Immunogenomic characterization of classic Hodgkin lymphoma variant of Richter transformation reveals shared biology with de novo classic Hodgkin lymphoma

Abstract

Richter transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) into classic Hodgkin lymphoma (CHL-RT) is rare and remains incompletely understood. Two histologic subtypes are recognized: type 1 (CLL/SLL with scattered Hodgkin/Reed-Sternberg (HRS) cells) and type 2 (HRS cells within a polymorphous inflammatory background). Previous studies suggest that type 1 represents an earlier stage of type 2 and that both may be clonally related to the underlying CLL/SLL. However, the immune evasion phenotype of HRS cells in CHL-RT and the genetic features of precursor CLL/SLL remain incompletely defined. In this multi-institutional study of 77 patients with CHL-RT (27 type 1 and 50 type 2), we characterized immune evasion markers, PD-L1/PD-L2 copy number alterations, tumor microenvironment, and performed targeted next-generation sequencing on 37 CLL/SLL samples. HRS cells in both CHL-RT subtypes showed immune evasion features largely resembling de novo CHL. However, PD-L1 expression was less frequent in type 1 than type 2 CHL-RT (53.3% vs. 100%, p<0.001) and de novo CHL (85.7%, p=0.009). Gain/polysomy of PD-L1/PD-L2 was common (83.3%), whereas amplification was uncommon (8.3%). Type 2 CHL-RT demonstrated a suppressive tumor microenvironment enriched in CTLA-4+ T cells, similar to de novo CHL. CLL/SLL with CHL-RT showed increased frequencies of mutations involving XPO1, FBXW7, BIRC3, TRAF3, and HLA-A versus reference CLL/SLL. No significant mutational differences were observed between CLL/SLL associated with type 1 versus type 2 CHL-RT, supporting a biological continuum. Overall, CHL-RT shares immune evasion mechanisms with de novo CHL and may arise from CLL/SLL with distinct genetic susceptibilities.