Background: Classic Hodgkin lymphoma (CHL) is a highly treatable lymphoid malignancy, characterized by rare neoplastic Hodgkin Reed–Sternberg cells (HRS-cells) embedded in a prominent reactive infiltrate. Despite current therapies, about 20% of patients relapse within five years of standard treatment. Identifying patients at risk of subsequent relapse will help develop novel therapeutic strategies for such high-risk patients.
Methods: Using multiparametric flow cytometric analysis, we retrospectively evaluated the impact of the proportion of HRS-cells; the proportion of HRS-cells with T-cell rosettes; proportions of T-cells, B-cells, neutrophils, and eosinophils; proportions of activated T-cells, and activated B-cells; and CD4:CD8 ratio on the likelihood of disease relapse in a cohort of 62 patients.
Results: The median follow-up period was 69.5 months. Patients >35 years of age had a significantly higher percentage of HRS-cells (P=0.017) and a significantly lower percentage of B cells (P=0.017). The nodular sclerosis subtype had a significantly higher percentage of B-cells (P=0.046) and activated B-cells (P=0.03). Patients who experienced disease relapse (DR) had a significantly lower percentage of rosetted HRS-cells as compared to patients who achieved sustained clinical remission (SCR) (P=0.022; Figure 1). Patients experiencing DR also had a marginally lower B-cell% (P=0.11), and higher neutrophil% (P=0.107) and eosinophil% (P=0.095). The proportion of SCR and DR subsets did not differ by histological subtypes, disease stage, or age-groups.
Conclusions: CHL demonstrates a prominent tumor microenvironment (TME) where HRS-cells and the TME result in HRS-cells receiving pro-survival signals and dampening the antitumor immune responses. In our study, patients who experienced DR had a lower proportion of HRS-cells rosetted by T-cells; we hypothesize that HRS-cells in biologically advanced/aggressive CHL are less dependent on its intimate contact or interactions with the T-cells for survival and growth. Likewise, a non-significant higher proportion of eosinophils and neutrophils in the TME of CHL patients who experienced DR was observed, possibly due to the ability of these cells to promote proliferation and growth of HRS-cells. Our study also identifies novel quantifiable biomarkers in CHL. Larger independent studies and multi-institutional studies are essential to validate our findings.
Jonathan Fromm, Claire Tang, Kikkeri N. Naresh