Pediatric Resident Golisano Children's Hospital at The University of Rochester Medical Center Rochester, New York, United States
Background: Pediatric Hodgkin lymphoma (HL) has a favorable prognosis, but survival after relapse is suboptimal. High-throughput sequencing (HTS) of clonal immunoglobulin (Ig) rearrangements has had revolutionary impact on measuring treatment response for relapse prediction in other B cell-derived malignancies (Wood et al., 2018), but there are no comparable methods for pediatric HL. HL staging and response evaluation rely on imaging alone (i.e. CT and PET). However, children with HL may benefit from new ways to personalize treatment by molecular response assessment to improve outcomes and avoid treatment-related toxicity. HTS monitoring relies on clonally expanded rearrangements of Ig heavy chain (IgH) variable, diversity, and joining genes, which serve as dominant sequences by which malignant cells can be tracked. The characteristic malignant Reed Sternberg cells of HL also derive from B cell origin and have been reported to also contain clonal IgH rearrangements (Marafioti et al., 2000), but the clinical utility of IgH HTS in HL has not been explored. Objective: The goals of this project are to test the feasibility of Ig HTS in pediatric HL for a) minimal disseminated disease detection and b) monitoring therapy response and/or surveillance. As a first step, we are measuring the incidence of clonal IgH rearrangements via HTS of pre-treatment tumor tissue from 41 patients with HL. Design/Methods: We performed IgH HTS via an IRB-reviewed protocol on 41 pediatric HL tumor specimens via our established methods (Fries et al., 2020). We defined clonal IgH sequences by their shared complementarity determining region 3 sequence comprising ≥5% of IgH reads. In our preliminary analysis of 5 patients thus far, we have identified a clonal IgH in 2 (40%). If IgH clones are prevalent in HL, we will then test for circulating tumor DNA (ctDNA) detectable by the IgH clonal signature in blood samples from HL patients. This analysis will take 4 months and inform the feasibility of IgH HTS as a means of non-invasive molecular treatment response assessment and disease surveillance in pediatric HL.
