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Genetic risk and immune dysregulation of classic Hodgkin lymphoma transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma: a multicentric study

Yan, M.; Parikh, S. A.; Sampaio De Melo, M. K.; Hampel, P. J.; Aleynick, N.; Chan, A.; Eren, O. C.; Lopez, K.; Cohen, A.; Roshal, M.; Lim, M. S.; Boiocchi, L.; Dogan, A.; Zhang, Y.; Sinha, S.; Rabe, K. G.; Kay, N. E.; Jaffe, E. S.; King, R. L.; Xiao, W.

2026-05-20 hematology
10.64898/2026.05.11.26352584 medRxiv
Show 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). 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 CHL-RT displayed immune evasion phenotypes similar to de novo CHL, though PD-L1 expression was lower in type 1 cases. PD-L1/PD-L2 gain/polysomy were frequent (83.3%). CLL/SLL with CHL-RT harbored increased mutations in XPO1, FBXW7, BIRC3, TRAF3, and HLA-A versus reference CLL/SLL. Similar mutational profiles, demographics, and survival outcomes support a biological continuum between type 1 and type 2 CHL-RT, with distinct genetic features in CLL/SLL predisposing to CHL transformation.

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