Assay Development and Prognostic Model for Predicting Early Clinical Failure in Follicular Lymphoma

ABSTRACT Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (NHL) subtype with a highly variable clinical course. While asymptomatic and low-tumor burden patients can initially be managed by observation, symptomatic patients and patients with high-tumor burden disease are typically managed at

diagnosis with immunochemotherapy (IC). We have shown that IC-treated FL patients who achieve event- free (i.e., no disease progression or re-treatment) status at 24 months after diagnosis (EFS24) have a subsequent life expectancy of the background age and sex-matched general population (thus doing well on

standard of care), while those who fail to achieve EFS24 have aggressive disease with poor outcomes and represent a patient population with an unmet need. However, there is limited ability to identify this patient population at diagnosis. Building off our prior genome-wide biomarker discovery efforts, we have developed

and internally validated a digital gene expression signature in formalin-fixed, paraffin-embedded tissue (FFPET) biopsies that predicts early clinical failure (defined as failing to achieve EFS24) in IC-treated FL using the NanoString nCounter platform, which we call FL24Cx (for FL EFS24 status classifier). We propose

to use the UH2/UH3 mechanism to refine and validate our gene expression assay for use in routinely collected FFPET using a proven, clinical grade technology with which we have extensive experience. The goals of the UH2/UH3 proposal are to 1) analytically validate FL24Cx (UH2 Phase) and 2) clinically

validate FL24Cx (UH3 Phase). In the UH2 Phase, we will challenge our preliminary tissue-based assay and algorithm, evaluate its analytical performance, and adjust as needed to optimize its prognostic power. Using our extensive test development experience, we will migrate the resulting locked assay to a clinical grade

platform with rapid turnaround time. We will follow the federal guidelines for laboratory developed tests in a CAP-CLIA certified laboratory, so that the resulting test will be suitable for use in clinical trials and the clinic. In the UH3 Phase, we will rigorously validate FL24Cx in IC-treated FL patients. This will be conducted in both

the geographically and racially/ethnically diverse Lymphoma Epidemiology of Outcomes (LEO) observational cohort study (NCT02736357) and in the large Southwest Oncology Group (SWOG) phase III clinical trial S0016 (NCT00006721). We will also evaluate FL24Cx in two additional NCTN clinical trials in FL.

Furthermore, we will evaluate FL24Cx performance in subgroups defined on initial treatment approach, age, race/ethnicity, and other clinical factors as well as incorporate use of FL24Cx in the context of clinical models, further enhancing clinical utility. This application is highly responsive to PAR-20-313 (Assay Validation for

High Quality Markers for NCI-supported Clinical Trials) and at the completion of this study, we will have rigorously validated FL24Cx to identify patients at high risk of early clinical failure, which is a missing clinical tool to rapidly conduct informative trials and effectively manage FL patients in the clinic.