OAI-003 - UNDERSTANDING THE ASSOCIATIONS BETWEEN HIGH-DOSE METHOTREXATE PHARMACOKINETICS AND THE RISK OF TOXICITIES IN INFANTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA.

Z. Taylor¹, T. Miller², N. DeGroote³, S. Board⁴, E. Poweleit⁴, A. Chavana⁵, N. Ambrosino⁴, A. Weisnicht⁵, A. Brown⁵, B. Bernhardt⁶, E. Schafer⁵, M. O'Brien⁴, S. Castellino⁷, L. Ramsey⁸; ¹Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, ²Department of Pediatrics, Emory University School of Medicine, , , ³Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, , , ⁴Cincinnati Children's Hospital Medical Center, , , ⁵Baylor College of Medicine, , , ⁶St. Jude's Children's Research Hospital, , , ⁷Emory Univ School of Medicine, , , ⁸Children's Mercy, , .

Background: High-dose methotrexate (HDMTX) is used to treat infants with acute lymphoblastic leukemia (ALL). Infants undergo rapid physiological changes that can alter the disposition of methotrexate, which could contribute to increased toxicities. Current infant protocols (4 g/m2) reduce the dose of HDMTX compared to non-infant ALL protocols (5 g/m2) in hopes of decreasing the risk of HDMTX-induced toxicities in infant patients; however, more evidence is needed to further understand the PK-toxicity relationship and optimize HDMTX dosing in infants. The goal of this study is to compare the PK and toxicity in infants with ALL compared to non-infants with ALL.

Methods: PK and toxicity data were retrospectively collected for infant, pediatric, and adolescent-young adult patients who received HDMTX for the treatment of ALL at 3 children’s hospitals. Infants were defined as ≤ 1 year of age at the time of treatment or were enrolled on an infant-specific protocol. PK data was analyzed in NONMEM using a 3-compartment model to estimate PK parameters. Toxicities following each HDMTX infusion were identified by manual chart review and graded according to the CTCAE v5.0. Fisher’s exact test with odds ratio was used to compare the frequencies for each toxicity. Mann-Whitney test was used to compare continuous data between infants and non-infants.

Results: A total of 172 (3.95%) administrations and 50 (4.4%) patients were identified as infants in our ALL population. Despite the lower dose, infant administrations had significantly higher frequencies of Grade 4 neutropenia, Grade 3+ thrombocytopenia, and any grade mucositis, which resulted in a higher use of dose reductions (Figure) compared to non-infant ALL administrations. Infant administrations were also associated with reduced clearance (7.8 L/h/1.73m2) compared to non-infant administrations (8.4 L/h/1.73m2, p < 0.0001). Infants with documented mucositis had 7% slower clearance (p = 0.03) compared to infants with no documented mucositis.

Conclusion: These data illustrate that infants are at a greater risk of HDMTX-induced toxicity despite doses lower than older children. Optimization of dosing in infants 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 infants with ALL.