Abstract：
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.
摘要：
甲氨蝶呤(MTX),尽管当代儿童急性淋巴细胞白血病（ALL）/淋巴瘤（LBL）治疗方案在改善预后方面不可或缺的一部分，会导致严重的神经毒性和长期后果。病因，MTX诱导的神经毒性的诱发因素和治疗方法尚不明确.我们研究的目的是检测发病率，在接受统一方案治疗的大型儿科ALL/LBL患者队列中，评估MTX诱导的神经毒性的总体结局。我们对2018年1月至2022年12月期间诊断为ALL和LBL的622名连续儿童（≤14岁）的病历进行了回顾性审核，并在儿科肿瘤科接受了改良的BFM-95方案治疗。区域癌症中心，Thiruvananthapuram.使用二元逻辑回归分析确定了诱发MTX引起的神经毒性的危险因素。43例儿童被诊断为MTX引起的神经毒性，发生率为6.9％。超过三分之二的患者患有高级别MTX诱导的CTCAEv5.0神经毒性，中位年龄为9岁（范围：9个月至14岁）。几乎一半的患者在方案M期间出现MTX神经毒性,随后是Ib期巩固(15%)。这些患者中的大多数（84%，36/43）再次受到MTX的挑战，11％（4/36）发展复发。在最后一次随访中，有15％的人存在持续的神经功能缺损。单因素分析发现年龄较大(年龄>5岁)(p<0.001)，T细胞表型（p=0.040），诱导过程中的肿瘤溶解综合征（p<0.001），MTX暴露前的基线肾脏问题(p<0.001)和中枢神经系统白血病受累(p<0.003)与MTX神经毒性显著相关。在多变量分析中，年龄较大（>5岁），诱导过程中的肿瘤溶解和中枢神经系统白血病保持统计学意义(p<0.05)。甲氨蝶呤在儿科急性淋巴细胞白血病/淋巴瘤治疗期间诱导的神经毒性在大多数情况下是短暂的现象，用MTX再次攻击通常是安全的。在ALL/LBL治疗期间，在诱导和中枢神经系统白血病受累期间发生肿瘤溶解的年龄较大的儿童在MTX诱导的神经毒性的风险增加。
