Sequencing of cellular therapy and bispecific antibodies for the management of diffuse large B-cell lymphoma

Abstract

Historically, management of relapsed or refractory (R/R) Diffuse large B-cell (DLBCL) following first-line chemoimmunotherapy has been second-line chemotherapy, followed by high-dose chemotherapy and consolidative autologous hematopoietic stem cell transplantation (auto-HSCT), resulting in durable remissions in approximately 40% of patients. In 2017, chimeric antigen receptor (CAR) T-cell therapy changed the landscape of treatment for patients with R/R DLBCL, with complete response rates ranging from 40-58% and long-term disease-free survival of >40% in the highest risk subgroups, including patients who relapsed after auto-HSCT. Since that time further studies have demonstrated improved overall response rates (ORRs) and survival outcomes in patients with primary refractory or early-relapse (relapse <1 year) DLBCL treated with CAR T-cell therapy compared with auto-HSCT, advancing CAR T-cell therapy into the second-line setting. However, >50% of patients will relapse in the post-CAR T-cell setting. In the past two years, two CD20 x CD3 bispecific antibodies (BsAbs) were FDA approved for the treatment of R/R DLBCL after two or more lines of systemic therapy. These BsAbs have demonstrated ORRs exceeding 50% and durable remissions at > 2yrs of follow-up. Additionally, a notable treatment advantage of BsAbs is their ability to be administered in the community setting, making treatment more accessible for patients. The development and advancement of these novel therapies raise questions regarding the ongoing role of HSCT in the management of relapsed and refractory DLBCL and how to best sequence cellular and Bi-specific therapies to optimize patient outcomes.