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Targeted Therapies in DLBCL
Evolving Targeted Therapies for Relapsed/Refractory DLBCL

Released: August 06, 2026

Elizabeth Budde
Elizabeth Budde, MD, PhD
Gilles Salles
Gilles Salles, MD, PhD
Pier Luigi Zinzani
Pier Luigi Zinzani, MD, PhD
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Key Takeaways
  • GemOx has a limited role as a standalone second-line therapy in the current DLBCL treatment landscape, but may still be useful, particularly when CAR T-cell therapy, bispecific antibodies, or antibody–drug conjugates are not accessible.
  • CAR T-cell therapy remains a key potentially curative option for eligible patients with relapsed/refractory DLBCL, and treatment decisions should be guided by eligibility, performance status, organ function, and biologic rather than chronologic age.
  • Bispecific antibodies and antibody–drug conjugates play an important role in the management of patients with relapsed/refractory DLBCL, although further comparative studies are needed to define optimal sequencing post relapse on CAR T-cell therapy.

In this commentary, Elizabeth Budde, MD, PhD, Gilles Salles, MD, PhD, and Pier Luigi Zinzani, MD, PhD, address key questions posed by the audience during a recent symposium held in conjunction with the 2026 EHA Congress titled, “Optimizing DLBCL Treatment: An Expert Roundtable on the Role of New and Emerging Targeted Therapies”. During this symposium, the experts discussed the current utility and role of new and emerging targeted therapies and provided clinical guidance on the personalization of care for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).

In the current era, is there still any role for gemcitabine/oxaliplatin (GemOx) in the treatment of patients with DLBCL requiring second-line therapy?

Elizabeth Budde, MD, PhD:
Currently, the utility of GemOx as second-line therapy is limited. It may be used for a short-term period as bridging therapy towards CAR T-cell infusion. 

Pier Luigi Zinzani, MD, PhD:
I do not think that there is any further role for GemOx alone in this new and exciting era of targeted therapies for the management of patients with DLBCL.

Gilles Salles, MD, PhD:
Regarding GemOx, it is important to note that other agents can now be combined with it. For instance, for patients who are not candidates for CAR T-cell therapy, the bispecific antibodies epcoritamab and glofitamab can be used in combination with GemOx. Also, the antibody–drug conjugate (ADC) polatuzumab vedotin can be used in combination with GemOx in patients who are not eligible to receive CAR T-cell therapy.

For patients who are candidates for CAR T-cell therapy, GemOx alone or in combination with rituximab is an option as holding therapy (pre pheresis) or bridging therapy (post pheresis). Aside from eligibility, it should be noted that treatment with CAR T-cell therapy largely depends on access and availability at the cancer center in which the patient is receiving care. So, for patients being treated at centers where CAR T-cell therapy is not accessible or is unavailable, or if unable to receive a bispecific antibody or polatuzumab vedotin, GemOx in combination with rituximab can be considered as second-line therapy, although clearly suboptimal.

Pier Luigi Zinzani, MD, PhD:
In Italy, the referral to CAR T-cell treatment centers is not yet optimized. Eligible patients need to be promptly referred to CAR T-cell centers, especially in the second-line setting. Also, unlike in other countries, such as the United States, Italy imposes an age cutoff for the use of CAR T-cell therapy. In fact, Italy is the only European country with an age limit for CAR T-cell therapy, with the cutoff being 75 years of age. I think this is appropriate because CAR T-cell therapy may be more difficult for a patient older than 75 years of age than for a younger patient, especially considering the requirements for hospitalization, manufacturing process, and monitoring for adverse events.

Elizabeth Budde, MD, PhD:
Although an age cutoff may seem appropriate in some case scenarios, a patient’s chronologic age is relative and should not be used as a standalone factor when making treatment decisions. Treatment decisions regarding eligibility for CAR T-cell therapy should consider the patient’s performance status and organ function.

At my institution, we are able to treat patients with DLBCL in their 80s with CAR T-cell therapy as long as they are eligible and have good performance status and organ function. In my experience, the response to CAR T-cell therapy and side effect profiles are similar to those reported in younger patients. I think that in most institutions with the capability to administer CAR T-cell therapy, these agents will become more available for older patients as the technology continues to evolve with better safety profiles without sacrificing efficacy outcomes.

Pier Luigi Zinzani, MD, PhD:
I agree. To date, the 2 approved CAR T-cell therapies for patients with R/R DLBCL are axicabtagene ciloleucel and lisocabtagene maraleucel. Of note, both are autologous and target CD19. Emerging investigational CAR T-cell therapies are utilizing different mechanisms. For instance, zamtocabtagene autoleucel, KITE-363, and prizloncabtagene autoleucel are autologous CAR T-cell therapies that simultaneously target CD19 and CD20 on cancer cells. Also, cemacabtagene ansegedleucel is a CD19-directed allogeneic CAR T-cell therapy that is under investigation in R/R large-B-cell lymphoma. As we continue to advance CAR T-cell technology and develop newer, next-generation agents in this class of drugs, the future for our patients with R/R DLBCL continues to be promising and exciting.

When compared to what has been reported with CAR T-cell therapies, do you think that the available bispecific antibodies and ADCs can cure patients with DLBCL?

Gilles Salles, MD, PhD:
The addition of bispecific antibodies or ADCs to chemotherapy backbones has resulted in impressive responses and safety profiles. However, in my experience, CAR T-cell therapies have formally demonstrated curative potential for patients with DLBCL, whereas such data are immature for bispecific antibodies when used alone or in combination with other agents.

Elizabeth Budde, MD, PhD:
I think the available bispecific antibodies and ADCs have curative potential in DLBCL. For instance, long-term follow-up results from the phase III POLARIX trial of polatuzumab vedotin plus R-CHP vs R-CHOP alone demonstrated that some patients have sustained and durable complete remissions after 5 years of treatment with polatuzumab vedotin plus R-CHP, with a 5-year progression-free survival rate of approximately 65% and a 5-year OS rate of 82.3%.

The bispecific antibodies, epcoritamab and glofitamab, are increasingly being incorporated into routine clinical practice in the community setting for patients with R/R DLBCL. As healthcare professionals become more comfortable with managing the associated adverse events, more patients will be able to receive these agents. However, because CAR T-cell therapies are given as a one-time single infusion, they are preferred by many patients.

It is important to note that glofitamab and epcoritamab are approved by the EMA and FDA for patients with R/R DLBCL. Odronextamab is another bispecific antibody with EMA authorization for use for patients with DLBCL. Of note, these 3 bispecific antibodies target CD20 and CD3. A novel and investigational bispecific antibody, surovatamig, acts using a different mechanism in that it targets CD19 and CD3. Initial phase I study of surovatamig in R/R DLBCL demonstrated very encouraging results. When administered as a single agent at the target dose of 25 mg IV, the overall response and complete response rates in 13 patients with R/R DLBCL were 77% and 54%, respectively. The overall response rates across different target doses for patients with R/R DLBCL were 47% at the 7.2-mg dose, 59% at the 15-mg dose, and 77% at the 25-mg dose. Among all patients who received surovatamig at a target dose of 7.2-25 mg, it was estimated that 91.2% would have a duration of complete response of 12 months. 

Also, among 11 patients with disease progression after receiving a CD20-directed T-cell engager, surovatamig elicited a complete response rate of 45%, and among 31 patients with disease progression post anti-CD19 CAR T-cell therapy, the complete response rate was 35%. These results demonstrate remarkable efficacy.

Although surovatamig appears to be a promising salvage therapy after previously receiving a CD20-directed bispecific antibody or CD19-directed CAR T-cell therapy, it is unclear if its efficacy will be equivalent to that achieved with CAR T-cell therapy. At present, the potential mechanisms of resistance to surovatamig are unknown, and future studies will provide more insight into the remaining questions about its utility in R/R DLBCL.

Pier Luigi Zinzani, MD, PhD:
I agree. Without direct comparisons in clinical trials, we will be unable to fully answer these questions. We need future studies that will compare the efficacy and safety of bispecific antibody– and ADC-based therapies vs CAR T-cell therapy for patients with R/R DLBCL to shed more light on the roles of these agents. However, such a trial will be difficult to design and complete, especially because of the differences in the duration of treatment with these agents.

Which bispecific antibody would you recommend for patients with DLBCL after experiencing relapse on an anti-CD19 CAR T-cell therapy?

Pier Luigi Zinzani, MD, PhD:
After progression on a CD19-directed CAR T-cell therapy, I would recommend glofitamab, if available, if the disease is CD20-positive. In the phase II LYSA trial of glofitamab for patients with R/R DLBCL post disease progression or relapse on CAR T-cell therapy, the overall response rate was 76% with a complete remission rate of 46% and a median duration of response of 20 months. These results are quite encouraging. The question, however, remains whether to include consolidation therapy with allogeneic transplant or not.

Elizabeth Budde, MD, PhD:
I agree. I think that post CAR T-cell therapy, outside of a clinical trial, the best treatment choice is to recommend a bispecific antibody as the preferred third-line therapy. However, for most patients achieving a subsequent remission, I would not include allogeneic stem cell transplant as consolidation therapy.

Gilles Salles, MD, PhD:
Around 2 years ago, allogeneic stem cell transplant would have been a reasonable option. However, emerging data have clearly shown that patients who achieved a complete response to a T-cell–engaging bispecific antibody appear to maintain the response for a prolonged period. This leaves allogeneic stem cell transplant as an option for consideration for only a minority of patients in this scenario.

Your Thoughts?
What questions do you have regarding the selection and sequencing of CAR T-cell therapies, bispecific antibodies, and ADCs in the care of your patients with DLBCL? Answer the polling question and join the conversation in the discussion box below.

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