SOHO State of the Art Updates and Next Questions | Management of Most Difficult Cases of Chronic Lymphocytic Leukemia: Relapse After Both BTK and BCL2 Inhibition and Richter Transformation

The introduction of targeted therapies in chronic lymphocytic leukemia (CLL) has ushered in a new era in which patients achieve better control of their disease, survive longer, and experience fewer toxicities than before. Despite this progress, a subgroup of patients with CLL will develop resistance to both Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 inhibitors. In addition, a subgroup of CLL cases will transform into aggressive lymphoma - called Richter transformation - either before or during targeted therapy. These two subgroups of patients have a poor prognosis, and available therapies lead to long-term remission in only a minority of patients. In this paper, two cases are presented that are reflective of these difficult scenarios. In the first case, a patient with CLL, complex karyotype, del 17p, and a mutation in TP53 experiences progression after ibrutinib, venetoclax, bendamustine, rituximab, and idelalisib. In the second case, a patient with CLL and del 17p develops a Richter transformation to diffuse large B-cell lymphoma after treatment with obinutuzumab, chlorambucil, ibrutinib, venetoclax, and idelalisib. The aggressive lymphoma is refractory to chemoimmunotherapy, and she expires. The literature pertaining to these two scenarios is reviewed, including the role of available targeted therapies, chemoimmunotherapy, and hematopoietic cell transplantation. Emerging novel therapies, including reversible BTK inhibitors and CAR T cell therapy, are discussed.