Although high-dose chemotherapy, autologous hematopoietic stem cell transplantation, and CAR T-cell therapy offer the potential for cure in  patients with R/R DLBCL, there is still a group of patients who cannot receive these therapies due to comorbidities, patient preference, or a lack of access to CAR T-cell therapy. These individuals have very high-risk disease, but there are commercially available options that can be prescribed with palliative intent.

In the last few years, we have seen tremendous innovation in this field with the FDA approval of several active compounds, each with its own strengths and weaknesses. The combination of polatuzumab vedotin plus bendamustine and rituximab (Pola-BR), the combination of the CD19-directed antibody tafasitamab plus lenalidomide, and the monotherapies loncastuximab tesirine and selinexor have been approved by the FDA.

Pola-BR was the first regimen that was found to improve overall survival in patients with R/R DLBCL in a randomized clinical trial. The triplet improved the overall response rate, complete response rate, and overall survival compared with BR alone; the risk of death was reduced by 58%. Tafasitamab plus lenalidomide was evaluated in the L-MIND study, in which patients with lower-risk disease (ie, relapsed but not refractory DLBCL) had durable responses. Loncastuximab tesirine monotherapy is an antibody-drug conjugate that delivers a pyrrolobenzodiazepine dimer toxin payload that is directed against CD19. In the LOTIS-2 trial, loncastuximab tesirine monotherapy had an overall response rate approaching 50%, with approximately 48% of patients experiencing a complete or partial response. Selinexor is an oral selective inhibitor of the nuclear export protein XPO1 that was approved by the FDA based on data from the SADAL trial, in which the overall and complete response rates were 28% and 12%, respectively.

Thus, we have this new broadening armamentarium of treatments that are currently available for R/R DLBCL, offering hope for patients who had very few active options only 3 years ago. In addition, there are several treatments that are in clinical development, including bispecific antibodies, which may be even more tolerable than CAR T-cell therapies. Bispecific antibodies have lower rates of cytokine release syndrome and a lower severity of neurotoxicity than CAR T cells. There is also the potential for a broadening of the pool of patients who could be eligible for T-cell–activating therapy beyond that which is currently available through CAR T cells themselves.

With these options, and with clinical trials to consider, it is important that each patient understands all of their choices for treatment. This involves having honest discussions on an individual basis and helping to inform the patient and their family about standard-of-care options; what clinical trials are available; and the pros, cons, risks, and rewards of each approach.