Comparison of Severe Toxicities Following High Dose Methotrexate Administration By Demographics and over Time in Pediatric Patients with Acute Lymphoblastic Leukemia
Authors: Miller Tamara P. , DeGroote Nicholas P. , Pommert Lauren , Awoniyi Oluwafunbi , Board Sarah , Ugboh Ngozi , Joshi Vivek , Ambrosino Nicholas , Weisnicht Allison , Hsiao Heidi , Bernhardt Melanie Brooke , Schafer Eric S , O'Brien Maureen M. , Castellino Sharon M. , Ramsey Laura B. 
Published: November 2021

Background: Methotrexate (MTX) is a cornerstone of therapy for pediatric patients with acute lymphoblastic leukemia (ALL). Administration of high dose (HD) MTX requires hospitalization and concurrent intravenous fluids and leucovorin while awaiting drug excretion. HDMTX has been associated with acute adverse events (AEs), such as mucositis, neurotoxicity, and myelosuppression, that can impact quality of life and ability to administer subsequent chemotherapy. There are limited data evaluating differences in AEs after HDMTX among demographic groups.

Objective: The objective of this study was to describe AEs for patients receiving HDMTX (defined as &gt;500 mg/m2 to account for dose reductions from protocol dosing) and to compare rates by age, race, ethnicity and dose number using a multicenter cohort.

Methods: A multi-center retrospective study collected data on pediatric ALL patients ages 0-21 years at diagnosis who received at least one dose of HDMTX at Children's Healthcare of Atlanta or Cincinnati Children's Hospital Medical Center from January 2010 through December 2020. Demographic (age, sex, race, ethnicity) and clinical (vital status, Down Syndrome, HDMTX doses) variables were manually abstracted from the electronic medical record. Algorithms were developed a priori based on Common Terminology Criteria for Adverse Events v5 to identify the presence and grade of targeted AEs after HDMTX administration. The following AEs were abstracted for the time period from each HDMTX dose until the next HDMTX or other chemotherapy administration: mucositis, neurotoxicity, neutropenia, and thrombocytopenia. Only grade 4 neutropenia and grades 3-4 thrombocytopenia were collected. Institutional review board approval was obtained at each site. Descriptive and inferential statistics, including chi-square, Fisher's exact test, and generalized estimating equations (GEE) as appropriate, were calculated to evaluate differences in AEs by dichotomized age (&lt;10, 10+), race, ethnicity, and HDMTX administration number. All analyses were performed using SAS Enterprise Guide v7.1.

Results: Across sites, 543 patients with ALL patients received HDMTX (2064 administrations). The median age at first HDMTX was 8.0 years (0.1-21.0); 230 (42.4%) were female, 381 (70.2%) were White, and 441 (81.2%) were Non-Hispanic or Latino (Table 1). The median number of HDMTX administrations was 4.0 (Range 1-10). In total, 469 (86.4%) patients had at least one AE. Mucositis occurred in 386 (71.1%) patients, grade 4 neutropenia occurred in 243 (50.1%) and grade 3-4 thrombocytopenia occurred in 156 (32.2%, Table 2). Mucositis, neurotoxicity, and thrombocytopenia were significantly more likely in patients 10+ years (p=0.02, p&lt;0.01, p&lt;0.01, respectively, Table 2). There were no significant differences in AE rates by race or ethnicity. Table 3 describes percentages of administrations with each AE grade. Half of HDMTX administrations had at least one AE. AE rates decreased significantly from first to fourth administration (67.5% of first and 33.0% of fourth administrations with at least one AE, p&lt;0.01). Rates of mucositis and neurotoxicity individually decreased over administrations (p&lt;0.01, Table 3).

Conclusion: AEs after administration of HDMTX are common, with 86% of patients experiencing at least one AE after receipt of HDMTX and half of administrations leading to at least one AE. Greater than half of patients experienced mucositis and neutropenia. Older patients experienced significantly more mucositis, neurotoxicity, and thrombocytopenia. Unsurprisingly, we found that overall the rate of AEs was highest after the first HDMTX administration and decreased significantly across doses, which is likely due to dose reductions in HDMTX or concurrent antimetabolite therapy and to increased supportive care (hydration and leucovorin) after experience of an AE. Chart abstraction is ongoing at a third hospital that will increase the sample size of patients, particularly those of Hispanic/Latino ethnicity, to delineate potential differences by race and ethnicity. In addition, current analyses are evaluating the impact of supportive care and dosing changes between administrations on the burden of HDMTX-related AEs and differences by age. The results of this study will provide valuable data regarding who is at highest risk for AEs and can be used to tailor supportive care during this potentially toxic chemotherapy.

Figure 1 Figure 1.

Disclosures

Bernhardt: Bristol Myers Squibb: Research Funding; BTG International: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Jazz Pharmaceuticals: Consultancy; Mesoblast: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. O'Brien: Jazz: Honoraria; Pfizer: Honoraria, Research Funding. Ramsey: BTG Specialty Pharmaceuticals: Honoraria, Research Funding.