Richter Syndrome: From Molecular Pathogenesis to Druggable Targets

Simple Summary Chronic lymphocytic leukemia represents the most frequent leukemia in adults and evolves from an indolent phase to an aggressive lymphoma in 5-10% of the cases. Such clinico-pathologic transformation is known as Richter syndrome and represents a major unmet medical need because of treatment refractoriness, lack of targeted therapeutic strategies and unsatisfactory survival rates. Molecular investigations by innovative approaches have clarified in detail the pathogenesis of Richter syndrome and have led to the identification of the genetic and biologic changes associated with its evolution from indolent to aggressive disease. Knowledge of the molecular profile of Richter syndrome has revealed several molecular targets that may be exploited for devising novel therapeutic strategies, both with small molecules acting as pathway inhibitors and with monoclonal antibodies, that also include drug immunoconjugates. Clinical trials with these novel medicines are ongoing and may pave the way to a precision medicine approach to Richter syndrome. Richter syndrome (RS) represents the occurrence of an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), in patients with chronic lymphocytic leukemia (CLL). Most cases of RS originate from the direct transformation of CLL, whereas 20% are de novo DLBCL arising as secondary malignancies. Multiple molecular mechanisms contribute to RS pathogenesis. B-cell receptor (BCR) overreactivity to multiple autoantigens is due to frequent stereotyped BCR configuration. Genetic lesions of TP53, CDKN2A, NOTCH1 and c-MYC deregulate DNA damage response, tumor suppression, apoptosis, cell cycle and proliferation. Hyperactivation of Akt and NOTCH1 signaling also plays a role. Altered expression of PD-1/PD-L1 and of other immune checkpoints leads to RS resistance to cytotoxicity exerted by T-cells. The molecular features of RS provide vulnerabilities for therapy. Targeting BCR signaling with noncovalent BTK inhibitors shows encouraging results, as does the combination of BCL2 inhibitors with chemoimmunotherapy. The association of immune checkpoint inhibitors with BCL2 inhibitors and anti-CD20 monoclonal antibodies is explored in early phase clinical trials with promising results. The development of patient-derived xenograft mice models reveals new molecular targets for RS, exemplified by ROR1. Although RS still represents an unmet medical need, understanding its biology is opening new avenues for precision medicine therapy.