Several CD19-directed therapies have received FDA approval, with others in development, and some of these therapies are effective in patients who are completely chemotherapy refractory. Available CD19-directed agents include CAR T cells, antibody-drug conjugates, and monoclonal antibodies; bispecific antibodies are under investigation as well.

Axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel are the 3 available CD19-directed CAR T-cell therapies. These agents have been fantastic additions to the management of relapsed DLBCL. Each agent has curative potential in the relapsed setting, and more patients may be candidates for CAR T-cell therapy than autologous stem cell transplantation. Still, older patients with comorbidities may not be candidates for these newer cellular therapies. Another limitation is the time needed for the collection and processing of the CAR T cells. DLBCL is a very proliferative malignancy, and a patient may need treatment right away.

There are a number of other CD19-directed agents that may be considered when a patient is not a candidate for CAR T-cell therapy. For example, tafasitamab is an anti-CD19 monoclonal antibody that has modest activity when used as a single agent but impressive activity when used in combination with lenalidomide. In the L-MIND trial, the overall objective response rate was nearly 60%, with complete responses reported in 40% of patients. Responses had good durability, which may be related to the indefinite administration of tafasitamab. Of note, the included patients had relatively favorable characteristics, so results in the real world may not be as good. However, it is still a very good option, particularly for older patients or for those with comorbidities.

More recently, loncastuximab tesirine was FDA approved for R/R DLBCL based on the results of the LOTIS-2 trial. Loncastuximab tesirine is a CD19-directed antibody with a pyrrolobenzodiazepine conjugate. It uses a sophisticated linker technology for the internalization of the payload; however, you still see some toxicities outside of the targeted cancer cells. In LOTIS-2, loncastuximab tesirine was associated with an overall response rate of approximately 48%, with complete responses reported in 24% of patients with high-risk characteristics for poor prognosis (eg, double-hit, triple-hit, transformed, or primary refractory DLBCL). Responses were durable, with a median duration of approximately 13 months. I have observed loncastuximab tesirine working in patients who are completely chemotherapy refractory, and that was exciting (ie, administering an antibody-drug conjugate and seeing it put patients who had perhaps just progressed through EPOCH chemotherapy or R-CHOP chemotherapy into complete remission). There is definitely some potency there that is impressive, but one does have to be mindful of the toxicities that can be caused by the agent. A confirmatory phase 3 study is underway to evaluate loncastuximab tesirine with rituximab vs immunochemotherapy in patients with R/R DLBCL (LOTIS 5). 

A precaution with all of these off-the-shelf CD19-directed agents is the theoretical risk that you could have CD19-negative mutant clones emerge that would prevent the CAR T-cell therapy from working. Although there are limited data to guide decision making thus far, we currently avoid them immediately before or immediately after CAR T-cell therapy. If you have a patient who has relapsed after CAR T-cell therapy and you want to administer CD19-directed therapy, it would be wise to get a biopsy to prove that the tumor cells still express CD19.