Acute central nervous system toxicity during treatment of pediatric acute lymphoblastic leukemia: phenotypes, risk factors and genotypes

Abstract

Central nervous system (CNS) toxicity is common at diagnosis and during treatment of pediatric acute lymphoblastic leukemia (ALL). We studied CNS toxicity in 1 464 children aged 1.0–17.9 years, diagnosed with ALL and treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol. Genome-wide association studies (GWAS), and a candidate single-nucleotide polymorphism (SNP; n=19) study were performed in 1 166 patients. Findings were validated in an Australian independent cohort of children with ALL (n=797) where two phenotypes were evaluated: diverse CNS toxicities (n=103) and methotrexate-related CNS toxicity (n=48). In total, 135/1 464 (9.2%) patients experienced CNS toxicity with cumulative incidence of 8.7% (95% CI: 7.31–10.20) at 12 months from diagnosis. Patients aged ≥10 years had higher risk of CNS toxicity than younger patients (16.3% vs 7.4%; p

Patterns and Outcomes of Acute Central Nervous System Complications During Treatment of Childhood Acute Lymphoblastic Leukemia: A Single-center Experience

“…In a study by Anastasopoulou and colleagues, patients ≥10 years of age had a higher risk of CNS toxicity than younger patients (16.3% vs. 7.4%; P <0.001). Immunophenotype (T-cell), initial CNS status as CNS III, and induction therapy (dexamethasone) were significant in univariate analyses but did not reach significance in the multivariate model, probably due to co-variation 20 . In agreement with Anastasopoulou et al, 21 older age is a risk factor for PRES, seizures, and MTX-induced CNS toxicity.…”

“…Immunophenotype (T-cell), initial CNS status as CNS III, and induction therapy (dexamethasone) were significant in univariate analyses but did not reach significance in the multivariate model, probably due to co-variation. 20 In agreement with Anastasopoulou et al, 21 older age is a risk factor for PRES, seizures, and MTX-induced CNS toxicity. Lowe et al 22 showed that hyperleukocytosis as an indicator of high-risk disease was significantly predictive of neurological complications with a significant P value of 0.006.…”

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

“…Logistic regression analysis identified baseline CNS leukaemic involvement to be a significant risk for developing MTX‐induced neurotoxicity. Although paediatric patients with CNS leukaemic involvement (CNS2/3) are at higher risk of CNS toxicity, its association with MTX‐induced neurotoxicity is not well established 3,19 . Intensification of both systemic and intra‐thecal chemoprophylaxis with uniform administration of HDMTx at 5 g/m 2 for HR/VHR might have contributed to more patients developing MTX neurotoxicity in our study cohort.…”

“…Although paediatric patients with CNS leukaemic involvement (CNS2/3) are at higher risk of CNS toxicity, its association with MTX-induced neurotoxicity is not well established. 3,19 Intensification of both systemic and intra-thecal chemoprophylaxis with uniform administration of HDMTx at 5 g/m 2 for HR/VHR might have contributed to more patients developing MTX neurotoxicity in our study cohort. However, direct neurotoxic effect of leukaemic blasts and methotrexate blasts interaction contributing to MTX neurotoxicity needs to be studied.…”

“…We conducted retrospective audit of medical records of all paediatric (≤14 years) acute lymphoblastic leukaemia/lymphoma patients treated between January 2018 and December 2022 (5 years) with institutional modified BFM-95 protocol (Table S1). High-risk (HR) arm was administered to T-cell phenotype, B-cell ALL with NCI high risk, significant organomegaly (liver or spleen ≥5 cm below the costal margin irrespective of age and weight), testicular involvement and CNS leukaemic involvement (CNS2/3) at presentation, t (1,19), poor prednisolone response, end induction bone marrow flow-cytometric minimal residual disease (BM-MRD) positivity (≥0.01%), mixed phenotypic acute leukaemia (MPAL) and LBL (irrespective of stage), who received HDMtx at 5 g/ m 2 as intravenous infusion over 24 h along with hydration, alkalinisation and injection folinic acid (15 mg/m 2 ) rescue beginning at 42 h after the start of HDMtx, continued every 6th hourly till serum MTX < 0.3 μmol/L during interim maintenance (protocol M). Very high-risk (VHR) arm of the protocol was given to B-ALL patients who were Philadelphia positive, Hypodiploid (Chr≤44), IAMP21, t (17,19), MLL rearrangement, induction failure and post-consolidation BM-MRD positivity (≥0.01%) with high-risk blocks (3)(4)(5)(6) containing HDMtx at 5 g/m 2 as 24-h infusion with injection folinic acid rescue as described earlier.…”