The biology and evolution of Richter transformation in chronic lymphocytic leukemia

Richter transformation (RT) is a relatively rare but clinically challenging event in the natural history of chronic lymphocytic leukemia (CLL), characterized by the abrupt transformation of CLL into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). RT is diagnosed through histopathological confirmation, often prompted by clinical signs such as rapid lymph node enlargement, B symptoms, and elevated metabolic activity on PET-CT. Its incidence ranges from 2 % to 10 % over the CLL course, with higher risk in patients harboring specific high-risk (immuno)genetic features. Clonal relationship to the original CLL clone is crucial to understand the biology of the disease and may guide treatment decisions and anticipate RT evolution. Biologically, RT is driven by genomic instability, loss of cell cycle control, MYC activation, NOTCH alterations, and immune evasion mechanisms, including PD-1/PD-L1 upregulation. Transformation timing varies, occurring either early or late in the CLL course, may be preceded by a phase of accelerated disease, and their seeds may be traced back years before their clinical manifestation. Preclinical models, including genetically engineered mice and patient-derived xenografts, have been instrumental in elucidating the molecular underpinnings of RT, assess its interactions with the tumor microenvironment -including through the B-cell receptor-, and offer platforms for testing novel therapeutic strategies. In this review, we will deepen into the biology and evolution of DLBCL-type RT, revisiting recent publications and discussing new avenues for research in this paradigmatic evolution of CLL.