UBC Theses and Dissertations
The biology and clinical significance of the microenvironment of pediatric Hodgkin lymphoma Johnston, Rebecca Lea
Hodgkin lymphoma (HL) is a highly curable malignancy of the pediatric population with 5-year overall survival > 96%. However, dose-intensified chemotherapy regimens in combination with radiation therapy come at a high cost in the form of long-term toxicity and morbidity. Current clinical trials aim to achieve the optimal equilibrium between high survival rates and limiting treatment-related toxicity. However, risk stratification in pediatric HL is limited to the use of clinical factors, as no robust molecular-based biomarkers for treatment outcome exist. The aim of our study was to develop an expression-based prognostic model to tailor first-line therapy in pediatric HL, and to explore biological differences between pediatric and adult HL. We obtained a training cohort of 175 patients with pre-treatment formalin-fixed paraffin-embedded tissue (FFPET) biopsies from the Children’s Oncology Group clinical trial AHOD0031, and determined expression levels of 784 genes using NanoString technology. A model for event free survival (EFS) separating patients into low- and high-risk groups was generated using Cox regression, and subsequently applied to an independent validation cohort of 71 patients enriched for events from the same trial. We developed a 9-cellular component model based on tumour microenvironment signatures to predict EFS in pediatric HL patients. Application of the model to the validation cohort identified a significant difference in 5-year EFS between high- and low-risk groups (75.7% vs. 90.5%, respectively; weighted log-rank p-value = 0.0138). Additionally, we utilized gene expression profiles of 290 pre-treatment FFPET biopsies from adult HL patients enrolled in the E2496 Intergroup trial to perform differential expression analysis and Spearman correlation between age groups. We discovered that unique microenvironment signatures are associated with age. Specifically, we revealed that eosinophil, B-cell, and mast cell signatures are more abundant in younger patients, and macrophage and stroma cell signatures are more pronounced in older patients. An expression-based prognostic model of EFS is a clinically relevant tool for pediatric HL patients allowing refinement of risk stratification at diagnosis. To investigate the utility of the 9-cellular component EFS model, future studies should incorporate the model into clinical trial designs.
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