Novel strategies toward improving outcomes in large B-cell lymphoma

I am a hematologist/oncologist whose practice focuses on caring for patients with lymphoma. My goal is to develop more effective and less toxic therapies for large B-cell lymphoma (LBCL). LBCL is an aggressive disease representing the most common subtype of lymphoma in the United States. This proposal includes a single-center study evaluating an oral agent, zanubrutinib, in combination with an immunochemotherapy backbone of high-dose methotrexate with polatuzumab vedotin, rituximab, cyclophosphamide, adriamycin, and prednisone (polatuzumab-R-CHP), in patients with LBCL where the disease has spread to central nervous system structures, such as the brain, meninges, eye, and spine. There is no standard-of-care treatment in this scenario, and it is associated with a poor prognosis despite recent advances in drug development. Therefore, developing effective therapies remains an unmet need. The second study is a genomic and minimal residual disease (MRD) driven de-escalation study where patients with untreated LBCL will receive polatuzumab-R-CHP in combination with the antiCD20xCD3 bispecific antibody glofitamab. In this study, the length of treatment will be decided based on these characteristics. Patients without high-risk genomics in the diagnostic tissue biopsy and undetectable MRD in blood will receive lower cycles of cytotoxic chemotherapy, aiming to decrease treatment-associated toxicity but retaining efficacy. This study will pave the way for the development of personalized medicine in lymphoma. The third study includes a multicenter study evaluating an off-the-shelf therapy with the antiCD20xCD3 bispecific antibody epcoritamab in combination with the antiCD19 antibody-drug conjugate loncastuximab tesirine in LBCL when the disease returns (relapse) after first-line immunochemotherapy or when this one is not effective (refractory). Relapsed or refractory LBCL remains associated with poor prognosis, underscoring the need for novel approaches. Epcoritamab and loncastuximab tesirine demonstrated single-agent activity in LBCL without overlap toxicity. Therefore, this combination may significantly further improve responses and survival. In these three clinical trials, we will conduct innovative exploratory studies, including imaging biomarkers, molecular response assessment through MRD analysis, and genomic analysis, to better understand the mechanisms of resistance in patients who do not respond to these agents.