New Data at ASH 2025 Reshapes Lymphoma Care From Frontline to Relapsed Disease

Rafaella Litvin, MD Taussig Cancer Center, Cleveland Clinic

Lymphoma Panel with Dr. Andrew Evens and Dr. Urshila Durani

A rapidly evolving lymphoma landscape took center stage at the 2025 ASH Annual Meeting, with an expert panel highlighting how traditional standards like R-CHOP are being challenged, bispecific antibodies are moving earlier in treatment, and emerging data are reshaping care across diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and mantle cell lymphoma. 

Panelists Andrew Evens, DO, MBA, MSc, of Rutgers Cancer Institute, and Urshila Durani, MD, MPH, of Mayo Clinic, discussed these themes with Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center. A unifying theme centered on balancing efficacy, toxicity, and patient-centered outcomes as therapeutic choices broaden.

Frontline DLBCL: POLARIX and Real-World Decision-Making

The panel opened the discussion with the role of cell of origin (COO) in guiding frontline treatment decisions for DLBCL. The 5-year update of the POLARIX trial, presented at ASH 2025, reinforced pola-R-CHP for patients with an International Prognostic Index score of 2 or greater—regardless of COO—showing modest progression-free survival (PFS) but no overall survival (OS) benefit when compared with R-CHOP. 

However, in practice, approaches vary. Subgroup analyses suggest non–germinal center (GC) patients derive the most benefit, but as Dr. Evens noted, POLARIX used gene expression profiling for COO, while clinical practice relies on immunohistochemistry (IHC), which can misclassify cases. For this reason, Dr. Evens treats all eligible patients with pola-R-CHP. At Mayo Clinic, Dr. Durani takes a more conservative approach, treating only non–GC patients identified by IHC.

CAR T and Bispecifics Expand Options 

CD19-targeted chimeric antigen receptor (CAR) T-cell therapy remains the preferred option for patients who are refractory or relapse within the first 12 months. The panel highlighted recent FDA changes, including a reduction in the required observation period near treatment centers from 4 to 2 weeks, which should improve access.

Bispecific antibodies are also becoming increasingly important in relapsed/refractory (R/R) DLBCL, typically after two or more lines of therapy, and are expected to move into earlier lines soon. Epcoritamab and glofitamab are considered equally effective, and the panel emphasized a patient-centered approach when choosing between them. Epcoritamab is administered subcutaneously as continuous therapy, while glofitamab is given intravenously in a time-limited schedule. Both carry risks of cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome, although severe events are rare. Glofitamab may be associated with more frequent cytopenias. With growing experience, some centers start treatment at an academic site and continue locally, while others now deliver the full course in the community.

For follicular lymphoma, the EPCORE FL-1 data emerged as one of the most significant updates of ASH 2025 in the field of lymphoma. The study compared epcoritamab combined with rituximab and lenalidomide (epco plus R²) versus R² alone, showing an overall response rate of 95% versus 79%, with an estimated 16-month PFS of 85.5% versus 40.2%. 

Dr. Durani emphasized that treatment goals must guide therapy decisions: is the priority quality of life and longevity, or prolonged remissions and time off treatment? While the epco plus R² combination may extend treatment-free intervals, it was significantly more toxic than R² alone. 

The panel suggested reserving this regimen for patients with high disease burden or relapsed/refractory disease ineligible for CAR T-cell therapy, while bendamustine plus rituximab (BR) remains the preferred frontline option. The benefit of starting with BR or R² followed by epcoritamab at relapse versus the upfront triple combination remains uncertain.

Managing Infection Risk

Infection prevention is another key consideration with bispecific antibodies. Antiviral and PJP prophylaxis have become standard, while antibacterial prophylaxis is infrequently used. The panelists employ intravenous immunoglobulin supplementation for patients with IgG levels below  400, based on real-world lymphoma experience and extrapolated multiple myeloma data, although prospective lymphoma data are lacking.

Advances and Practical Considerations Across Lymphoma Subtypes

Sonrotoclax and mesutoclax, emerging B-cell lymphoma 2 inhibitors, showed complete response rates around 50% in the R/R mantle cell lymphoma setting. As venetoclax continues to be incorporated into frontline, chemotherapy-free regimens—especially for high-risk TP53-mutated patients—it remains to be seen whether these new agents will maintain their efficacy in R/R disease.

Furthermore, the approval of lisocabtagene maraleucel (liso-cel) for marginal zone lymphoma (MZL) offers an additional tool, although most MZL cases respond well to rituximab, even upon retreatment. Bruton tyrosine kinase inhibitors and rituximab combinations are also effective in R/R disease. Patients who might benefit most are those with suspected transformation to DLBCL where biopsy is not feasible.

In Hodgkin lymphoma, the 3-year update of SWOG S1826 confirmed the superiority of nivolumab-AVD over brentuximab vedotin-AVD in the frontline setting, with a 3-year PFS of 91% versus 82%. Although less commonly used in the United States, BrECADD remains an effective option favored in Europe, delivering durable responses in more than 90% of patients after 4 cycles with reduced anthracycline exposure.

Audience discussion centered on interim PET scans and minimal residual disease (MRD) testing. In DLBCL, the timing and value of interim PET scans are unclear, as only a small minority of patients—around 5%—have management changes based on results. MRD testing with circulating tumor DNA, recently added to NCCN guidelines, remains mostly confined to clinical trials. Practical application continues to be defined.