Richter's transformation, the progression of chronic lymphocytic leukemia into an aggressive lymphoma, affects an estimated 2% to 10% of CLL patients and is overwhelmingly of the diffuse large B-cell lymphoma subtype. Outcomes with standard R-CHOP chemoimmunotherapy are poor, with median survival of roughly 9 to 12 months, a reality acknowledged by the European Research Initiative on CLL in its consensus statement. Experts note that while R-CHOP remains the de facto standard, there is broad agreement that it is not good enough.
Treatment is therefore shifting toward clinical trials and combination strategies. At MD Anderson, Nitin Jain highlighted ongoing studies pairing venetoclax or BTK inhibitors with R-CHOP, as well as checkpoint inhibitors, bispecific antibodies, and chemotherapy-free regimens. Adam Kittai of NYU Langone favors pola-R-CHP based on the POLARIX data, and points to CAR T-cell therapy as a promising avenue. Early-phase results have been mixed but encouraging: venetoclax plus R-CHOP produced complete responses in about half of patients, while zanubrutinib plus tislelizumab achieved a 58.3% overall response rate, and the bispecific antibody epcoritamab showed a 60% response rate with 50% complete responses.
Allogeneic stem cell transplant remains the only established path to prolonged survival after deep remission, but only about 10% of patients are fit enough to reach it. That gap is driving the first phase III trial in previously untreated Richter's transformation, SWOG S2504, which is testing pirtobrutinib plus R-CHOP against R-CHOP alone. Until better options are proven, experts say enrollment in clinical trials should be the preferred approach for eligible patients.