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T-cell engaging therapeutic approaches have significantly changed the treatment paradigm for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in recent years.

"They are, by a wide margin, the most impactful new therapies for all B-cell lymphomas, but especially DLBCL, in the last 40 years, if not ever," said Joshua Brody, MD, of the Tisch Cancer Institute at Mount Sinai in New York City.

Currently, these cellular immunotherapies fall into two buckets: chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engaging antibodies.

There are three CAR T-cell therapies approved for DLBCL: tisagenlecleucel (Kymriah) in the third line, axicabtagene ciloleucel (axi-cel; Yescarta) initially approved in 2017 in the third line and in the second line, and lisocabtagene maraleucel (Breyanzi) in 2021 in the third line and in in the second line. In 2023, two bispecific antibodies also gained approval as third-line treatment options: first epcoritamab (Epkinly) and shortly after, glofitamab (Columvi). Each treatment comes with its own set of advantages and disadvantages. The challenge now for clinicians is determining the best order in which to employ these new treatment strategies.

Second-Line After Rapid Relapse

In terms of the best second-line option for patients with early relapse, the CAR T-cell therapy axi-cel should be standard of care, according to Brody.

Axi-cel gained its approval as a second-line option based on results of the ZUMA-7 trial, a randomized trial comparing axi-cel following fludarabine and cyclophosphamide chemotherapy versus chemoimmunotherapy followed by autologous stem cell transplant in patients with primary refractory DLBCL or those who had relapse within 12 months of first-line therapy.

"If you go back prior to CAR T-cell therapy approval, the median survival of people with relapsed, refractory DLBCL was something like 6 months if they had high-risk relapses," said Michael Jain, MD, PhD, of Moffitt Cancer Center in Tampa, Florida. "With CAR T-cell therapy, we think that somewhere between 30% to 40% of people can be cured."

The ZUMA-7 trial showed that axi-cel significantly improved progression-free survival, but also yielded an overall survival advantage (HR 0.73, 95% CI 0.54-0.98, P=0.03).

"Maybe two-thirds of relapses of DLBCL happen within the first year," Brody said. "This should be practice-changing for eligible early relapse patients."

Third-Line Questions

If both treatment options are available to a patient in the third line, a clinician may have to weigh the risks and benefits of each approach.

Jain said that in a large referral center like Moffitt, CAR T-cell therapy is still often the treatment of choice in the third line for a number of reasons.

"One reason is that the real-world experience with bispecific antibodies is very limited," Jain said. "The clinical trials for these drugs looked great, but we have had a phenomenon in DLBCL with approved drugs that looked good in clinical trials but out in the real world performed very poorly."

Another reason Jain mentioned was that although bispecific antibodies are touted as easy-to-administer and "off-the-shelf," he said that they are more logistically complicated than standard therapies that community oncologists are delivering.

Brody agreed, "CAR-T has a greater precedent of efficacy, been around longer, and probably cures 35% or more of patients, and bispecifics have not yet shown that."

However, Brody added that most patients will likely end up needing both of these therapies. Therefore it is important to consider which to give first.

"My opinion is if you relapse from CAR-T therapy quickly, a bispecific is unlikely to be helpful because the chemotherapy you get before CAR-T makes the patient have almost no T cells and without T cells, bispecifics won't work well," Brody said.

By contrast, a bispecific followed by CAR T-cell therapy seems much more reasonable immunologically. The question, Brody said, is not option A versus option B, but A followed by B or B followed by A. There, he sees an advantage to bispecifics given first.

Patient Preference

Even as more real-world experience with bispecific antibodies is gained, there are still situations where patient preference may factor into the treatment decision.

The logistics of these two treatments are quite different, Jain said.

"For CAR T-cell therapy, if a patient lives a few hours away from the center, they have to move to Tampa for a month," Jain said, "but after that month we see them infrequently and they are not on any treatment."

In contrast, many bispecific antibodies are dosed weekly for 3 months, with a short hospital stay occurring during step-up dosing with almost all of them. Later, treatment is given every 2 weeks, and then monthly.

"That is a lot of burden if you have to come every week and stay for several hours to receive therapy," Jain said. "Both treatments have different kinds of burden and preference can definitely be a factor in that decision."

Other Factors

Individual patient and disease factors may also affect which therapeutic approach is best, Brody said. For example, patients with high-bulk disease have a higher risk of toxicity, so in many cases physicians won't use CAR T-cell therapy until the disease has been debulked; whereas, bispecifics don't have that restriction.

Ability to control disease can also affect use of bispecific antibodies, which require step-up dosing, Jain said.

"If the patient has aggressive disease, they may not have their disease controlled long enough to make it to that full dose," Jain said. "Day 1 patients get the test dose, and on day 8 a bit more, but they often don't receive that full dose until day 15. It is not always the case that rapidly progressing disease benefits from bispecifics."

Patient age and susceptibility to side effects also play a role. According to Brody, bispecifics are "relatively safer" compared with CAR T-cell therapy in terms of the risk for high-grade cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome.

"The risk of both is many times lower with bispecifics," Brody said.

However, bispecific antibodies are associated with risk of infection that Jain said is "significant and burdensome."

Brody said that although both of these approaches are currently competing in the third line, it is likely that in the next 5 years bispecific antibodies will be approved in combination with other therapies in the second line, and eventually even the first line.

"To extrapolate, polatuzumab [Polivy] alone is not very powerful in DLBCL causing remission in less than 25% of patients, and when polatuzumab was added to frontline chemotherapy in POLARIX it was successful, but barely," Brody said. "In contrast, bispecifics are quite powerful monotherapies; instead of 25% response rate we have seen greater than 60% response rates and these are gentler and better tolerated than polatuzumab. It seems like a no-brainer that these can greatly improve frontline therapy."

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