Understanding the Associations between High-Dose Methotrexate Pharmacokinetics and the Risk of Adverse Events in Children and Adolescents with Down Syndrome Associated High-Risk Acute Lymphoblastic Leukemia
Authors: Westmoreland Kate D. , Taylor Zachary L , Miller Tamara P. , Chavana Ashley , Rabin Karen R , Brown Austin L , Bernhardt Melanie Brooke , Schafer Eric S. , O'Brien Maureen M. , Castellino Sharon M. , Ramsey Laura B. 
Published: December 2024

Introduction: Individuals with Down syndrome (DS) have a 20-fold increased risk of developing acute lymphoblastic leukemia (ALL). Clinically, DS-associated ALL (DS-ALL) has poorer outcomes including lower survival, high risk of relapse, and increased risk of certain treatment-related adverse events (AEs). High-dose methotrexate (HDMTX) is used to treat high-risk DS-ALL but individuals with DS have a known increased risk of MTX-related toxicity due to alterations in metabolic enzymes and transporters encoded on chromosome 21. To counter this increased risk, some current high-risk DS-ALL protocols reduce the dose of HDMTX (2 g/m2) compared to non-DS-ALL protocols (5 g/m2). However, more evidence is needed to further understand the MTX pharmacokinetics (PK)-toxicity relationship and optimize HDMTX dosing in DS-ALL to balance risk for AEs and antileukemic effect. The goal of this study is to compare HDMTX PK and AEs in those with DS-ALL compared to those with non-DS-ALL.
Methods: This retrospective cohort study included data from all pediatric, adolescent, and young adult patients treated for ALL at Children's Healthcare of Atlanta, Texas Children's Hospital, or Cincinnati Children's Hospital Medical Center from January 2010 through December 2020 who received ≥1 dose of HDMTX. Individuals with DS were treated with various DS-specific regimens. PK data were analyzed in NONMEM using a 3-compartment model to estimate PK parameters. AEs following each HDMTX infusion were identified by manual chart review and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Chi-squared test with odds ratio was used to compare the frequencies for each AE. Mann-Whitney test was used to compare continuous data between DS-ALL and non-DS-ALL.
Results: Of 1,126 individuals with ALL who received 4,314 administrations of HDMTX, 17 individuals (1.5%) had DS and 63 (1.4%) of HDMTX administrations were in those with DS. In the DS cohort, 12 (70%) were male, median age was 10 years (interquartile range (IQR) 6-15 years), 9 (53%) were Hispanic, and race was identified as 14 (82%) White, 2 (12%) American Indian, and 1 (6%) Middle Eastern. As expected with DS-ALL regimens, administrations for DS-ALL patients had a lower dose of HDMTX [median 1.5 g/m2 (IQR 1.4-2.0 g/m2)] than individuals with non-DS-ALL [median 4.9 g/m2 (IQR 4.7-5.0 g/m2), p&lt;0.01]. Despite the lower dose, HDMTX administrations for children with DS had significantly higher frequencies of total AEs [54 (85%) for DS-ALL vs 2,834 (66%) for non-DS-ALL, p&lt;0.01], mucositis of any grade [38 (60%) for DS-ALL vs 1,782 (41%) for non-DS-ALL, p&lt;0.01], and ≥ grade 3 mucositis [15 (24%) for DS-ALL vs 442 (10%) for non-DS-ALL, p&lt;0.01]. There were no differences in the frequency of ≥ grade 3 infection [6 (9%) for DS-ALL vs 251 (6%) for non-DS-ALL, p=0.39], nephrotoxicity [≥ grade 2 serum creatinine was 2 (3%) for DS-ALL vs 348 (8%) for non-DS-ALL, p=0.15], hepatotoxicity [≥ grade 3 total bilirubin was 2 (3%) for DS-ALL vs 45 (1%) for non-DS-ALL, p=0.23], or neurotoxicity of any grade [0 for DS-ALL vs 51 (1%) for non-DS-ALL, p=0.58]. There were more frequent dose reductions for DS-ALL [30 (47%)] compared to non-DS-ALL [282 (6.5%), p&lt;0.01] HDMTX administrations. The PK clearance of HDMTX was 14% slower in DS-ALL administrations [7.2 L/h/1.73m2 (IQR 6.3-7.8 L/h/1.73m2)] compared to non-DS-ALL administrations [8.4 L/h/1.73m2 (IQR 7.5-9.3 L/h/1.73m2), p&lt;0.01].
Conclusion: These data illustrate that individuals with DS-ALL have slower PK clearance of HDMTX and are at a greater risk of HDMTX-induced AEs despite doses lower than non-DS-ALL. Optimization of dosing in DS-ALL is critical to ensure that the dose can achieve adequate drug exposure while mitigating these toxicities. Further modeling and simulation can establish optimal dosing strategies in DS-ALL.