Introduction: While modern therapy has led to high survival rates for acute lymphoblastic leukemia (ALL), treatment can lead to adverse events (AEs) and significant morbidity. Infection is one of the most common AEs. Development of infection can lead to unplanned hospitalizations, cause delays or changes in therapy, and even be fatal. However, not all patients develop infections during therapy, and infection rates can vary significantly between individuals. It is unclear if there are patient-specific factors that lead to increased risk of developing infections. Although the causative pathways are not fully elucidated, there is a growing body of literature suggesting that dopamine plays an important role in immunoregulation and immune cell function. Dopamine is metabolized by several enzymes, including catechol-O-methyltransferase (COMT). Higher COMT activity has been associated with lower extracellular dopamine. Given the potential association between dopamine metabolism and development of infections, this study aimed to evaluate if polymorphisms in COMT genes and predicted COMT activity influence rates of development of infectious AEs in children undergoing treatment for ALL.

Methods: This retrospective cohort study included patients aged 1-21 years diagnosed with ALL at Children's Healthcare of Atlanta (CHOA) from 1/2018 through 5/2022. Manual chart abstraction identified the presence and grade of infections per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 definitions during all courses of upfront therapy with available electronic health record (EHR) data at CHOA. Age, sex, race, and ethnicity were extracted from the EHR. Patients had OneOme RightMed genetic testing sent at the time of ALL diagnosis to identify COMT polymorphisms. Patients with GG diplotype in SNP rs4680 were considered high COMT activity and GA or AA diplotypes were considered intermediate/low COMT activity. Pearson's Chi-squared test determined differences in the proportion of patients who had at least one infection or high-grade (CTCAE grade 3+) infection by COMT activity. Negative binomial regression models were used to determine if rates over therapy (total number of infections relative to days on therapy) varied by COMT activity. Statistical analyses were performed in R version 4.4.0.

Results: Of the 331 patients in the cohort, 142 (44%) were female, 228 (69%) where White, 59 (18%) were Black, and 94 (29%) were Hispanic/Latino. Of the 331, 108 (33%) patients had high COMT activity and 223 (67%) had intermediate/low activity. COMT activity differed by race such that a higher proportion of White patients had intermediate/low COMT activity compared to Black patients (75% vs 44%, p< .001). Infections were common: 245 (74%) patients had at least one infection during therapy and 171 (52%) patients experienced at least one high grade infection. A higher proportion of patients with intermediate/low COMT activity had at least one infection compared to patients with high activity (78% vs 67%, p = 0.034). The proportion of patients who experienced at least one high-grade infection did not vary based on diplotype (55% vs 45%, p = 0.11). Neither rates of infection throughout therapy nor rates of high-grade infection varied by diplotype (p=0.141 and p=0.893, respectively). The incident rate ratios (IRRs) of 1.21 and 1.02 for infection rate and high-grade infection rate (respectively) suggest a marginal, non-significant increase in infection rates associated with intermediate/low COMT activity compared to high COMT activity.

Conclusions: As expected, development of at least one infection during therapy for childhood ALL was common. Patients with altered COMT activity were at higher risk of developing an infection of any grade during therapy, although COMT diplotype was not associated with development of a greater total number or higher grade of infections. These results begin to elucidate why some patients develop infections during therapy and others do not. Work is ongoing to evaluate if intermediate/low COMT activity is associated with development of certain types of infections or pathogens and if demographic factors mediate results. Future directions also include incorporation of use of prophylaxis after development of first infection as this may impact the results related to the total number of infections patients developed during therapy.

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2025
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