ADCs, BiTEs, CARs, and Small Molecules: A New Era of Targeted Therapy in Non-Hodgkin Lymphoma.

Novel immunotherapies and small molecular inhibitors are transforming our approach to previously treated and newly diagnosed patients across the spectrum of non-Hodgkin lymphomas (NHLs). Anti-CD19 CAR T cells are now indicated for the treatment of relapsed/refractory aggressive B-cell lymphomas after at least two previous lines of therapy in which durable remissions are achieved in approximately 40% of previously incurable patients. Second-line chemoimmunotherapy remains the standard of care at first relapse, but poor outcomes with conventional treatment in this setting creates an appealing rationale for earlier use of CAR T cells, which is currently under investigation, along with even earlier use in selected high-risk patients in the frontline setting. Other emerging immunotherapies include antibody-drug conjugates (ADCs), such as polatuzumab vedotin for multiple-relapsed diffuse large B-cell lymphoma (DLBCL) in combination with bendamustine-rituximab. Multiple bispecific antibodies that bring malignant B cells in contact with effector T cells appear promising in early clinical trials and will likely emerge as off-the-shelf immunotherapy options. Chemotherapy-free small molecule-based regimens are increasingly available for mantle cell (MCLs) and follicular lymphomas (FLs). Bruton tyrosine kinase inhibitors (BTKi) now represent standard second-line therapy for MCL and are being investigated in combination and as initial therapy. Lenalidomide-rituximab is an active regimen in both FL and MCL and may be used in either relapsed/refractory or previously untreated disease. Three PI3K inhibitors are approved for multiple-relapsed FL and can induce durable remissions in patients with chemotherapy- and rituximab-refractory disease. Additional emerging targeted therapies include BCL2 inhibition in MCL and EZH2 inhibition in FL.