Date of Award

12-2019

Degree Name

Doctor of Philosophy (PhD)

Advisor(s)

LAURA E. MITCHELL

Second Advisor

MICHAEL SCHEURER

Third Advisor

AUSTIN BROWN

Abstract

Introduction: Polyethylene glycol (PEG)-asparaginase is one of the first-line drugs in pediatric ALL treatment. Although a complete and prolonged treatment with PEGasparaginase has been instrumental in improving the survival of ALL patients, it is associated with four common toxicities: hypersensitivity, hyperbilirubinemia, pancreatitis, and venous thromboembolism (VTE). PEG-asparaginase-related toxicities may require modifications and delays in treatment, which often leads to poor treatment outcomes. Previous studies of PEG-asparaginase-related toxicities have mainly focused on individual toxicities. Further, these studies were conducted in study populations which were predominantly self-reported non-Hispanic whites. Therefore, there is a gap in the knowledge regarding the cumulative burden of the toxicities in a multi-ethnic population and the role of genetic ancestry in the development of these toxicities. This study focused on the clinical and demographic factors influencing the incidence of individual and cumulative burden of PEG-asparaginase-related toxicities. Methods: Data from 548 newly diagnosed patients with ALL were analyzed to examine the association of clinical factors and self-reported race/ethnicity with individual and cumulative burden of PEG-asparaginaserelated toxicities. Using a novel approach of k-mode cluster analysis, we identified groups of patients with distinct toxicity profiles. From 170 patients who had genotype data available, we analyzed the role of Native American ancestry in the development of PEG-asparaginase related toxicities using multivariable logistic regression. Results: Older (>10 years) patients and those with higher BMI (overweight/obese) were at an increased risk of individual PEGasparaginase-related hyperbilirubinemia, pancreatitis, and VTE; and were at a higher risk of co-occurring toxicities. Hypersensitivity was more likely in patients treated with high/very high-risk treatment protocols compared to low/standard risk treatment protocols. Although we did not find a significant association with self-reported or genetically defined race/ethnicity and PEG-asparaginase-related toxicities, the proportion of Native American genetic ancestry increased with an increasing number of toxicities. Conclusion: The incidence and cumulative burden of PEG-asparaginase-related toxicities are associated with age at diagnosis, BMI, and ALL risk group. More research with a larger more diverse population is necessary to improve the risk-benefit ratio of treatment with PEGasparaginase.

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