Older age, CNS leukaemic involvement and induction tumour lysis increases the risk of methotrexate (MTX)‐induced neurotoxicity in childhood acute lymphoblastic leukaemia/lymphoma: Experience from a tertiary care centre in South India

Summary 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‐term consequences. The aetiopathogenesis, predisposing factors and treatment for MTX‐induced 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‐induced 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 (≤14 years) diagnosed with ALL and LBL between January 2018 and December 2022 and treated on modified BFM‐95 protocol at the Department of Pediatric Oncology, Regional Cancer Centre, Thiruvananthapuram. Risk factors predisposing to MTX‐induced neurotoxicity were identified using binary logistic regression analysis. Forty‐three children were diagnosed with MTX‐induced neurotoxicity with an incidence rate of 6.9%. More than two‐thirds of them had high‐grade MTX‐induced neurotoxicity CTCAE v5.0 with a median age of 9 years (range: 9 months to 14 years). Almost half of them developed MTX neurotoxicity during Protocol M followed by Phase‐Ib 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‐up. Univariate analysis found older age (age > 5 years) ( p < 0.001), T‐cell phenotype ( p = 0.040), tumour lysis syndrome during induction ( p < 0.001), baseline renal problems prior to MTX exposure (p < 0.001) and CNS leukaemic involvement ( p < 0.003) to be significantly associated with MTX neurotoxicity. On multivariate analysis, older age (>5 years), tumour lysis during induction and CNS leukaemia retained statistical significance ( p < 0.05). Methotrexate‐induced neurotoxicity during paediatric acute lymphoblastic leukaemia/lymphoma therapy is a transient phenomenon in majority and re‐challenge with MTX is generally safe. Older age children who develop tumour lysis during induction and CNS leukaemic involvement are at increased risk for MTX‐induced neurotoxicity during ALL/LBL treatment.