Impact of Ethnicity on Toxicities Associated with Dose Escalating Methotrexate in Pediatric Patients with Acute Lymphoblastic Leukemia

Background:

Epidemiologic studies in pediatric oncology have demonstrated disparities in Acute Lymphoblastic Leukemia (ALL) outcomes and survival for various ethnic minorities including Hispanic patients. While differences between outcomes and survival of different racial/ethnic groups in pediatric ALL is well documented, the impact of race/ethnicity on the incidence of methotrexate related toxicities in this population has not been fully described.

Methotrexate, a mainstay of pediatric ALL regimens, has the potential to cause a variety of toxicities including myelosuppression, hepatic injury, acute kidney injury (AKI), mucositis, and central nervous system (CNS) injury. Recent literature suggests that Hispanic ethnicity may be associated with an increased risk of methotrexate toxicity, specifically neurotoxicity (Giordano (2017)). This project evaluated ethnicity associated with the incidence of methotrexate toxicities that could lead to dose reduction or delays in therapy such as grade 3 or 4 myelosuppression, hepatic injury, nephrotoxicity, and mucositis in patients receiving dose escalating methotrexate.

Methods:

A single-center, retrospective chart review was conducted at a 224 bed pediatric hospital. Patients were eligible for inclusion if they had a diagnosis of ALL and received intravenous (IV) dose escalating methotrexate between August 1, 2011 and March 31, 2019. Electronic medical records were used to identify eligible patients using medication identification numbers cross referenced with diagnosis codes. Toxicity data was collected to evaluate interruption in dose escalation of IV methotrexate due to grade 3 or 4 liver dysfunction, nephrotoxicity, mucositis, neutropenia, or thrombocytopenia. The primary outcome was percentage of doses which resulted in a dose-limiting toxicity. A two-sample t-test was performed for the primary outcome between Hispanic white and non-Hispanic white patients.

Results:

Of the 64 patients initially identified, 60 patients were included for final analysis. Two patients were excluded due to a diagnosis of Acute Biphenotypic Leukemia, one patient did not receive IV methotrexate per protocol due to delay in therapy and was subsequently ineligible, and one patient did not receive dose escalating methotrexate per protocol for unspecified reasons. A total of 460 doses were given to 60 patients. The sample size consisted of 22 non-Hispanic white, 21 Hispanic white, 9 Black, 3 Hispanic black, 1 Asian, 1 multi-racial, and 3 patients with unspecified ethnicity. The percentage of patients who experienced at least one toxicity was 58.3% (35 patients). The most common grade 3 or 4 toxicity experienced per dose was thrombocytopenia (6.5%), followed by neutropenia (6.3%), mucositis (1.3%), liver dysfunction (0.22%), and no patient experienced nephrotoxicity. When comparing the rate of toxicity between Hispanic and non-Hispanic patients, Hispanic patients experienced toxicity at a rate of 17.4% per dose compared to non-Hispanic patients at 12.2% per dose, although this was not a statistical significant difference (p = 0.61).

Hispanic white and non-Hispanic white patients received the same amount of doses at 165 doses of IV methotrexate. Hispanic white patients experienced a toxicity rate of 19.4% per dose compared to 12.1% per dose in the non-Hispanic white patients. Hispanic white patients experience more thrombocytopenia, where as non-Hispanic white patients experienced more neutropenia.

Although not statistically significant possibly due to small sample size, Hispanic ethnicity was associated with higher rates of methotrexate toxicities. Understanding the impact of methotrexate toxicity in respect to ethnicity is important to improving treatment outcomes for pediatric patients with ALL. More robust studies with a larger sample size are warranted to explore the potential impact of ethnicity on tolerability of this regimen.