DLBCL Relapse: EHA 2026 Addresses Gaps in Treatment Strategy

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma. Approximately 30-40% of patients with DLBCL will experience relapse or become refractory to initial chemoimmunotherapy, typically R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone).¹ For these patients, outcomes are historically poor, with a median overall survival (OS) of less than 6 months in the pre-CAR T-cell era for those refractory to second-line therapy.² The advent of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) improved outcomes for chemosensitive relapses, but a substantial unmet need persists for patients who are refractory to salvage chemotherapy or ineligible for ASCT.³

Current daily practice for R/R DLBCL typically involves salvage chemotherapy regimens such as R-ICE (rituximab, ifosfamide, carboplatin, etoposide), R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin), or R-GDP (rituximab, gemcitabine, dexamethasone, cisplatin).⁴ Patients achieving a complete or partial response to salvage therapy are often considered for ASCT. However, a significant proportion of patients do not achieve chemosensitivity or relapse post-ASCT, leading to a need for further therapeutic options.⁵

Addressing Gaps and Next Moves

The EHA 2026 discussions highlighted several critical gaps in the current management of R/R DLBCL. One primary concern is the lack of consensus on optimal sequencing of novel agents, particularly in the second-line setting. Chimeric antigen receptor (CAR) T-cell therapies, such as axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), have demonstrated superior event-free survival (EFS) compared to standard of care in second-line R/R DLBCL, particularly for patients with primary refractory disease or early relapse (within 12 months of initial therapy).^6,7 For instance, the ZUMA-7 trial showed a Hazard Ratio (HR) of 0.40 (95% CI, 0.31-0.51; p < 0.0001) for EFS with axi-cel versus standard of care.⁶ Despite these advances, a substantial proportion of patients (approximately 60% in some trials) still do not achieve durable responses with CAR T-cell therapy or experience relapse post-CAR T.⁸

Another significant gap is the management of patients who are ineligible for or fail CAR T-cell therapy. Bispecific antibodies targeting CD3 and CD20, such as epcoritamab and glofitamab, have shown promising activity in heavily pretreated R/R DLBCL.^9,10 For example, glofitamab, administered as a fixed-duration regimen, achieved a complete response (CR) rate of 39.4% (95% CI, 30.0-49.3) in a pivotal phase 2 study.¹⁰ Similarly, polatuzumab vedotin, an antibody-drug conjugate, in combination with bendamustine and rituximab (Pola-BR), demonstrated improved OS compared to BR alone in relapsed/refractory patients ineligible for ASCT, with a HR of 0.42 (95% CI, 0.24-0.73).¹¹ The challenge lies in integrating these agents into existing treatment algorithms, especially in earlier lines of therapy, and identifying patient subsets most likely to benefit.¹²

Discussions at EHA 2026 also focused on the role of novel combinations and strategies to overcome resistance mechanisms. This includes exploring combinations of CAR T-cells with checkpoint inhibitors or other targeted agents, as well as developing next-generation CAR T-cell constructs.¹³ Furthermore, the importance of real-world data and biomarker identification to guide treatment selection was emphasized. The heterogeneity of DLBCL, both clinically and molecularly, necessitates a personalized approach, moving beyond a one-size-fits-all strategy.¹⁴ The ongoing development of predictive biomarkers for response to CAR T-cell therapy and other novel agents is critical to optimize patient selection and improve resource allocation.¹⁵