Management of Primary Refractory Diffuse Large B-Cell Lymphoma in Patients Unsuitable for CAR T-Cell Therapy

Primary refractory Diffuse Large B-Cell Lymphoma is associated with poor outcomes and limited responsiveness to conventional salvage therapies. Although CAR T-cell therapy represents the standard of care in this setting, a substantial proportion of patients cannot receive it despite meeting disease-related criteria. In this review, "unsuitable" refers to patients who are temporarily or functionally unable to undergo CAR T-cell therapy because of reversible clinical conditions, rapidly progressive disease requiring immediate cytoreduction, or logistical and social barriers, rather than permanent contraindications. For these patients, prompt alternative strategies are required. Conventional platinum-based or gemcitabine- and bendamustine-containing regimens retain a role for short-term disease control but offer limited durability. In contrast, novel antibody-based therapies, including polatuzumab-containing combinations, loncastuximab tesirine, and tafasitamab plus lenalidomide, have expanded treatment options with improved tolerability. Most notably, CD20 × CD3 bispecific antibodies represent a major therapeutic advance, providing off-the-shelf immune engagement with predominantly outpatient administration. From a practical perspective, early identification of reversible barriers to CAR T-cell therapy and timely use of bispecific antibodies or other antibody-based regimens are critical to achieve rapid disease control, preserve organ function, and, when feasible, restore eligibility for cellular therapy.