Novel Approaches for the Treatment of Patients with Richter's Syndrome

Abstract

In the last 10-15 years, the way to treat cancers has dramatically changed towards precision medicine approaches. These treatment options are mainly based on selective targeting against signaling pathways critical for or detrimentally activated in cancer cells in cancer cells, as well as exploiting molecules that are specifically expressed on neoplastic cells, also known as tumor-associated antigens. These considerations hold true also in the hematological field where a plethora of novel targeted agents have reached patients' bedside, significantly improving clinical responses. Chronic lymphocytic leukemia (CLL) is an example of how targeted therapies, such as BTK, PI3K, or Bcl-2 inhibitors as well as anti-CD20 antibodies, have improved patients' management, even when adopted as frontline treatment. However, these advancements do not apply to Richter's syndrome (RS), the transformation of CLL into a very aggressive and fatal lymphoma, occurring in 2-10% of patients. RS is usually a fast-growing lymphoma of the diffuse large B cell or the Hodgkin's variant, with a dismal prognosis. Despite advancements in depicting and understanding the genetic background of RS and its pathogenesis, no significant clinical results have been registered. In the last couple of years, several studies have started to investigate the impact of novel drugs or drug combinations and some of them have opened for clinical trials, currently in phase I or II, whose results will be soon available. This review will present an overview of current and most recent therapeutic options in RS, discussing also how results coming from xenograft models may help in designing and identifying novel treatment opportunities to overcome the lack of effective therapies.

Keywords: Antibody-drug conjugates; Kinase inhibitors; Monoclonal antibodies; Richter’s syndrome; Targeted therapy.

Fig. 1

Schematic representation of novel therapeutic approaches to treat RS patients. The main novel therapeutic approaches to treat RS patients are summarized. Small molecules targeted therapies (A), antibody-based therapies (B), and CAR-T (C). Bcl-2 (B-cell lymphoma 2), XPO1 (exportin 1), BTK (Bruton tyrosine kinase), BCR (B-cell receptor), PI3K (phosphoinositide 3-kinase), ADC (antibody-drug conjugate), ROR1 (receptor tyrosine kinase-like orphan receptor 1), PD1 (programmed death 1), PD-L1 (programmed death 1 Ligand), TCR (T-cell receptor), RNA Pol II (RNA polymerase 2), CAR (chimeric antigen receptor), NES (nuclear export signal).