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CD19 is nearly ubiquitously expressed on B-lymphocytes and in B-cell malignancies. Although CD19-directed CAR T cells have greatly improved outcomes in B-cell malignancies, there are significant limitations with this therapy. CD19 can also be effectively targeted by other drug classes, such as monoclonal antibodies, antibody-drug conjugates, and bispecific T cell engagers or antibodies. However, the optimal patient selection and sequencing of these novel therapies has not yet been established. In this review, we discuss the utilization of CD19 as a target for the treatment of DLBCL, focusing on tafasitamab, loncastuximab tesirine, and blinatumomab. We provide a comprehensive review of the pivotal clinical trials, discussing the strength and limitations of the data for each agent. We explore the emerging evidence that CD19 expression is retained following exposure to these agents and that patients can be successfully re-challenged with anti-CD19 therapies of a different drug class upon disease relapse post-CAR T cells. Finally, we discuss how these drugs potentially fit into the most current treatment paradigm for DLBCL. [ABSTRACT FROM AUTHOR]

In the past 5 years, 3 chimeric antigen receptor (CAR) T-cell therapies, 2 antibody-drug conjugates (ADCs), 1 CD19-directed monoclonal antibody, and 1 exportin-1 inhibitor have been approved by the Food and Drug Administration for patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). The noncellular therapies received accelerated approval based on the overall response rate in clinical trials that differ in multiple aspects of the patient populations enrolled, including age, performance status, prior lines of therapy, and inclusion of patients with primary refractory DLBCL, transformed lymphoma, or high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6. ADCs approved for DLBCL differ in target antigen, antibody structure, linker, and cytotoxin, which results in a different safety and efficacy profile. Here, we comprehensively review the current knowledge of recently approved and emerging strategies for the management of R/R DLBCL with a focus on ADCs. • Replacing vincristine with polatuzumab vedotin in R-CHOP improved PFS in newly diagnosed DLBCL • CAR-T cell therapy improved EFS relative to ASCT in patients with early relapse or refractory DLBCL • Loncastuximab tesirine was recently approved for R/R DLBCL, including high-grade B-cell lymphoma • Emerging ADCs with novel targets include STRO-001, Trph-222, VLS-101, and naratuximab emtansine [ABSTRACT FROM AUTHOR]