Abstract IA003: Multitargeted combination strategies to cure patients with Large B-cell Lymphoma

Abstract

Large B-cell lymphomas (LBCL) are a group of aggressive lymphomas that are curable with anthracycline-based chemotherapy as well as immunotherapy approaches including anti-CD19 chimeric antigen receptor T-cell therapy. LBCL is characterized by striking underlying genetic heterogeneity that leads to differential responses to chemotherapy and targeted agents including inhibitors of the B-cell receptor. Overcoming the barrier of genetic heterogeneity by developing targeted agents within genetic subtypes forms the basis of precision medicine, but targeted agent delivered as monotherapy lead to rapid onset of acquired resistance and do not reliably induce durable remissions in LBCL. Recently, investigators at the National Cancer Institute developed a multi-targeted combination of rational agents targeting multiple survival pathways in LBCL called VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) which demonstrated remarkable activity in relapsed/refractory LBCL including durable remissions in specific genetic subtypes, activated B-cell (ABC) subtype and high-grade B-cell lymphoma with double-hit (HGBL-DH), suggesting for the first time that targeted agents may be curative in high-risk subtypes of LBCL without the use of DNA-damaging agents (i.e. chemotherapy) or immunotherapy. This abstract will highlight the key pre-clinical and clinical principles underlying the proof-of-principle development of the VIPOR regimen, including the importance of translational research which uncovered an unknown dependency of HGBL-DH on apoptosis that is successfully targeted with BCL2 inhibitors. Additional concepts that will be discussed in this presentation including the relative lack of long-term toxicities with VIPOR (lack of second malignancies and late onset immunologic effects) and the ongoing efforts to validate these original findings in an ongoing multicenter study being conducted by the Eastern Cooperative Oncology Group and Cancer Therapeutics Evaluation Program in these two specific genetic subtypes. Real-world data has emerged suggesting that this can be safely administered outside of clinical trials. Next steps of development including moving VIPOR-based combination to the frontline setting will be presented.