alessandra)(, 72, 73, ), Pungolino, (Pungolino, E, Ester)( 74, ), Menna, (Menna, G, Giuseppe), Pane, (Pane, F, Fabrizio)( 76, ), Gottardi, (Gottardi, E, Enrico)(, 77, 78, ), Rege-Cambrin, (Rege-Cambrin, G, Giovanna)(, 77, Binotto, (Binotto, G, Gianni)( 79, ), Putti, (Putti, Mc, Maria Caterina)( 80, ), Falzetti, (Falzetti, F, Franca)( 81, ), Visani, (Visani, G, Giuseppe)( 82, ), Galimberti, (Galimberti, S, Sara)( 83, ), Musto, (Musto, P, Pellegrino)( 84, ), Abruzzese, (Abruzzese, E, Elisabetta)( 85, ), Breccia, (Breccia, M, Massimo)( 86, ), Giona, (Giona, F, Fiorina)( 86, ), Chiusolo, (Chiusolo, P, Patrizia)( 87, ), Sica, (Sica, S, Simona)( 87, ), Fava, (Fava, C, Carmen)( 88, ), Ferrero, (Ferrero, D, Dario)( 88, ), Tiribelli, (Tiribelli, M, Mario)( 89, ), Bonifacio, (Bonifacio, M, Massimiliano)( 90, ), Griskevicius, (Griskevicius, L, Laimonas)( 91, ), Musteata, (Musteata, V, Vasile)( 92, ), Janssen, (Janssen, J, Jeroen)( 93, ), Prejzner, (Prejzner, W, Witold)( 94, ), Sacha, (Sacha, T, Tomasz)( 95, ), Waclaw, (Waclaw, J, Joanna)( 95, ), Almeida, (Almeida, Am, Antonio Medina)( 96, ), Kulikov, (Kulikov, S, Sergei)( 97, ), Turkina, (Turkina, A, Anna)( 97, ), Bogdanovic, (Bogdanovic, A, Andrija)( 98, ), Zupan, (Zupan, I, Irena)( 99, ), Marce, (Marce, S, Silvia)( 100, ), Cervantes, (Cervantes, F, Francisco)( 101, ), Steegmann, (Steegmann, Jl, Juan Luis)( 102, ), Kotlyarchuk, (Kotlyarchuk, K, Konstyantyn)( 103, ), Milner, (Milner, Bj, ( 104 ), Benedict J., Rose, (Rose, S, Susan)( 105, ), Clench, (Clench, T, Tim)( 106, ), Waits, (Waits, P, Paula)( 107, ), Austin, (Austin, S, Steve)( 108, ), Wickham, (Wickham, C, Caroline)( 109, ), Clark, (Clark, R, Richard)( 110, ), Apperley, (Apperley, J, Jane), Claudiani, (Claudiani, S, Simone)( 111, ), Foroni, (Foroni, L, Letizia)( 111, ), Szydlo, (Szydlo, R, Richard)( 111, ), Burt, (Burt, E, Emma)( 112, ), Bescoby, (Bescoby, R, Ruth)( 113, ), Cork, (Cork, L, Leanne)( 113, ), O'Brien, (O'Brien, S, Stephen)( 113, ), Green, (Green, B, Bethaney)( 114, ), Hawtree, (Hawtree, S, Sarah)( 114, ), Watson, (Watson, M, Mark)( 114, ), Bengio, (Bengio, Rm, Raquel Maria)( 115, ), Larripa, (Larripa, I, Irene)( 115, ), Pavlovsky, (Pavlovsky, C, Carolina)( 116, ), Moiraghi, (Moiraghi, B, Beatriz)( 117, ), Pinna, De, CAR (Requiao de Pinna, Cristiane Almeida)( 118, ), Magalhaes, GHR (Romani Magalhaes, Gustavo Henrique)( 119, ), Pagnano, (Pagnano, K, Katia)( 120, ), Funke, (Funke, V, Vaneuza)( 121, ), Tavares, (Tavares, Rs, Renato Sampaio)( 122, ), Prado, (Prado, A, Adriana)( 123, ), Azevedo, (Azevedo, Aa, Alita Andrade)( 124, ), Fogliatto, (Fogliatto, L, Laura)( 125, ), Bonecker, (Bonecker, S, Simone)( 126, ), Centrone, (Centrone, R, Renato)( 127, ), Moellman, (Moellman, A, Artur)( 128, ), Conchon, (Conchon, M, Monika)( 130, ), Centurion, (Centurion, Me, Maria Elida)( 131, ), (Prado, Ai, Ana-Ines)( 132, ), Lopez, (Lopez, Jl, ( 133 ), J. L., Petruzziello, (Petruzziello, F, Fara)( 75, ), Bendit, (Bendit, I, Israel), Baccarani M., Castagnetti F., Gugliotta G., Rosti G., Soverini S., Albeer A., and Pfirrmann M.
- Subjects
Male ,0301 basic medicine ,Cancer Research ,bcr-abl ,Fusion Proteins, bcr-abl ,Global Health ,0302 clinical medicine ,hemic and lymphatic diseases ,80 and over ,Odds Ratio ,Prevalence ,Age Factor ,Chronic ,Young adult ,Child ,MOLECULAR RESPONSE ,Leukemic ,Aged, 80 and over ,Leukemia ,Hematology ,Gene Expression Regulation, Leukemic ,CHRONIC MYELOGENOUS LEUKEMIA ,Age Factors ,Myeloid leukemia ,Middle Aged ,Oncology ,Child, Preschool ,030220 oncology & carcinogenesis ,Female ,Life Sciences & Biomedicine ,Human ,Adult ,Transcriptional Activation ,medicine.medical_specialty ,Adolescent ,Immunology ,IMATINIB MESYLATE ,DENDRITIC CELLS ,CML PATIENTS ,Young Adult ,03 medical and health sciences ,Myelogenous ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,medicine ,Humans ,1112 Oncology and Carcinogenesis ,BCR/ABL TRANSCRIPT ,Preschool ,CYTOGENETIC RESPONSE ,Aged ,Science & Technology ,CHRONIC-PHASE ,business.industry ,Infant, Newborn ,Fusion Proteins ,ABL FUSION PROTEINS ,P190 BCR-ABL ,Infant ,1103 Clinical Sciences ,Odds ratio ,Newborn ,medicine.disease ,International BCR-ABL Study Group ,Settore MED/15 - MALATTIE DEL SANGUE ,030104 developmental biology ,Imatinib mesylate ,Gene Expression Regulation ,BCR-ABL Positive ,business ,Chronic myelogenous leukemia - Abstract
There are different BCR-ABL1 fusion genes that are translated into proteins that are different from each other, yet all leukemogenic, causing chronic myeloid leukemia (CML) or acute lymphoblastic leukemia. Their frequency has never been systematically investigated. In a series of 45503 newly diagnosed CML patients reported from 45 countries, it was found that the proportion of e13a2 (also known as b2a2) and of e14a2 (also known as b3a2), including the cases co-expressing e14a2 and e13a2, was 37.9% and 62.1%, respectively. The proportion of these two transcripts was correlated with gender, e13a2 being more frequent in males (39.2%) than in females (36.2%), was correlated with age, decreasing from 39.6% in children and adolescents down to 31.6% in patients ≥ 80 years old, and was not constant worldwide. Other, rare transcripts were reported in 666/34561 patients (1.93%). The proportion of rare transcripts was associatedwith gender (2.27% in females and 1.69% in males) and with age (from 1.79% in children and adolescents up to 3.84% in patients ≥ 80 years old). These data show that the differences in proportion are not by chance. This is important, as the transcript type is a variable that is suspected to be of prognostic importance for response to treatment, outcome of treatment, and rate of treatment-free remission.
- Published
- 2019
- Full Text
- View/download PDF
5. Treatment and outcome of 2904 CML patients from the EUTOS population-based registry
- Author
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Hoffmann, V S, primary, Baccarani, M, additional, Hasford, J, additional, Castagnetti, F, additional, Di Raimondo, F, additional, Casado, L F, additional, Turkina, A, additional, Zackova, D, additional, Ossenkoppele, G, additional, Zaritskey, A, additional, Höglund, M, additional, Simonsson, B, additional, Indrak, K, additional, Sninska, Z, additional, Sacha, T, additional, Clark, R, additional, Bogdanovic, A, additional, Hellmann, A, additional, Griskevicius, L, additional, Schubert-Fritschle, G, additional, Sertic, D, additional, Guilhot, J, additional, Lejniece, S, additional, Zupan, I, additional, Burgstaller, S, additional, Koskenvesa, P, additional, Everaus, H, additional, Costeas, P, additional, Lindoerfer, D, additional, Rosti, G, additional, Saussele, S, additional, Hochhaus, A, additional, and Hehlmann, R, additional
- Published
- 2016
- Full Text
- View/download PDF
6. Frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the European ENEST1st study
- Author
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Hochhaus, A, primary, Rosti, G, additional, Cross, N C P, additional, Steegmann, J L, additional, le Coutre, P, additional, Ossenkoppele, G, additional, Petrov, L, additional, Masszi, T, additional, Hellmann, A, additional, Griskevicius, L, additional, Wiktor-Jedrzejczak, W, additional, Rea, D, additional, Coriu, D, additional, Brümmendorf, T H, additional, Porkka, K, additional, Saglio, G, additional, Gastl, G, additional, Müller, M C, additional, Schuld, P, additional, Di Matteo, P, additional, Pellegrino, A, additional, Dezzani, L, additional, Mahon, F-X, additional, Baccarani, M, additional, and Giles, F J, additional
- Published
- 2015
- Full Text
- View/download PDF
7. The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia
- Author
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Andrija Bogdanovic, Boris Labar, Martin Höglund, Edgar Faber, Hele Everaus, Richard E. Clark, Adriana Colita, Rüdiger Hehlmann, Sonja Heibl, Anna G. Turkina, Ulla Olsson-Strömberg, Francisco Cervantes, Michele Baccarani, Tomasz Sacha, Verena S. Hoffmann, Michael Lauseker, Daniela Zackova, Markus Pfirrmann, Andreas Hochhaus, Laimonas Griskevicius, Perttu Koskenvesa, Susanne Saussele, Irena Preložnik Zupan, Joerg Hasford, Andrey Zaritskey, Gert J. Ossenkoppele, Fausto Castagnetti, Witold Prejzner, François Guilhot, Joelle Guilhot, Hematology laboratory, CCA - Cancer Treatment and quality of life, HUS Comprehensive Cancer Center, Department of Oncology, Hematologian yksikkö, University of Helsinki, Helsinki University Hospital Area, Pfirrmann M., Clark R.E., Prejzner W., Lauseker M., Baccarani M., Saussele S., Guilhot F., Heibl S., Hehlmann R., Faber E., Turkina A., Ossenkoppele G., Hoglund M., Zaritskey A., Griskevicius L., Olsson-Stromberg U., Everaus H., Koskenvesa P., Labar B., Sacha T., Zackova D., Cervantes F., Colita A., Zupan I., Bogdanovic A., Castagnetti F., Guilhot J., Hasford J., Hochhaus A., and Hoffmann V.S.
- Subjects
Registrie ,Male ,Cancer Research ,Epidemiology ,European LeukemiaNet ,0302 clinical medicine ,Risk groups ,BOSUTINIB ,Registries ,CML ,Aged, 80 and over ,0303 health sciences ,DASATINIB ,Hazard ratio ,FRONTLINE ,Myeloid leukemia ,Hematology ,IMATINIB TREATMENT ,Middle Aged ,Prognosis ,3. Good health ,Oncology ,030220 oncology & carcinogenesis ,Female ,PROGNOSTIC DISCRIMINATION ,Sokal Score ,Human ,Adult ,medicine.medical_specialty ,Adolescent ,Prognosi ,Concordance ,MODELS ,3122 Cancers ,Protein Kinase Inhibitor ,VALIDATION ,Article ,03 medical and health sciences ,Young Adult ,Survival prognosis ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Long term survival ,medicine ,Humans ,Hematologi ,Protein Kinase Inhibitors ,030304 developmental biology ,Aged ,Probability ,business.industry ,Risk factors ,business - Abstract
Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.
- Published
- 2020
- Full Text
- View/download PDF
8. Increase in peg-asparaginase clearance as a predictor for inactivation in patients with acute lymphoblastic leukemia.
- Author
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Dam M, Centanni M, Friberg LE, Centanni D, Karlsson MO, Stensig Lynggaard L, Johannsdottir IM, Wik HS, Malmros J, Vaitkeviciene GE, Griskevicius L, Hallböök H, Jónsson ÓG, Overgaard U, Schmiegelow K, Hansen SN, Heyman M, and Albertsen BK
- Subjects
- Humans, Asparaginase, Polyethylene Glycols, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Hypersensitivity drug therapy, Antineoplastic Agents therapeutic use
- Abstract
Asparaginase is an essential component of acute lymphoblastic leukemia (ALL) therapy, yet its associated toxicities often lead to treatment discontinuation, increasing the risk of relapse. Hypersensitivity reactions include clinical allergies, silent inactivation, or allergy-like responses. We hypothesized that even moderate increases in asparaginase clearance are related to later inactivation. We therefore explored mandatory monitoring of asparaginase enzyme activity (AEA) in patients with ALL aged 1-45 years treated according to the ALLTogether pilot protocol in the Nordic and Baltic countries to relate mean AEA to inactivation, to build a pharmacokinetic model to better characterize the pharmacokinetics of peg-asparaginase and assess whether an increased clearance relates to subsequent inactivation. The study analyzed 1631 real-time AEA samples from 253 patients, identifying inactivation in 18.2% of the patients. This inactivation presented as mild allergy (28.3%), severe allergy (50.0%), or silent inactivation (21.7%). A pharmacokinetic transit compartment model was used to describe AEA-time profiles, revealing that 93% of patients with inactivation exhibited prior increased clearance, whereas 86% of patients without hypersensitivity maintained stable clearance throughout asparaginase treatment. These findings enable prediction of inactivation and options for either dose increments or a shift to alternative asparaginase formulations to optimize ALL treatment strategies., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
9. The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia.
- Author
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Pfirrmann M, Clark RE, Prejzner W, Lauseker M, Baccarani M, Saussele S, Guilhot F, Heibl S, Hehlmann R, Faber E, Turkina A, Ossenkoppele G, Höglund M, Zaritskey A, Griskevicius L, Olsson-Strömberg U, Everaus H, Koskenvesa P, Labar B, Sacha T, Zackova D, Cervantes F, Colita A, Zupan I, Bogdanovic A, Castagnetti F, Guilhot J, Hasford J, Hochhaus A, and Hoffmann VS
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Male, Middle Aged, Probability, Prognosis, Protein Kinase Inhibitors therapeutic use, Registries, Young Adult, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality
- Abstract
Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.
- Published
- 2020
- Full Text
- View/download PDF
10. NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia.
- Author
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Tulstrup M, Grosjean M, Nielsen SN, Grell K, Wolthers BO, Wegener PS, Jonsson OG, Lund B, Harila-Saari A, Abrahamsson J, Vaitkeviciene G, Pruunsild K, Toft N, Holm M, Hulegårdh E, Liestøl S, Griskevicius L, Punab M, Wang J, Carroll WL, Zhang Z, Dalgaard MD, Gupta R, Nersting J, and Schmiegelow K
- Subjects
- Adolescent, Antimetabolites, Antineoplastic therapeutic use, Child, Child, Preschool, DNA metabolism, Female, Gene Frequency drug effects, Gene Frequency genetics, Genome-Wide Association Study methods, Genotype, Humans, Infant, Male, Mercaptopurine therapeutic use, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Recurrence, Thioguanine metabolism, 5'-Nucleotidase genetics, Germ Cells metabolism, Polymorphism, Single Nucleotide genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism
- Abstract
The antileukaemic drug 6-mercaptopurine is converted into thioguanine nucleotides (TGN) and incorporated into DNA (DNA-TG), the active end metabolite. In a series of genome-wide association studies, we analysed time-weighted means (
wm ) of erythrocyte concentrations of TGN (Ery-TGN) and DNA-TG in 1009 patients undergoing maintenance therapy for acute lymphoblastic leukaemia (ALL). In discovery analyses (454 patients), the propensity for DNA-TG incorporation (wm DNA-TG/wm Ery-TGN ratio) was significantly associated with three intronic SNPs in NT5C2 (top hit: rs72846714; P = 2.09 × 10-10 , minor allele frequency 15%). In validation analyses (555 patients), this association remained significant during both early and late maintenance therapy (P = 8.4 × 10-6 and 1.3 × 10-3 , respectively). The association was mostly driven by differences inwm Ery-TGN, but in regression analyses adjusted forwm Ery-TGN (P < 0.0001), rs72846714-A genotype was also associated with a higherwm DNA-TG (P = 0.029). Targeted sequencing of NT5C2 did not identify any missense variants associated with rs72846714 orwm Ery-TGN/wm DNA-TG. rs72846714 was not associated with relapse risk, but in a separate cohort of 180 children with relapsed ALL, rs72846714-A genotype was associated with increased occurrence of relapse-specific NT5C2 gain-of-function mutations that reduce cytosol TGN levels (P = 0.03). These observations highlight the impact of both germline and acquired mutations in drug metabolism and disease trajectory.- Published
- 2018
- Full Text
- View/download PDF
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