{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:29:56Z","timestamp":1791822596384,"version":"4.3.4"},"reference-count":128,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["IZLIZ3_200243"],"award-info":[{"award-number":["IZLIZ3_200243"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]},{"award":["IZLIZ3_200243"],"award-info":[{"award-number":["IZLIZ3_200243"]}],"id":[{"id":"https:\/\/ror.org\/00yjd3n13","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Department of Biotechnology","award":["IC-12044(12)\/3\/2022-ICD-DBT"],"award-info":[{"award-number":["IC-12044(12)\/3\/2022-ICD-DBT"]}]},{"award":["IC-12044(12)\/3\/2022-ICD-DBT"],"award-info":[{"award-number":["IC-12044(12)\/3\/2022-ICD-DBT"]}],"id":[{"id":"https:\/\/ror.org\/03tjsyq23","id-type":"ROR","asserted-by":"publisher"}]},{"name":"CANSEARCH Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Childhood and adolescent acute lymphoblastic leukemia (ALL) survival outcomes have improved significantly, but treatment-related toxicities (TRTs) remain a major concern affecting dose intensity and quality of life. Germline pharmacogenetic variations contribute to inter-individual differences in chemotherapy response, yet consistent replication of associations has been limited by differences in treatment protocols, ethnic backgrounds, and toxicity definitions. Methods: This systematic review and meta-analysis (PROSPERO CRD42021229748) included 68 studies in the qualitative synthesis, with 42 high-quality studies undergoing structured synthesis and, where appropriate, quantitative meta-analysis. Studies focused on the toxicities of thiopurines, methotrexate, glucocorticoids, vincristine, and asparaginase. Results: Meta-analyses showed strong evidence linking the NUDT15 rs116855232 variant to thiopurine-induced myelosuppression (OR 19.0, 95% CI 1.6\u2013224; I2 = 86.5%) and a significant association between the TYMS enhancer repeat polymorphism and osteonecrosis (OR 6.66, 95% CI 3.67\u201312.11; I2 = 0%). In contrast, MTHFR variants and VDR polymorphisms showed no significant associations with methotrexate-induced myelosuppression or osteonecrosis, respectively. Narrative synthesis highlighted clinically actionable associations: TPMT and NUDT15 with thiopurine toxicity; CEP72 with vincristine neuropathy; and HLA haplotypes with asparaginase hypersensitivity. Population allele frequency comparisons (IndiGenomes, gnomAD, UK Biobank) showed strong concordance (r = 0.919\u20130.997), supporting the broad generalisability of identified variants, which remains to be evaluated prospectively. The main limitations included heterogeneous toxicity definitions, non-uniform genetic models, evolving treatment protocols, population heterogeneity, and a lack of harmonised reporting. Conclusions: The review supports routine TPMT and NUDT15 genotyping and highlights the need for harmonised definitions, multi-ethnic studies, standardised data representation, and prospective validation. A literature-based candidate gene list for future PGx association studies was generated.<\/jats:p>","DOI":"10.3390\/ph19081204","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T01:43:27Z","timestamp":1785721407000},"page":"1204","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacogenetic Predictors of Chemotherapy Treatment-Related Toxicities in Paediatric and Adolescent Acute Lymphoblastic Leukemia: A Systematic Review, Meta-Analysis and Literature-Based Candidate Prioritization"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7466-1037","authenticated-orcid":false,"given":"Santenna","family":"Chenchula","sequence":"first","affiliation":[{"name":"Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), Bhopal 462020, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4127-3243","authenticated-orcid":false,"given":"Suresh Kumar","family":"Srinivasamurthy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, RAK College of Medical Sciences, RAK Medical & Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4268-0951","authenticated-orcid":false,"given":"Vinnyfred","family":"Vincent","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Carver College of Medicine, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Himani","family":"Thakkar","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Carver College of Medicine, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7296-6088","authenticated-orcid":false,"given":"Shuvadeep","family":"Ganguly","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry 605006, India"},{"name":"Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry 605006, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smita","family":"Kayal","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry 605006, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2834-3868","authenticated-orcid":false,"given":"Swaminathan","family":"Keerthivasagam","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry 605006, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0446-7260","authenticated-orcid":false,"given":"Jaikumar","family":"Ramamoorthy","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry 605006, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3484-4485","authenticated-orcid":false,"given":"Swetambri","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamali","family":"Murugadoss","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry 605006, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6487-6632","authenticated-orcid":false,"given":"Archna","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepam","family":"Pushpam","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayanthi","family":"Mathaiyan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry 605006, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bani","family":"Jolly","sequence":"additional","affiliation":[{"name":"Karkinos Healthcare Pvt. Ltd., Mumbai 400021, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinod","family":"Scaria","sequence":"additional","affiliation":[{"name":"Karkinos Healthcare Pvt. Ltd., Mumbai 400021, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8790-0479","authenticated-orcid":false,"given":"Yvonne","family":"Gloor","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Gynecology and Obstetrics, CANSEARCH Research Platform in Pediatric Oncology and Haematology, University of Geneva, 1205 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8059-3015","authenticated-orcid":false,"given":"Frederic","family":"Baleydier","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Gynecology and Obstetrics, CANSEARCH Research Platform in Pediatric Oncology and Haematology, University of Geneva, 1205 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameer","family":"Bakhshi","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biswajit","family":"Dubashi","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry 605006, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Ansari","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Gynecology and Obstetrics, CANSEARCH Research Platform in Pediatric Oncology and Haematology, University of Geneva, 1205 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8928-7049","authenticated-orcid":false,"given":"Chakradhara Rao S.","family":"Uppugunduri","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry 605006, India"},{"name":"Department of Pediatrics, Gynecology and Obstetrics, CANSEARCH Research Platform in Pediatric Oncology and Haematology, University of Geneva, 1205 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/S2352-4642(18)30066-X","article-title":"Global efforts toward the cure of childhood acute lymphoblastic leukaemia","volume":"2","author":"Pui","year":"2018","journal-title":"Lancet Child. 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