Abstract

AbstractClassical Hodgkin lymphoma (cHL) is a common malignancy in children and adolescents. Although cHL is highly curable, treatment with chemotherapy and radiation often come at the cost of long-term toxicity and morbidity. Effective risk-stratification tools are needed to tailor therapy. Here, we used gene expression profiling (GEP) to investigate tumor microenvironment (TME) biology, to determine molecular correlates of treatment failure, and to develop an outcome model prognostic for pediatric cHL. A total of 246 formalin-fixed, paraffin-embedded tissue biopsies from patients enrolled in the Children's Oncology Group trial AHOD0031 were used for GEP and compared with adult cHL data. Eosinophil, B-cell, and mast cell signatures were enriched in children, whereas macrophage and stromal signatures were more prominent in adults. Concordantly, a previously published model for overall survival prediction in adult cHL did not validate in pediatric cHL. Therefore, we developed a 9-cellular component model reflecting TME composition to predict event-free survival (EFS). In an independent validation cohort, we observed a significant difference in weighted 5-year EFS between high-risk and low-risk groups (75.2% vs 90.3%; log-rank P = .0138) independent of interim response, stage, fever, and albumin. We demonstrate unique disease biology in children and adolescents that can be harnessed for risk-stratification at diagnosis. This trial was registered at www.clinicaltrials.gov as #NCT00025259.

Highlights

  • Classical Hodgkin lymphoma is one of the most common malignancies in children and adolescents.[1]

  • We report the development of a gene expression–based model using cellular component scores, which identifies a subset of pediatric patients at high risk of treatment failure in an international, multisite, randomized clinical trial

  • To test the performance of our previously published adult Classical Hodgkin lymphoma (cHL) overall survival (OS) prognostic model trained using cases from the Intergroup E2496 trial,[5] we applied the 23-gene model to the training cohort of pediatric patients from the Children’s Oncology Group (COG) trial AHOD0031.10 According to this model, 51 pediatric patients were classified as “high risk” and 124 as “low risk”

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Summary

KEY POINTS

Gene signatures reflecting tumor microenvironment composition correlate with event-free survival of patients in the COG AHOD0031 trial. An outcome prognostic model risk stratifies patients according to 5-year event-free survival. We used gene expression profiling (GEP) to investigate tumor microenvironment (TME) biology, to determine molecular correlates of treatment failure, and to develop an outcome model prognostic for pediatric cHL. A total of 246 formalinfixed, paraffin-embedded tissue biopsies from patients enrolled in the Children’s Oncology Group trial AHOD0031 were used for GEP and compared with adult cHL data. We developed a 9-cellular component model reflecting TME composition to predict event-free survival (EFS). We demonstrate unique disease biology in children and adolescents that can be harnessed for risk-stratification at diagnosis. This trial was registered at www.clinicaltrials.gov as

Introduction
Mast 2 1 0 Th2 –1 –2 –3 HRS
Results and discussion
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