Combination therapy can improve survival for people with aggressive lymphoma

Combination therapy can improve survival for people with aggressive lymphoma

A new clinical trial suggests that combining bispecific antibodies and antibody-drug conjugates with CAR T-cell therapy can significantly increase one-year progression-free survival in people with aggressive lymphoma.

In just a few years, treatment options for aggressive lymphoma have evolved rapidly. However, many patients show a consistent pattern: powerful new therapies work quickly, but often cannot keep lymphoma at bay long-term, says Dr. Jay Spiegel, a transplant and cell therapy physician at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine.

Spiegel will present the initial results on December 8 at the American Society of Hematology (ASH) 2025 Annual Meeting in Orlando.

We have vastly improved lymphoma care. But there are still many patients for whom current approaches do not provide a cure.”

Jay Spiegel, MD, transplant and cell therapy physician, Sylvester Comprehensive Cancer Center

This challenge inspired a new clinical trial - researchers led by senior author Dr. Lazaros Lekakis, a professor of clinical medicine at the Miller School, combined three of the most promising lymphoma treatments with the goal of improving outcomes.

Clinical trial data suggests that combining these treatments can significantly improve progression-free survival at one year.

Multilayered therapies prolong reactions

Large B-cell lymphoma is the most common aggressive lymphoma in adults. The most common subtype, diffuse LBCL, affects approximately 25,000 people in the United States each year. Initial treatments work in about 70% of patients.

For the 30% whose lymphoma recurs or never completely goes away, the next step is often CAR T-cell therapy, such as: B. Axicabtagene ciloleucel, which was approved in 2017. It trains a patient's immune cells to respond specifically to lymphoma.

“CAR T works incredibly well right from the start,” Spiegel said, “but we learned that it is often not enough in the long term – only about 40% of patients remain in remission after five years.”

That's why researchers have developed other new therapies. Mosunetuzumab is a two-headed bispecific antibody that connects a T cell to a lymphoma cell, activating the immune system to attack. Polatuzumab is an antibody-drug conjugate, meaning it delivers a small dose of chemotherapy directly into lymphoma cells. Both are initially effective, but alone cannot reliably keep the disease away.

To increase the durability of these new treatments, the Sylvester team integrated all three approaches. “Simultaneously attacking three different antigens could help overcome several of the reasons for CAR T’s failure,” Spiegel said. "The hope was that the combination could really increase effectiveness, and so far it's been pretty special."

The phase 2 study enrolled 25 adults with relapsed or refractory LBCL. They received mosunetuzumab and polatuzumab before and after CAR-T treatment. Of the 24 patients who reached day 90, 90% were in complete remission. After one year, about 80% were still in remission, a significant increase from an estimated 50% after one year of CAR T alone.

“I didn’t think it would work so well,” Spiegel said. “It really surprised me to enroll patients with this type of aggressive disease and have so many still in remission after a year.”

The Sylvester study may provide a way to achieve longer remissions. "We have an exciting result," said Spiegel, "but now we need to show that it is possible on a larger scale. That is the goal of the next study, to prove that the juice is worth the squeeze."

As encouraging as the results are, they are in a field that is moving at extraordinary speed as researchers continue to test new immunotherapies, improve CAR-T treatments and explore new drug targets. “With lymphoma, everything happens at once,” Spiegel said. “It makes the field exciting, but also complicated.”

This pace presents both opportunity and complexity as physicians work to understand how each advance fits into the broader treatment landscape—and how they can work together. The current challenge is figuring out the best sequences and combinations for these new treatments — and how to use them without depleting the immune system, Spiegel said.

Given this flood of treatment options, the message for patients is increasingly hopeful. “If you have a relapse of disease, even aggressive disease, there are now several approaches that can still cure your lymphoma,” Spiegel said. “That wasn’t true seven years ago.”

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