{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:10:58Z","timestamp":1789603858320,"version":"build-2803163510"},"reference-count":19,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,5,26]],"date-time":"2024-05-26T00:00:00Z","timestamp":1716681600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Methotrexate (MTX), although an indispensable part of contemporary treatment protocols for childhood acute lymphoblastic leukaemia (ALL)\/lymphomas (LBL) in improving outcomes, can lead to serious neurotoxicity with long\u2010term consequences. The aetiopathogenesis, predisposing factors and treatment for MTX\u2010induced neurotoxicity are not yet well defined. The aim of our study was to detect the incidence, risk factors and to assess the overall outcomes of MTX\u2010induced neurotoxicity among large cohort of paediatric ALL\/LBL patients treated on a uniform protocol. We conducted retrospective audit of medical records of 622 consecutive children (\u226414\u2009years) diagnosed with ALL and LBL between January 2018 and December 2022 and treated on modified BFM\u201095 protocol at the Department of Pediatric Oncology, Regional Cancer Centre, Thiruvananthapuram. Risk factors predisposing to MTX\u2010induced neurotoxicity were identified using binary logistic regression analysis. Forty\u2010three children were diagnosed with MTX\u2010induced neurotoxicity with an incidence rate of 6.9%. More than two\u2010thirds of them had high\u2010grade MTX\u2010induced neurotoxicity CTCAE v5.0 with a median age of 9\u2009years (range: 9\u2009months to 14\u2009years). Almost half of them developed MTX neurotoxicity during Protocol M followed by Phase\u2010Ib consolidation (15%). Majority of these patients (84%, 36\/43) were challenged again with MTX, with 11% (4\/36) developing recurrence. Fifteen per cent had persistent neurological deficits at last follow\u2010up. Univariate analysis found older age (age\u2009&gt;\u20095\u2009years) (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), T\u2010cell phenotype (<jats:italic>p<\/jats:italic>\u2009=\u20090.040), tumour lysis syndrome during induction (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), baseline renal problems prior to MTX exposure (p\u2009&lt;\u20090.001) and CNS leukaemic involvement (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.003) to be significantly associated with MTX neurotoxicity. On multivariate analysis, older age (&gt;5\u2009years), tumour lysis during induction and CNS leukaemia retained statistical significance (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Methotrexate\u2010induced neurotoxicity during paediatric acute lymphoblastic leukaemia\/lymphoma therapy is a transient phenomenon in majority and re\u2010challenge with MTX is generally safe. Older age children who develop tumour lysis during induction and CNS leukaemic involvement are at increased risk for MTX\u2010induced neurotoxicity during ALL\/LBL treatment.<\/jats:p>","DOI":"10.1111\/bjh.19559","type":"journal-article","created":{"date-parts":[[2024,5,26]],"date-time":"2024-05-26T19:54:51Z","timestamp":1716753291000},"page":"220-228","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Older age, <scp>CNS<\/scp> leukaemic involvement and induction tumour lysis increases the risk of methotrexate (<scp>MTX<\/scp>)\u2010induced neurotoxicity in childhood acute lymphoblastic leukaemia\/lymphoma: Experience from a tertiary care centre in South India"],"prefix":"10.1111","volume":"205","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2375-3251","authenticated-orcid":false,"given":"Thirumala","family":"Rupakumar","sequence":"first","affiliation":[{"name":"Department of Pediatric Oncology Regional Cancer Centre  Thiruvananthapuram Kerala India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8985-2124","authenticated-orcid":false,"given":"Ajay","family":"Sankar","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology Regional Cancer Centre  Thiruvananthapuram Kerala India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3796-8782","authenticated-orcid":false,"given":"Kalasekhar","family":"Vijayasekharan","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology Regional Cancer Centre  Thiruvananthapuram Kerala India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasanth","family":"Varikkattu\u00a0Rajendran","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology Regional Cancer Centre  Thiruvananthapuram Kerala India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guruprasad","family":"Chellapan\u00a0Sojamani","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology Regional Cancer Centre  Thiruvananthapuram Kerala India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binitha","family":"Rajeswari","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology Regional Cancer Centre  Thiruvananthapuram Kerala India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manjusha","family":"Nair","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology Regional Cancer Centre  Thiruvananthapuram Kerala India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakesh","family":"Anandarajan","sequence":"additional","affiliation":[{"name":"Department of Radiology Regional Cancer Centre  Thiruvananthapuram Kerala India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Dennis","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics Regional Cancer Centre  Thiruvananthapuram Kerala India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyakumari","family":"Thankamony","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology Regional Cancer Centre  Thiruvananthapuram Kerala India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,5,26]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra052603"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.20517\/cdr.2022.18"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2020.268565"},{"key":"e_1_2_13_5_1","first-page":"376","article-title":"It takes a village: maximizing supportive care and minimizing toxicity during childhood leukemia therapy: managing therapy\u2010associated neurotoxicity in children with ALL","volume":"2021","author":"Bhojwani D","year":"2021","journal-title":"ASH Educ Program"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.34646"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2022.920214"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13081939"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1159\/000069773"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.53.0808"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2014.01.048"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.21764"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(16)30110-7"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.23876\/j.krcp.20.074"},{"key":"e_1_2_13_15_1","unstructured":"Cancer Institute N. Common Terminology Criteria for Adverse Events (CTCAE).Common Terminology Criteria for Adverse Events (CTCAE) v5.0 [Internet].2017Available from:https:\/\/www.meddra.org\/"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2023.2245093"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-018-2525-0"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/3687134"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.34067\/KID.0000952019"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2021.280016"}],"container-title":["British Journal of Haematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bjh.19559","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T09:09:53Z","timestamp":1753261793000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bjh.19559"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,26]]},"references-count":19,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,7]]}},"alternative-id":["10.1111\/bjh.19559"],"URL":"https:\/\/doi.org\/10.1111\/bjh.19559","archive":["Portico"],"relation":{},"ISSN":["0007-1048","1365-2141"],"issn-type":[{"value":"0007-1048","type":"print"},{"value":"1365-2141","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,26]]},"assertion":[{"value":"2024-03-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}