When diffuse large B-cell lymphoma (DLBCL) fails to respond to front-line treatment or the disease later returns, Jeremy S. Abramson, MD, MMSc, wants to know when the disease progressed, if the patient is eligible for chimeric antigen receptor (CAR) T-cell therapy, and whether or not such treatment is accessible. For primary refractory disease or relapse within a year, he favors CAR T-cell therapy in the second line, he said at the recent 2026 National Comprehensive Cancer Network (NCCN) Hematologic Malignancies Congress.
Jeremy S. Abramson, MD, MMSc
Dr. Abramson explained that for these patients, the previous approach was salvage chemotherapy first. Those whose lymphoma responded to salvage chemotherapy could then undergo autologous stem-cell transplantation. But patients who relapsed after transplant or could not tolerate high-dose therapy once had almost no opportunity for cure.
CAR T-cell therapy changed that in the third-line and later settings, demonstrating the ability to “cure previously incurable patients,” said Dr. Abramson, Professor of Medicine at Harvard Medical School and Director of the Jon and Jo Ann Hagler Center for Lymphoma at the Mass General Cancer Center in Boston. “Surely, we can move that treatment up into the second-line setting.”
CAR T-Cell Therapy in Early Relapse
The shift toward CAR T-cell therapy rests on two positive phase III randomized trials. In TRANSFORM1 and ZUMA-7,2 second-line lisocabtagene maraleucel (liso-cel) and axicabtagene ciloleucel (axi-cel), respectively, improved outcomes over salvage chemotherapy followed by transplant for patients with primary refractory or early relapsed large B-cell lymphoma. A third trial, BELINDA,3 did not show a benefit with tisagenlecleucel.
With longer follow-up, 4-year progression-free survival was 52% with liso-cel vs less than 25% with standard of care in TRANSFORM (hazard ratio [HR] = 0.42), and 42% with axi-cel vs 24% with standard of care in ZUMA-7 (HR = 0.51).
“What we know looking at these two respective CAR T-cell trials is that axi-cel has a lot more cytokine-release syndrome [CRS] and neurologic toxicities.”
In TRANSFORM, 49% of patients receiving liso-cel developed CRS, and 1% had grade 3 CRS; neurologic toxicity occurred in 11%, including grade 3 events in 4%. In ZUMA-7, 92% of patients receiving axi-cel developed CRS and 6% had grade 3 or higher CRS. Neurologic toxicity occurred in 60%, with grade 3 or higher events in 21%.
According to Dr. Abramson, neurologic toxicity is harder to manage than CRS. He described CRS as generally treatable with tocilizumab and dexamethasone, whereas severe neurologic effects “can really be quite profound.”
To compare the two “highly effective” products in the absence of a head-to-head trial, Dr. Abramson pointed to France’s DESCAR-T registry4 as “probably the best we have.” The analysis adjusted for differences between patients who received axi-cel and liso-cel and found similar efficacy. But Dr. Abramson described rates of CRS and neurologic toxicity as “dramatically lower” with liso-cel.
“Where either one is an option, I prefer liso-cel for toxicity reasons,” Dr. Abramson said. He may choose axi-cel when a patient’s disease is progressing too quickly to wait for liso-cel, which he said takes about a week longer to manufacture.
Transplant remains an option for a small group whose disease relapses more than a year after front-line therapy. “The young, fit late relapser is still the patient who should go to high-dose chemotherapy and transplant for chemosensitive disease,” Dr. Abramson said. He estimated that group comprising about 10% of patients with relapsed large B-cell lymphoma.
CAR T-Cell Therapy Beyond Transplant-Eligible Patients
Being ineligible for transplant does not necessarily rule out CAR T-cell therapy, Dr. Abramson emphasized. There is no fixed upper age limit for CAR T-cell therapy, and patients may be able to receive it despite organ function or performance status that would preclude high-dose chemotherapy and transplant.
For transplant-ineligible patients, prior treatment options offered little chance of durable disease control. “Historically, we’ve had pretty miserable options available,” he said. In a meta-analysis of all trials in second-line transplant-ineligible DLBCL, 1-year progression-free survival was about 24% overall.5
But according to Dr. Abramson, liso-cel opened a curative-intent treatment path for patients who could not undergo transplant. In the 61-patient PILOT study6 of second-line liso-cel, the median age was 74, and more than half the patients had primary refractory disease. The complete response rate was 54%, and just over 48% remained progression free at 18 months. “This is the first time we are proving that we can cure second-line, non-transplant-eligible patients,” he said, adding that the FDA label and NCCN guidelines include second-line liso-cel for transplant-ineligible patients with DLBCL, regardless of the duration of their initial remission.
But being able to receive CAR T-cell therapy medically does not mean a patient can access it. Dr. Abramson said registry and Medicare claims data suggest that fewer than one-quarter of patients who should receive it actually do. Referral and travel to a treatment center, a caregiver who can stay with the patient for about a month, and the manufacturing period can all prevent treatment. Some patients’ disease progresses too quickly to allow that time.
When CAR T-Cell Therapy Is Out of Reach
Dr. Abramson prefers CAR T-cell therapy before a bispecific antibody in the second line when it is accessible. CAR T-cell therapy has longer follow-up demonstrating cures, he said, and there is more evidence for bispecifics after CAR T-cell therapy than for the reverse sequence. But for patients who cannot receive CAR T-cell therapy, he favors bispecific antibody combinations.
In the randomized phase III STARGLO7 trial, glofitamab-gxbm plus gemcitabine and oxaliplatin (Glofit-GemOx) was compared with rituximab plus GemOx (R-GemOx) in transplant-ineligible patients treated in the second line or later.
“Three years later, we see a dramatic improvement in complete response with Glofit-GemOx,” he said. Complete responses occurred in 58.5% of patients receiving Glofit-GemOx vs 25.3% receiving R-GemOx, and 38% vs 15% were progression free at 30 months. The trial also met its primary overall survival endpoint: at 36 months, overall survival was 47% with Glofit-GemOx vs 27% with R-GemOx.8 Cytokine-release syndrome occurred in 44% of patients receiving Glofit-GemOx, but was almost entirely low grade and generally occurred during the first cycle of step-up dosing, Dr. Abramson reported.
Another bispecific and chemotherapy combination, epcoritamab-bysp plus GemOx, produced a complete response rate of about 60% in a phase II study.9 At 1 year, 44% of patients remained progression free. Severe CRS occurred in 1% of patients, severe infections occurred in 32%, and fatal treatment-emergent adverse events in 13%. “This was generally a very well tolerated treatment, with similarly encouraging results,” he said.
The phase III SUNMO trial10 tested a chemotherapy-sparing approach: the bispecific antibody(CD20 x CD3) mosunetuzumab-axgb plus the anti-CD79b antibody drug conjugate, polatuzumab vedotin (Mosun-Pola). In the randomized trial, complete responses occurred in 50% of patients given Mosun-Pola vs 24% given R-GemOx, and Mosun-Pola reduced the risk of progression or death by 60%. However, Dr. Abramson noted that its polatuzumab component may make it less appealing for patients whose disease was refractory to front-line polatuzumab vedotin/rituximab/cyclophosphamide/doxorubicin/prednisone (Pola-R-CHP).
Other Second-Line Options
For patients who cannot receive either CAR T-cell therapy or a bispecific antibody, Dr. Abramson pointed to the randomized POLARGO trial.11 It compared polatuzumab vedotin plus R-GemOx (Pola-R-GemOx) with R-GemOx in transplant-ineligible patients who had not previously received polatuzumab. With Pola-R-GemOx, the complete response rate was about 40%, median progression-free survival was 7 months, and 40% of patients were progression free at 1 year. He called it an appealing option in this setting, although he said its response rate and durability did not look as strong as those of the second-line bispecific combinations.
He placed two older available regimens—polatuzumab vedotin plus bendamustine and rituximab (Pola-BR)12, and tafasitamab-cxix plus lenalidomide13—lower in his current treatment hierarchy. According to Dr. Abramson, their long-term efficacy in real-world studies has been substantially poorer than that seen with CAR T-cell therapy or bispecifics, and he generally considers them only in the third-line or later setting, after those treatments have been used.
Third Line and Beyond
The evidence for CAR T-cell therapy in the third-line setting predates its use in the second line. For patients who have not received it earlier, Dr. Abramson said it should ‘definitely’ be offered in the third line. At 5 years, disease-specific survival was 51% with axi-cel in ZUMA-114 and 52% with liso-cel in TRANSCEND.15 “That is a dramatic change to the natural history of this disease,” he stated. “It has shown us that we are definitively curing previously incurable patients.”
For patients whose disease progresses after CAR T-cell therapy, Dr. Abramson generally favors a bispecific antibody–based regimen. Although he prefers combinations to monotherapy, he pointed to a prospective phase II study16 of glofitamab alone after CAR T-cell therapy failure in which 46% of patients achieved a complete response and 29% remained progression free at 2 years. “This validates that a bispecific antibody-based approach should be our go-to therapy in a patient who relapsed despite CAR T-cell treatment,” he said.
Additional third-line and later options include loncastuximab tesirine-lpyl17 for patients whose lymphoma still expresses CD19, and pembrolizumab18 for relapsed primary mediastinal B-cell lymphoma. Dr. Abramson sees a limited role for the three-drug combination of brentuximab vedotin, rituximab, and lenalidomide,19 despite its FDA indication and NCCN listing.
At relapse after CAR T-cell therapy, Dr. Abramson emphasized repeating the biopsy to check antigen expression before choosing another treatment. For example, if the lymphoma has lost CD19, another CD19-directed therapy would no longer be appropriate. If it still expresses CD20, a CD20-directed bispecific regimen remains an option.
“It’s a very busy but optimistic landscape for DLBCL,” he said. “But it’s a field that continues to rapidly evolve.”
DISCLOSURE: Dr. Abramson reported no conflicts of interest.
REFERENCES
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