For patients with relapsed or refractory follicular lymphoma, the timing of progression is one of the factors Peter A. Riedell, MD, considers when choosing the next treatment. A long first remission may support another course of chemoimmunotherapy, but progression within 24 months of starting front-line treatment pushes him toward novel therapies or clinical trials, he said at the NCCN 2026 Annual Congress: Hematologic Malignancies in New York City.1
Dr. Riedell is Associate Program Director for Lymphoma and Director of Clinical Research for the Hematopoietic Cellular Therapy Program at the University of Chicago. He also discussed how he chooses between bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapy in later lines of treatment.
Historically, remissions have shortened with each successive line of treatment a patient receives, he noted. About one in five patients treated with front-line chemoimmunotherapy has progression of disease within 24 months, which is associated with inferior overall survival.2,3
For patients with early progression, “those are the patients [for whom] we need to really prioritize some of these novel treatment approaches and clinical trials,” he said.
Two New Second-Line Triplet Regimens
Two new triplet regimens in the relapsed/refractory follicular lymphoma space build on lenalidomide plus rituximab, adding either epcoritamab or tafasitamab. Both regimens are category 1 second-line recommendations in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), supported by the randomized phase III EPCORE FL-1 and inMIND trials, respectively.
Epcoritamab is a CD3 x CD20-directed bispecific T-cell engager, whereas tafasitamab is a CD19-directed monoclonal antibody. Dr. Riedell generally selects the tafasitamab triplet (lenalidomide/rituximab/tafasitamab) for patients who cannot manage the logistics of bispecific treatment, who decline it, or whose infection risk makes a bispecific less suitable.
EPCORE FL-1 compared a triplet regimen of epcoritamab plus lenalidomide/rituximab vs a doublet regimen of lenalidomide/rituximab in patients who were good candidates for bispecifics and who had received at least one prior chemoimmunotherapy regimen. Approximately 40% had progression of disease within 24 months of starting front-line therapy.Epcoritamab and lenalidomide were given for 12 cycles, with rituximab for five cycles and step-up epcoritamab dosing during the first cycle.4
Complete responses occurred in 83% of patients receiving the triplet regimen vs 50% receiving lenalidomide/rituximab. At a median follow-up of 14.8 months, median progression-free survival was not reached with the triplet regimen vs 11.7 months with lenalidomide/rituximab. The triplet regimen also reduced the risk of progression or death by 79% (hazard ratio [HR] = 0.21; P < .0001), with a benefit that extended to patients with progression of disease within 24 months of first remission and other high-risk features.
However, adding epcoritamab did increase toxicity, largely through neutropenia and infection. Grade 3 or higher infections occurred in 33% of patients receiving the triplet regimen vs 16% of those receiving lenalidomide/rituximab, and opportunistic infections in 18% vs 4%. Growth factor support was used in 83% of recipients receiving the triplet regimen; 87% received Pneumocystis jirovecii pneumonia prophylaxis and 71% received herpes simplex virus prophylaxis.
Is There a Role for HSCT in R/R Follicular Lymphoma?
For some patients with R/R follicular lymphoma, high-dose chemotherapy followed by SCT may be an option.
Autologous stem cell transplant may be considered as a consolidation option for chemosensitive relapsed patients—particularly those with early relapse (such as those experiencing disease progression within 24 months of initial diagnosis) who achieve remission after second-line therapy.
Allogeneic stem cell transplant may benefit selected patients who experience disease relapse following HDT/ASCR, although it is associated with significant transplant-related mortality. This is usually reserved for heavily pretreated, fit patients (typically after three or more systemic lines of therapy).
Most often considered for patients who have experienced CAR-T cell therapy failure, lack access to CAR-T, or have high-risk/transformed disease features.
Reduced-intensity conditioning regimens have made the procedure safer than older myeloablative approaches, though nonrelapse mortality and graft-versus-host disease remain significant risks.
Cytokine-release syndrome (CRS) generally clustered around the first full epcoritamab dose. Dr. Riedell noted that using three step-up doses reduced its incidence from 45% to 26%, with most events being grade 1 and manageable, he noted.
The other new triplet adds tafasitamab to lenalidomide/rituximab. In the randomized phase III inMIND trial, that combination was compared with placebo plus lenalidomide/rituximab in patients previously treated with at least one regimen containing an anti-CD20 antibody. Approximately 45% had progression of disease within 24 months when measured from the start of front-line treatment.5
Complete responses occurred in 45% vs 34%. At a median follow-up of 14.1 months, median progression-free survival was 22.4 vs 13.9 months. The tafasitamab triplet reduced the risk of progression or death by 57% (HR = 0.43; P < .0001), and the benefit was seen in patients with progression of disease within 24 months or anti-CD20–refractory disease, and across prior lines of therapy.
“With the addition of tafasitamab, we’re not really seeing a substantially increased toxicity burden,” Dr. Riedell said. Grade 3 or 4 adverse events occurred in 71% vs 69%, and lenalidomide dose reductions and discontinuations were similar between arms.
Bispecific Antibodies or CAR T-Cell Therapy
In the third-line and beyond, Dr. Riedell emphasized T-cell–mediated treatments, including the CD20 x CD3 bispecific antibodies mosunetuzumab-axgb and epcoritamab-bysp, and three CD19-directed CAR T-cell products.
Mosunetuzumab offers a fixed course: patients achieving a complete response receive eight cycles, whereas those with a partial response may receive up to 17 cycles. In a pivotal phase II trial of mosunetuzumab in patients with relapsed or refractory follicular lymphoma who had received at least two prior therapies, the complete response rate was 60%, and 37% remained progression free at 5 years.6
The most common adverse event was cytokine release syndrome, occurring in 44%. Adverse events resulting in treatment discontinuation took place in 4% of patients.
Epcoritamab monotherapy is given subcutaneously until progression or intolerance. In the single-arm phase II EPCORE NHL-1 trial, which included patients with relapsed or refractory follicular lymphoma after at least two prior therapies, the complete response rate was 63%, and estimated progression-free survival at 18 months was 49%. 7
Clinical trials of CAR T-cell therapy have also shown high response rates and durable remissions. In ZUMA-5, axicabtagene ciloleucel (axi-cel) produced complete responses in 79% of patients with follicular lymphoma; 5-year progression-free survival was 50% in the overall indolent lymphoma cohort.8,9 The corresponding figures for tisagenlecleucel (tisa-cel) in ELARA were 68% and 46%.10 In TRANSCEND FL, lisocabtagene maraleucel (liso-cel) had a complete response rate of 94% and 3-year progression-free survival of 68%.11
Dr. Riedell pointed to the flattening of the progression-free survival curves with longer follow-up. These are “probably, I would argue, the most durable responses we’re seeing among our relapsed/refractory treatment options,” he said.
Toxicity also helps distinguish the approaches. Across the trials he reviewed, severe CRS was uncommon with both, whereas the risk of immune effector cell-associated neurotoxicity syndrome (ICANS) was substantially higher with CAR T-cell therapy. Grade 3 or higher ICANS occurred in up to 15% of patients receiving axi-cel, he noted.
CAR T-cell therapy is “one and done,” Dr. Riedell said, but referral, testing, apheresis, manufacturing, arrangements for a caregiver, and proximity to a treatment center can delay treatment. Bispecific antibodies are available off the shelf and can be administered as outpatient treatment, although they require repeated visits. “I would often steer away from something like CAR T-cell therapy in a very elderly patient, or a patient with a higher comorbid burden,” he said, adding that these patients may be better suited to mosunetuzumab or epcoritamab.
Sequencing and Suspected Transformation
As more patients receive epcoritamab in the second-line setting, clinicians will increasingly need to choose what comes next if their lymphoma progresses.
Another possibility is retreatment with a bispecific antibody, particularly if the first treatment produced a long remission and the lymphoma still expresses CD20. However, evidence is limited, and there is no established remission duration to guide that choice. In a small cohort of 12 patients with indolent or aggressive B-cell lymphoma who relapsed after achieving a complete response to mosunetuzumab, retreatment with mosunetuzumab produced responses in 10 patients, including seven complete responses.12
Retrospective experience in diffuse large B-cell lymphoma suggests that prior bispecific treatment does not prevent subsequent effective CAR T-cell therapy, Dr. Riedell said. However, data guiding the sequence specifically in follicular lymphoma remain sparse.13
Concern for transformation also affects this choice. He cautioned that rapid growth, elevated lactate dehydrogenase, or very high uptake on positron-emission tomography should prompt efforts to obtain a biopsy. If transformation is suspected but cannot be confirmed, he may favor CAR T-cell therapy because of its durable responses in aggressive lymphoma.
Treatment After Progression
Repeat biopsy at progression can establish whether the lymphoma has retained the antigen needed for another targeted treatment. CD20 loss has been observed in approximately one-third of progression biopsies after bispecific therapy.14 For CD20-negative disease, Dr. Riedell favors switching targets, such as to CD19-directed CAR T-cell therapy.
If the lymphoma progresses despite retaining CD20, the problem may be that the T cells are no longer responding effectively to the bispecific antibody.15 Dr. Riedell discussed switching to CAR T-cell therapy or potentially allowing a treatment-free interval to give T cells time to recover before trying treatment again. He emphasized repeating the biopsy to confirm CD20 expression before giving another CD20-directed bispecific antibody.
Preparing for CRS and Preventing Infection
When administering bispecific antibodies, Dr. Riedell underscored the importance of preparing patients and health-care teams to recognize and manage CRS, which generally occurs around the first full dose.
His institution uses dexamethasone premedication and gives patients clear instructions about symptoms, whom to call, and when to seek urgent care.16 Patients receive at least a thermometer, with a blood pressure cuff and pulse oximeter when available. They also receive a dexamethasone prescription to use if symptoms develop at home, but must call the care team before taking it. The team determines whether they can manage the symptoms at home or need emergency evaluation.
Emergency department clinicians, nurses, and pharmacists must be prepared to recognize CRS and ICANS, he stressed, and tocilizumab and corticosteroids should be available to manage these complications. “We’ve seen that most bispecific antibody CRS is preventable in severity and predictable in timing,” Dr. Riedell said. “Hopefully, this will increase the utilization of these treatments in the community.”
In a meta-analysis of 27 studies involving 2,228 patients treated with CD20-directed bispecific antibodies, infections occurred in 44%, and grade 3 or higher infections in 20%. The pooled fatal infection rate was 3.5%.17
“Infection risk with bispecifics is really one of our biggest enemies, and it’s the leading cause of nonrelapse mortality,” he said.
Dr. Riedell uses Pneumocystis jirovecii pneumonia and herpes simplex virus or varicella-zoster virus prophylaxis and aims to give standard vaccinations before treatment. His institution checks immunoglobulin levels regularly and administers intravenous immunoglobulin when IgG levels fall below 400 mg/dL or patients have recurrent infections. He added that treatment should be held during active infection, and growth factor support can help manage neutropenia.
DISCLOSURE: Dr. Riedell has served as a consultant and/or advisory board member for AbbVie, ADC Therapeutics, BMS, CVS Caremark, Genentech, Genmab, Johnson & Johnson, Kite/Gilead, Lilly, Miltenyi, Novartis, and Pfizer; he has received research funding from AbbVie, AstraZeneca, BMS, Cellectis, Genentech, Kite/Gilead, Lilly, Lyell, and Novartis.
REFERENCES
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