Despite improving cure rates in childhood acute lymphoblastic leukemia (ALL), therapeutic side effects and relapse are ongoing challenges. These can also affect the central nervous system (CNS). Our aim was to identify germline gene polymorphisms that influence the risk of CNS events. Sixty single nucleotide polymorphisms (SNPs) in 20 genes were genotyped in a Hungarian non-matched ALL cohort of 36 cases with chemotherapy related acute toxic encephalopathy (ATE) and 544 controls. Five significant SNPs were further analyzed in an extended Austrian-Czech-NOPHO cohort (n = 107 cases, n = 211 controls) but none of the associations could be validated. Overall populations including all nations' matched cohorts for ATE (n = 426) with seizure subgroup (n = 133) and posterior reversible encephalopathy syndrome (PRES, n = 251) were analyzed, as well. We found that patients with ABCB1 rs1045642, rs1128503 or rs2032582 TT genotypes were more prone to have seizures but those with rs1045642 TT developed PRES less frequently. The same SNPs were also examined in relation to ALL relapse on a case-control matched cohort of 320 patients from all groups. Those with rs1128503 CC or rs2032582 GG genotypes showed higher incidence of CNS relapse. Our results suggest that blood-brain-barrier drug transporter gene-polymorphisms might have an inverse association with seizures and CNS relapse.

2nd Department of Pediatrics Semmelweis University H 1094 Budapest Hungary

Astrid Lindgren Children's Hospital Karolinska University Hospital S 14186 Stockholm Sweden

Central Laboratory Heim Pál Children's Hospital H 1089 Budapest Hungary

Childhood Cancer Research Unit Department of Women's and Children's Health Karolinska Institutet S 17177 Stockholm Sweden

CLIP Childhood Leukemia Investigation Prague Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol CZ 150 06 Prague Czech Republic

Department of Genetics Cell and Immunobiology Semmelweis University H 1089 Budapest Hungary

Department of Measurement and Information Systems Budapest University of Technology and Economics H 1111 Budapest Hungary

Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol CZ 150 06 Prague Czech Republic

Department of Paediatrics and Adolescent Medicine Rigshospitalet DK 2100 Copenhagen Denmark

Department of Pediatric Hematology and Oncology St Anna Children's Hospital Medical University of Vienna A 1090 Vienna Austria

Department of Pediatrics Pécs University H 7623 Pécs Hungary

MTA SE Immune Proteogenomics Extracellular Vesicle Research Group Semmelweis University H 1089 Budapest Hungary

Renate Panzer Grümayer Leukemia Biology Group Children's Cancer Research Institute A 1090 Vienna Austria

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Filbin M., Monje M. Developmental origins and emerging therapeutic opportunities for childhood cancer. Nat. Med. 2019;25:367–376. doi: 10.1038/s41591-019-0383-9. PubMed DOI PMC

Pui C., Pei D., Campana D., Cheng C., Sandlund J., Bowman W., Hudson M., Ribeiro R., Raimondi S., Jeha S., et al. A Revised Definition for Cure of Childhood Acute Lymphoblastic Leukemia. Leukemia. 2014;28:2336–2343. doi: 10.1038/leu.2014.142. PubMed DOI PMC

Coleman J.J., Pontefract S.K. Adverse drug reactions. Clin. Med. 2016;16:481–485. doi: 10.7861/clinmedicine.16-5-481. PubMed DOI PMC

Kearns G.L., Abdel-Rahman S.M., Alander S.W., Blowey D.L., Leeder J.S., Kauffman R.E. Developmental pharmacology - Drug disposition, action, and therapy in infants and children. N. Engl. J. Med. 2003;349:1157–1167. doi: 10.1056/NEJMra035092. PubMed DOI

Kim J.A., Ceccarelli R., Lu C.Y. Pharmacogenomic Biomarkers in US FDA-Approved Drug Labels (2000–2020) J. Pers. Med. 2021;11:179. doi: 10.3390/jpm11030179. PubMed DOI PMC

Cunningham L., Aplenc R. Pharmacogenetics of acute lymphoblastic leukemia treatment response. Expert Opin. Pharmacother. 2007;8:2519–2531. doi: 10.1517/14656566.8.15.2519. PubMed DOI

Stary J., Zimmermann M., Campbell M., Castillo L., Dibar E., Donska S., Gonzalez A., Izraeli S., Janic D., Jazbec J., et al. Intensive chemotherapy for childhood acute lymphoblastic leukemia: Results of the randomized intercontinental trial ALL IC-BFM 2002. J. Clin. Oncol. 2014;32:174–184. doi: 10.1200/JCO.2013.48.6522. PubMed DOI

Marchiano R.D.M., Sante G.D., Piro G., Carbone C., Tortora G., Boldrini L., Pietragalla A., Daniele G., Tredicine M., Cesario A., et al. Translational Research in the Era of Precision Medicine: Where We Are and Where We Will Go. J. Pers. Med. 2021;11:216. doi: 10.3390/jpm11030216. PubMed DOI PMC

Pui C.H., Howard S.C. Current management and challenges of malignant disease in the CNS in paediatric leukaemia. Lancet Oncol. 2008;9:257–268. doi: 10.1016/S1470-2045(08)70070-6. PubMed DOI

Parasole R., Petruzziello F., Menna G., Mangione A., Cianciulli E., Buffardi S., Marchese L., Nastro A., Misuraca A., Poggi V. Central nervous system complications during treatment of acute lymphoblastic leukemia in a single pediatric institution. Leuk. Lymphoma. 2010;51:1063–1071. doi: 10.3109/10428191003754608. PubMed DOI

Kembhavi S.A., Somvanshi S., Banavali S., Kurkure P., Arora B. Pictorial essay: Acute neurological complications in children with acute lymphoblastic leukemia. Indian J. Radiol. Imaging. 2012;22:98–105. doi: 10.4103/0971-3026.101080. PubMed DOI PMC

Magge R.S., De Angelis L.M. The double-edged sword: Neurotoxicity of chemotherapy. Blood Rev. 2015;29:93–100. doi: 10.1016/j.blre.2014.09.012. PubMed DOI PMC

Vagace J.M., de la Maya M.D., Caceres-Marzal C., Gonzalez de Murillo S., Gervasini G. Central nervous system chemotoxicity during treatment of pediatric acute lymphoblastic leukemia/lymphoma. Crit. Rev. Oncol. Hematol. 2012;84:274–286. doi: 10.1016/j.critrevonc.2012.04.003. PubMed DOI

De Carvalho D.C., Wanderley A.V., dos Santos A.M.R., Fernandes M.R., Cohen Lima de Castro A.d.N., Leitão L.P.C., de Carvalho J.A.N., de Souza T.P., Khayat A.S., dos Santos S.E.B., et al. Pharmacogenomics and variations in the risk of toxicity during the consolidation/maintenance phases of the treatment of pediatric B-cell leukemia patients from an admixed population in the Brazilian Amazon. Leuk. Res. 2018;74:10–13. doi: 10.1016/j.leukres.2018.09.003. PubMed DOI

Stanulla M., Schäffeler E., Arens S., Rathmann A., Schrauder A., Welte K., Eichelbaum M., Zanger U.M., Schrappe M., Schwabb M. GSTP1 and MDR1 genotypes and central nervous system relapse in childhood acute lymphoblastic leukemia. Int. J. Hematol. 2005;81:39–44. doi: 10.1532/IJH97.E0418. PubMed DOI

Mahadeo K.M., Dhall G., Panigrahy A., Lastra C., Ettinger L.J. Subacute methotrexate neurotoxicity and cerebral venous sinus thrombosis in a 12-year old with acute lymphoblastic leukemia and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: Homocysteine-mediated methotrexate neurotoxicity via direct endothelial injury. Pediatr. Hematol. Oncol. 2010;27:46–52. doi: 10.3109/08880010903341904. PubMed DOI

Egbelakin A., Ferguson M., MacGill E., Lehmann A., Topletz A., Quinney S., Li L., McCammack K., Hall S., Renbarger J. Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia. Pediatr. Blood Cancer. 2011;56:7. doi: 10.1002/pbc.22845. PubMed DOI PMC

Froklage F.E., Reijneveld J.C., Heimans J.J. Central neurotoxicity in cancer chemotherapy: Pharmacogenetic insights. Pharmacogenomics. 2011;12:379–395. doi: 10.2217/pgs.10.197. PubMed DOI

Kishi S., Cheng C., French D., Pei D., Das S., Cook E.H., Hijiya N., Rizzari C., Rosner G.L., Frudakis T., et al. Ancestry and pharm acogenetics of antileukemic drug toxicity. Blood. 2007;109:4151–4157. doi: 10.1182/blood-2006-10-054528. PubMed DOI PMC

Erdilyi D.J., Kámory E., Csókay B., Andrikovics H., Tordai A., Kiss C., Filni-Semsei A., Janszky I., Zalka A., Fekete G., et al. Synergistic interaction of ABCB1 and ABCG2 polymorphisms predicts the prevalence of toxic encephalopathy during anticancer chemotherapy. Pharmacogenomics J. 2008;8:321–327. doi: 10.1038/sj.tpj.6500480. PubMed DOI

Talaat R.M., El-Kelliny M.Y.K., El-Akhras B.A., Bakry R.M., Riad K.F., Guirgis A.A. Association of C3435T, C1236T and C4125A polymorphisms of the MDR-1 Gene in Egyptian children with acute lymphoblastic leukaemia. Asian Pacific J. Cancer Prev. 2018;19:2535–2543. doi: 10.22034/APJCP.2018.19.9.2535. PubMed DOI PMC

Ceppi F., Langlois-pelletier C., Gagné V., Rousseau J., Lorenzo S.D., Kevin K.M., Cijov D., Sallan S.E., Lewis B. Polymorphisms of the vincristine pathway and response to treatment in children with childhood acute lymphoblastic leukemia. Pharmacogenomics. 2014;15:1105–1116. doi: 10.2217/pgs.14.68. PubMed DOI PMC

Cole P.D., Beckwith K.A., Vijayanathan V., Roychowdhury S., Smith A.K., Kamen B.A. Folate Homeostasis in Cerebrospinal Fluid During Therapy for Acute Lymphoblastic Leukemia. Pediatr. Neurol. 2009;40:34–41. doi: 10.1016/j.pediatrneurol.2008.09.005. PubMed DOI

Özütemiz C., Roshan S.K., Kroll N.J., Benson J.C., Rykken J.B., Oswood M.C., Zhang L., McKinney A.M. Acute toxic leukoencephalopathy: Etiologies, imaging findings, and outcomes in 101 patients. Am. J. Neuroradiol. 2019;40:267–275. doi: 10.3174/ajnr.A5947. PubMed DOI PMC

Beitinjaneh A., McKinney A.M., Cao Q., Weisdorf D.J. Toxic Leukoencephalopathy following Fludarabine-Associated Hematopoietic Cell Transplantation. Biol. Blood Marrow Transplant. 2011;17:300–308. doi: 10.1016/j.bbmt.2010.04.003. PubMed DOI

Schmiegelow K., Attarbaschi A., Barzilai S., Escherich G., Frandsen T.L., Halsey C., Hough R., Jeha S., Kato M., Liang D.C., et al. Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: A Delphi consensus. Lancet Oncol. 2016;17:e231–e239. doi: 10.1016/S1470-2045(16)30035-3. PubMed DOI

Fulbright J.M., Raman S., McClellan W.S., August K.J. Late effects of childhood leukemia therapy. Curr. Hematol. Malig. Rep. 2011;6:195–205. doi: 10.1007/s11899-011-0094-x. PubMed DOI

Anastasopoulou S., Eriksson M.A., Heyman M., Wang C., Niinimäki R., Mikkel S., Vaitkevičienė G.E., Johannsdottir I.M., Myrberg I.H., Jonsson O.G., et al. Posterior reversible encephalopathy syndrome in children with acute lymphoblastic leukemia: Clinical characteristics, risk factors, course, and outcome of disease. Pediatr. Blood Cancer. 2019;66:1–10. doi: 10.1002/pbc.27594. PubMed DOI

Anastasopoulou S., Heyman M., Eriksson M.A., Niinimäki R., Taskinen M., Mikkel S., Vaitkeviciene G.E., Johannsdottir I.M., Myrberg I.H., Jonsson O.G., et al. Seizures during treatment of childhood acute lymphoblastic leukemia: A population-based cohort study. Eur. J. Paediatr. Neurol. 2020;27:72–77. doi: 10.1016/j.ejpn.2020.04.004. PubMed DOI

Olmos-Jiménez R., Díaz-Carrasco M.S., Galera-Miñarro A., Pascual-Gazquez J.F., Espuny-Miró A. Evaluation of standardized triple intrathecal therapy toxicity in oncohematological pediatric patients. Int. J. Clin. Pharm. 2017;39:126–132. doi: 10.1007/s11096-016-0408-0. PubMed DOI

Mateos M.K., Marshall G.M., Barbaro P.M., Quinn M.C., George C., Mayoh C., Sutton R., Revesz T., Giles J.E., Barbaric D., et al. Methotrexate-related central neurotoxicity: Clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia. Haematologica. 2021 doi: 10.3324/haematol.2020.268565. PubMed DOI PMC

Ritchey A.K., Pollock B.H., Lauer S.J., Andejeski Y., Buchanan G.R. Improved survival of children with isolated CNS relapse of acute lymphoblastic leukemia: A pediatric oncology group study. J. Clin. Oncol. 1999;17:3745–3752. doi: 10.1200/JCO.1999.17.12.3745. PubMed DOI

Tsurusawa M., Yumura-Yagi K., Ohara A., Hara J., Katano N., Tsuchida M. Survival outcome after the first central nervous system relapse in children with acute lymphoblastic leukemia: A retrospective analysis of 79 patients in a joint program involving the experience of three Japanese study groups. Int. J. Hematol. 2007;85:36–40. doi: 10.1532/IJH97.06085. PubMed DOI

Frishman-Levy L., Izraeli S. Advances in understanding the pathogenesis of CNS acutelymphoblastic leukaemia and potential for therapy. Br. J. Haematol. 2016;176:157–167. doi: 10.1111/bjh.14411. PubMed DOI

Krishnan S., Wade R., Moorman A.V., Mitchell C., Kinsey S.E., Eden T.O.B., Parker C., Vora A., Richards S., Saha V. Temporal changes in the incidence and pattern of central nervous system relapses in children with acute lymphoblastic leukaemia treated on four consecutive Medical Research Council trials, 1985–2001. Leukemia. 2010;24:450–459. doi: 10.1038/leu.2009.264. PubMed DOI PMC

Gao R.W., Dusenbery K.E., Cao Q., Smith A.R., Yuan J. Augmenting Total Body Irradiation with a Cranial Boost before Stem Cell Transplantation Protects Against Post-Transplant Central Nervous System Relapse in Acute Lymphoblastic Leukemia. Biol. Blood Marrow Transplant. 2018;24:501–506. doi: 10.1016/j.bbmt.2017.11.013. PubMed DOI PMC

Fukano R., Nishimura M., Ito N., Nakashima K., Kodama Y., Okamura J., Inagaki J. Efficacy of prophylactic additional cranial irradiation and intrathecal chemotherapy for the prevention of CNS relapse after allogeneic hematopoietic SCT for childhood ALL. Pediatr. Transplant. 2014;18:518–523. doi: 10.1111/petr.12276. PubMed DOI

Laver J.H., Barredo J.C., Amylon M., Schwenn M., Kurtzberg J., Camitta B.M., Pullen J., Link M.P., Borowitz M., Ravindranath Y., et al. Effects of cranial radiation in children with high risk T cell acute lymphoblastic leukemia: A Pediatric Oncology Group report. Leukemia. 2000;14:369–373. doi: 10.1038/sj.leu.2401693. PubMed DOI

Piette C., Suciu S., Bertrand Y., Uyttebroeck A., Vandecruys E., Plat G., Paillard C., Pluchart C., Sirvent N., Maurus R., et al. Long-term outcome evaluation of medium/high risk acute lymphoblastic leukaemia children treated with or without cranial radiotherapy in the EORTC 58832 randomized study. Br. J. Haematol. 2020;189:351–362. doi: 10.1111/bjh.16337. PubMed DOI

Jastaniah W., Elimam N., Abdalla K., AlAzmi A.A., Algamal A., Felimban S. Intrathecal dose intensification by CNS status at diagnosis in the treatment of children with acute lymphoblastic leukemia. Hematology. 2019;24:369–377. doi: 10.1080/16078454.2019.1590962. PubMed DOI

Pui C.H., Mahmoud H.H., Rivera G.K., Hancock M.L., Sandlund J.T., Behm F.G., Head D.R., Relling M.V., Ribeiro R.C., Rubnitz J.E., et al. Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood. 1998;92:411–415. doi: 10.1182/blood.V92.2.411. PubMed DOI

Kobayashi K., Ito M., Miyajima T., Fujii T., Okuno T. Successful management of intractable epilepsy with intravenous lidocaine and lidocaine tapes. Pediatr. Neurol. 1999;21:476–480. doi: 10.1016/S0887-8994(99)00026-0. PubMed DOI

NOPHO Participating Institutions. [(accessed on 1 October 2020)]; Available online: https://www.nopho.org/organization/treating_clinics/Participating%20Clinics%202019.pdf.

NIH Common terminology criteria for adverse events v4.0. NIH Publ. 2009;2009:1–71.

Zaliova M., Stuchly J., Winkowska L., Musilova A., Fiser K., Slamova M., Starkova J., Vaskova M., Hrusak O., Sramkova L., et al. Genomic landscape of pediatric B-other acute lymphoblastic leukemia in a consecutive European cohort. Haematologica. 2019;104 doi: 10.3324/haematol.2018.204974. PubMed DOI PMC

Sági J.C., Egyed B., Kelemen A., Kutszegi N., Hegyi M., Gézsi A., Herlitschke M.A., Rzepiel A., Fodor L.E., Ottóffy G., et al. Possible roles of genetic variations in chemotherapy related cardiotoxicity in pediatric acute lymphoblastic leukemia and osteosarcoma. BMC Cancer. 2018;18:1–14. doi: 10.1186/s12885-018-4629-6. PubMed DOI PMC

Wolthers B.O., Frandsen T.L., Abrahamsson J., Albertsen B.K., Helt L.R., Heyman M., Jónsson G., Kõrgvee L.T., Lund B., Raja R.A., et al. Asparaginase-associated pancreatitis: A study on phenotype and genotype in the NOPHO ALL2008 protocol. Leukemia. 2017;31:325–332. doi: 10.1038/leu.2016.203. PubMed DOI

Højfeldt S.G., Wolthers B.O., Tulstrup M., Abrahamsson J., Gupta R., Harila-Saari A., Heyman M., Henriksen L.T., Jónsson Ò.G., Lähteenmäki P.M., et al. Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008. Br. J. Haematol. 2019;184:405–417. doi: 10.1111/bjh.15660. PubMed DOI

Storey J.D. A direct approach to false discovery rates. J. R. Stat. Soc. 2002;64:479–498. doi: 10.1111/1467-9868.00346. DOI

Benjamini Y., Hochberg Y. Controlling the false discovery rate: A practical and powerful approach to multiple testing. J. R. Stat. Soc. 1995;57:289–300. doi: 10.1111/j.2517-6161.1995.tb02031.x. DOI

Therneau T. A Package for Survival Analysis in R. R package version 3.2-7. R Core Team; Vienna, Austria: 2020.

Stoer N.C., Samuelsen S.O. Weighted Cox-Regression for Nested Case-Control Data. R package version 1.2-2. R Core Team; Vienna, Austria: 2020.

Watanabe K., Arakawa Y., Oguma E., Uehara T., Yanagi M., Oyama C., Ikeda Y., Sasaki K., Isobe K., Mori M., et al. Characteristics of methotrexate-induced stroke-like neurotoxicity. Int. J. Hematol. 2018;108:630–636. doi: 10.1007/s12185-018-2525-0. PubMed DOI

Baker D.K., Relling M.V., Pui C.H., Christensen M.L., Evans W.E., Rodman J.H. Increased teniposide clearance with concomitant anticonvulsant therapy. J. Clin. Oncol. 1992;10:311–315. doi: 10.1200/JCO.1992.10.2.311. PubMed DOI

Schrøder H., Østergaard J.R. Interference of high-dose methotrexate in the metabolism of valproate? Pediatr. Hematol. Oncol. 1994;11:445–449. doi: 10.3109/08880019409140546. PubMed DOI

Hough R.E., Kirkwood A.A., Samarasinghe S., Rowntree C.J., Goulden N.J., Vora A. Major Deviations in the Delivery of Induction Chemotherapy Are Associated with an Increased Risk of Relapse in Acute Lymphoblastic Leukaemia: Results from UKALL2003. Blood. 2019;134:2579. doi: 10.1182/blood-2019-127223. DOI

Aberuyi N., Rahgozar S., Pourabutaleb E., Ghaedi K. Selective dysregulation of ABC transporters in methotrexate-resistant leukemia T-cells can confer cross-resistance to cytarabine, vincristine and dexamethasone, but not doxorubicin. Curr. Res. Transl. Med. 2020;69:103269. doi: 10.1016/j.retram.2020.09.003. PubMed DOI

Ramos-Peñafiel C., Olarte-Carrillo I., Maldonado R.C., de la Cruz Rosas A., Collazo-Jaloma J., Martínez-Tovar A. Association of three factors (ABCB1 gene expression, steroid response, early response at day + 8) on the response to induction in patients with acute lymphoblastic leukemia. Ann. Hematol. 2020;99:2629–2637. doi: 10.1007/s00277-020-04277-y. PubMed DOI

Olarte Carrillo I., Ramos Peñafiel C., Miranda Peralta E., Rozen Fuller E., Kassack Ipiña J.J., Centeno Cruz F., Garrido Guerrero E., Collazo Jaloma J., Nacho Vargas K., Martínez Tovar A. Clinical significance of the ABCB1 and ABCG2 gene expression levels in acute lymphoblastic leukemia. Hematology. 2017;22:286–291. doi: 10.1080/10245332.2016.1265780. PubMed DOI

Ankathil R. ABCB1 genetic variants in leukemias: Current insights into treatment outcomes. Pharmgenomics. Pers. Med. 2017;10:169–181. doi: 10.2147/PGPM.S105208. PubMed DOI PMC

Ma C.X., Sun Y.H., Wang H.Y. ABCB1 polymorphisms correlate with susceptibility to adult acute leukemia and response to high-dose methotrexate. Tumor Biol. 2015;36:7599–7606. doi: 10.1007/s13277-015-3403-5. PubMed DOI

Ramírez-Pacheco A., Moreno-Guerrero S., Alamillo I., Medina-Sanson A., Lopez B., Moreno-Galván M. Mexican Childhood Acute Lymphoblastic Leukemia: A Pilot Study of the MDR1 and MTHFR Gene Polymorphisms and Their Associations with Clinical Outcomes. Genet. Test. Mol. Biomarkers. 2016;20:597–602. doi: 10.1089/gtmb.2015.0287. PubMed DOI

Zhang Y.X., Ma Y., Zhang H., Zhang W.P., Yang X.Y. Genetic polymorphism in MDR1 C3435T is a determinant of methotrexate cerebrospinal fluid concentrations in Chinese children with acute lymphoblastic leukemia. Int. J. Clin. Pharmacol. Ther. 2020;58:254–260. doi: 10.5414/CP203462. PubMed DOI

Lopez-Lopez E., Gutierrez-Camino A., Astigarraga I., Navajas A., Echebarria-Barona A., Garcia-Miguel P., Garcia De Andoin N., Lobo C., Guerra-Merino I., Martin-Guerrero I., et al. Vincristine pharmacokinetics pathway and neurotoxicity during early phases of treatment in pediatric acute lymphoblastic leukemia. Pharmacogenomics. 2016;17:731–741. doi: 10.2217/pgs-2016-0001. PubMed DOI

Watson M.A., Stewart R.K., Smith G.B.J., Massey T.E., Bell D.A. Human glutathione S-transferase P1 polymorphisms: Relationship to lung tissue enzyme activity and population frequency distribution. Carcinogenesis. 1998;19:275–280. doi: 10.1093/carcin/19.2.275. PubMed DOI

Krull K.R., Bhojwani D., Conklin H.M., Pei D., Cheng C., Reddick W.E., Sandlund J.T., Pui C.H. Genetic mediators of neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia. J. Clin. Oncol. 2013;31:2182–2188. doi: 10.1200/JCO.2012.46.7944. PubMed DOI PMC

Leonardi D.B., Abbate M., Riccheri M.C., Nuñez M., Alfonso G., Gueron G., De Siervi A., Vazquez E., Cotignola J. Improving risk stratification of patients with childhood acute lymphoblastic leukemia: Glutathione-S-Transferases polymorphisms are associated with increased risk of relapse. Oncotarget. 2017;8:110–117. doi: 10.18632/oncotarget.8606. PubMed DOI PMC

Krajinovic M., Labuda D., Sinnett D. Childhood acute lymphoblastic leukemia: Genetic determinants of susceptibility and disease outcome. Rev. Environ. Health. 2001;16:263–279. doi: 10.1515/REVEH.2001.16.4.263. PubMed DOI

Anderer G., Schrappe M., Brechlin A.M., Lauten M., Muti P., Welte K., Stanulla M. Polymorphisms within glutathione S-transferase genes and initial response to glucocorticoids in childhood acute lymphoblastic leukaemia. Pharmacogenetics. 2000;10:715–726. doi: 10.1097/00008571-200011000-00006. PubMed DOI

Krajinovic M., Labuda D., Sinnett D. Glutathione S-transferase P1 genetic polymorphisms and susceptibility to childhood acute lymphoblastic leukaemia. Pharmacogenetics. 2002;12:655–658. doi: 10.1097/00008571-200211000-00010. PubMed DOI