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Treating DLBCL
Evolving Treatment Algorithms in Diffuse Large B-Cell Lymphoma

Released: January 30, 2026

Laurie H. Sehn
Laurie H. Sehn, MD, MPH
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Key Takeaways
  • Frontline therapy remains chemotherapy based, with pola-R-CHP now an option in practice.
  • Second-line treatment choices are based on timing of relapsed/refractory disease and risk for many and include CAR T-cell therapy and ASCT, with bispecific antibodies also a valuable part of the later-line treatment armamentarium.
  • Novel emerging treatment strategies include incorporating bispecific antibodies in combination with standard regimens, earlier integration of CAR T-cell therapy, and novel bispecific antibodies, CELMoD agents, BTK inhibitors, and BCL6 degraders.

Diffuse large B-cell lymphoma (DLBCL) management is evolving rapidly with the expansion of immunotherapy platforms and novel targeted agents. Despite this progress, curative-intent frontline therapy remains largely anchored in anthracycline-based chemoimmunotherapy. In this commentary, Laurie H. Sehn, MD, MPH, discusses contemporary approaches and emerging strategies in treating DLBCL.

Frontline Therapy: Enduring Chemotherapy Backbone
Rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) continues to serve as the reference standard for initial treatment in many patients with newly diagnosed DLBCL. Polatuzumab vedotin in combination with rituximab plus cyclophosphamide/doxorubicin/prednisone (pola-R-CHP) has emerged as an increasingly used alternative based on the improved progression-free survival (PFS) observed in the overall population of the phase III POLARIX study, in which patients with previously untreated DLBCL were randomized to receive pola-R-CHP or R-CHOP, with eligible adult patients being up to 80 years of age with an International Prognostic Index (IPI) score of 2-5. In practice, enthusiasm is particularly pronounced for patients with activated B-cell (ABC) biology, where subgroup analyses suggest not only PFS improvement but a possible overall survival advantage. Accordingly, treatment patterns vary: Some healthcare professionals deploy pola-R-CHP broadly when access permits, whereas others prefer to reserve it for biologically higher-yield subgroups such as the ABC one.

Decera Clinical Education, in collaboration with John N. Allan, MD; Jeremy S. Abramson, MD, MMSc; Brad Kahl, MD; Krish Patel, MD; and myself, have created an interactive online treatment decision support tool focused on DLBCL treatment. As a user of the tool, you can enter key patient and disease characteristics to define a patient scenario. After entering key patient and disease characteristics, you will select your intended treatment choice. After selecting your choice of therapy, the recommendations from all 5 experts for your individual set of characteristics will appear along with a link to additional information to consider.

For example, for a patient with previously untreated stage III/IV DLBCL not otherwise specified who is not older or frail and who does not have significant cardiac dysfunction, 2 experts would recommend pola-R-CHP, and 3 experts would recommend either pola-R-CHP or R-CHOP, with the former recommended specifically for those with non–germinal center B-cell/ABC DLBCL biology.

A major source of real-world variability lies in the management of patients unable to tolerate standard anthracycline-based chemoimmunotherapy. Emerging studies evaluating frontline bispecific antibody monotherapy and nonchemotherapy combinations in this population are generating clinical interest. However, these strategies remain investigational and are not yet approved for frontline use. This setting, therefore, remains an area of substantial unmet need in which trial enrollment is particularly consequential.

Second-line Therapy: Risk-Adapted Divergence Between CAR T-Cell Therapy and Transplant
Second-line management has undergone a paradigm shift defined by relapse timing and risk. For patients with primary refractory disease or early relapse, randomized phase III comparisons of CAR T-cell therapy (lisocabtagene maraleucel or axicabtagene ciloleucel) vs salvage chemotherapy followed by autologous stem cell transplant (ASCT) demonstrate a marked advantage favoring CAR T-cell therapy for this high-risk population, establishing it as the standard of care when feasible. By contrast, for late-relapsing patients who remain transplant eligible and chemotherapy sensitive, salvage therapy followed by ASCT remains a preferred curative strategy, with a clinically meaningful probability of long-term disease control.

Beyond CAR T-Cell Therapy and ASCT: Expanding Options With Limited Standardization
For patients ineligible for CAR T-cell therapy and/or ASCT or for those who progress following these modalities, no single standard approach is uniformly established. Decision-making is commonly individualized, integrating disease kinetics, prior depth and duration of response, comorbidity burden, logistical feasibility, and patient preferences.

Bispecific antibodies have assumed a central role in this later-line space, with mounting follow-up from pivotal trials suggesting increasing durability of responses and raising the prospect that a subset of patients may achieve long-term remission. Bispecific antibody–based combinations are also advancing into earlier lines, including second-line regimens (eg, glofitamab plus gemcitabine/oxaliplatin [GemOx] and mosunetuzumab plus polatuzumab). Of importance, as polatuzumab-containing regimens move into frontline care, the utility of polatuzumab-based salvage approaches may be attenuated for some patients, thereby increasing reliance on mechanistically distinct immunotherapies.

Let’s look at a case from our tool. For a patient who received first-line pola-R-CHP and second-line CAR T-cell therapy with CD19/CD20 expression maintained, 2 experts would specifically recommend glofitamab with or without GemOx, 1 would recommend glofitamab or epcoritamab, 1 would recommend a bispecific antibody with an antibody–drug conjugate (ADC) like loncastuximab tesirine, and 1 would recommend a bispecific antibody with or without chemotherapy. If we look at the case of a patient who received frontline pola-R-CHP but experienced primary refractory disease or early relapse within 12 months and who is not eligible for or cannot access CAR T-cell therapy, 4 experts would specifically recommend glofitamab plus GemOx, and 1 would more generally recommend a bispecific antibody with an ADC or chemoimmunotherapy.

Sequencing Considerations: CAR T-Cell Therapy vs Bispecific Antibodies
A prominent emerging question concerns the optimal sequencing of CAR T-cell therapy and bispecific antibodies. Current practice often prioritizes CAR T-cell therapy for eligible patients because of established curative potential and longer-term outcomes data. Nevertheless, bispecific antibodies may increasingly compete for earlier placement in select circumstances, particularly for patients who are marginal candidates for CAR T-cell therapy, those who prioritize off-the-shelf availability or in settings where CAR T-cell therapy access is delayed. In these scenarios, bispecific therapy may serve either as definitive treatment with the aim of durable remission or as a bridge that preserves later CAR T-cell therapy eligibility.

Investigational Horizons
Multiple ongoing trials are poised to reshape frontline therapy, including studies incorporating bispecific antibodies in combination with standard regimens (eg, epcoritamab with R-CHOP) or polatuzumab-containing backbones. In addition, investigational approaches evaluating earlier integration of CAR T-cell therapy for the highest-risk patients (eg, high IPI scores) reflect a broader trend toward relapse prevention rather than salvage.

Many novel treatment strategies are also being explored. These include novel bispecific antibodies (eg, surovatamig/AZD0486), novel immunomodulatory cereblon E3 ligase modulators (CELMoD agents like golcadomide), BTK inhibitors, and BCL6 degraders. For an in-depth look at novel approaches to DLBCL treatment, review an expert-authored text activity with downloadable slides here.

Final Thoughts
DLBCL management is transitioning from a linear chemotherapy–salvage paradigm to a dynamic sequencing framework integrating multiple potentially curative immunotherapy modalities. Although anthracycline-based chemoimmunotherapy remains the cornerstone of frontline care, pola-R-CHP has introduced clinically relevant refinement, and ongoing studies may further move bispecific antibodies, and potentially CAR T-cell therapy, into earlier treatment lines. In the relapsed/refractory setting, relapse timing increasingly dictates second-line strategy (CAR T-cell therapy for early relapses; ASCT for transplant-eligible late ones), whereas bispecific antibodies have become a preferred approach for patients ineligible for or progressing after CAR T-cell therapy/ASCT. As new agents move forward in line, therapeutic sequencing will become progressively individualized, shaped by patient fitness, access, biology, and prior exposure to key drug classes.

Your Thoughts
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