Background: Richter syndrome (RS) is defined as the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most often diffuse large B-cell lymphoma (DLBCL). It carries a poor prognosis and is often unresponsive to conventional chemo-immunotherapy. Furthermore, TP53 disruptions have been universally associated with poor prognosis and worse response to conventional chemotherapy. The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma is more common in Richter syndrome and is dependent on chronic activation of the B-cell that is mediated by Bruton's tyrosine kinase (BTK), leading to activation of nuclear factor kappa B. Ibrutinib is the first-in-class BTK inhibitor currently approved in several B-cell malignancies. The BCL-2 inhibitor venetoclax has shown activity in a wide array of malignant hematologic processes. Additionally, preclinical data have suggested synergistic activity between these two medications that work in a p53-independent manner. The activity of ibrutinib and venetoclax in RS remains poorly characterized.

Case Presentation: An 82-year-old gentleman, diagnosed with Richter transformation from small lymphocytic lymphoma (SLL), was started on a clinical trial with R-CHOP and brentuximab vedotin with partial response at end of therapy. Repeat biopsy confirmed RS with ABC-subtype and deletion 17p. He was started on single-agent ibrutinib with excellent clinical response. However, the patient experienced transient neutropenia, atrial fibrillation, and gastrointestinal bleeding, but continued ibrutinib given clinical benefit. Patient eventually progressed on single-agent ibrutinib after over three years of therapy. Upon progression, venetoclax was added to ibrutinib therapy and patient has again achieved CR for nearly two years. His most recent PET scan shows no evidence of recurrent disease with a tolerable side effect profile.

Discussion: Richter's syndrome patients carry a poor prognosis with a median survival of 19 months and less durable responses to traditional chemo-immunotherapy regiments. TP53 disruptions are found in 47.1% of patients and are independently associated with worse outcomes. Additionally, there are little to no data on optimal management of patients with RS, especially those with evidence of poor prognosis such as del17p as in this patient. In this case, we present an elderly male who has attained a CR over 5 years with the novel combination of ibrutinib and venetoclax.

Conclusion: This case report demonstrates that the novel combination of ibrutinib and venetoclax represents an important treatment option for patients with RS and TP53 disruptions as it can induce excellent and durable response with tolerable side effects. This supports further evaluation of novel treatment options in patients with limited proven effective treatment strategies and suboptimal responses to current standard of care.

Citation Format: John McKay, Jonathan Soray, Roger Riley, Victor Yazbeck. Durable and excellent response in patient with Richter's transformation and Del 17p treated with ibrutinib and venetoclax [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-52.