Relapsed or Refractory DLBCL: Reviewing the Expanding Treatment Landscape

The treatment landscape for relapsed or refractory large B-cell lymphoma (DLBCL) has shifted rapidly, with bispecific antibodies, antibody-drug conjugates (ADCs), and cellular therapies now available. But for many patients—especially those with early relapse or limited access to cell therapy—durable remission remains elusive.

In a review published in the Journal of Hematology & Oncology in July 2025, Drs. Allison M. Bock and Narendranath Epperla examine where these agents fit, what data gaps persist, and how emerging tools may refine future sequencing strategies.

Here's a quick summary of the review.

Therapeutic Classes and Mechanistic Overlap
Current therapies in relapsed DLBCL often target overlapping B-cell surface antigens—particularly CD19 and CD20—using different modalities. CD19-directed CAR-T cell therapies, including axi-cel and liso-cel, have demonstrated superior outcomes compared to autologous stem cell transplant (auto-SCT) for early relapsing disease.

Meanwhile, bispecific antibodies (BsAbs) targeting CD20 and CD3 such as epcoritamab, glofitamab, and odronextamab, have demonstrated high response rates. Each differs in molecular design, route of administration, and mitigation strategies for cytokine release syndrome and neurotoxicity, but no direct comparative studies are available to inform selection between them.

ADCs, including polatuzumab vedotin (CD79b-targeting), loncastuximab tesirine (CD19), and brentuximab vedotin (CD30), are also approved for relapsed DLBCL and remain viable options, particularly for patients ineligible for cell therapy. Of note, the toxicity profiles vary, driven largely by the payload and dosing intensity. The impact of prior exposure to CD19- or CD20-targeted agents on ADC efficacy remains an area of investigation.

Role of Timing and Eligibility in Treatment Outcomes
Treatment outcomes in DLBCL are influenced by the timing of relapse and eligibility for curative-intent therapies. Patients with early relapse (within 12 months of initial therapy) have historically demonstrated inferior outcomes across therapeutic classes. CAR-T products have demonstrated improved event-free survival and overall survival when used as second-line therapies compared to auto-SCT.

For patients who aren’t eligible for transplant or CAR-T, BsAbs have demonstrated response rates in single-arm studies. But real-world retrospective data suggest decreased response rates in high-risk populations, including those with prior CAR-T exposure or CD20-negative disease.

Target Expression and Limitations in Biomarker Use
Although several therapies are designed to target CD19 or CD20, the assessment of these antigens isn’t routinely standardized at relapse. And while loss of CD19 following CAR-T or other CD19-directed therapies has been reported in up to 30% of patients, the minimum expression threshold required for therapeutic effect remains undefined.

Along with varying treatment outcomes in select populations, this highlights the urgent need for biomarkers with defined expression thresholds for clinicians to use for selecting treatment and predicting resistance in this treatment setting.

Current Gaps in Evidence and Practice
The authors note that while the therapeutic options for relapsed DLBCL have expanded, the lack of comparative data means there’s no prospective framework to determine optimal sequencing of treatments. And while novel agents have demonstrated durable responses in a subset of patients, a high proportion still relapse within the first 6 months of treatment, suggesting current regimens may delay, but not overcome, resistance. Treatment selection remains dependent on institutional experience, toxicity profiles, and access rather than evidence-based pathways.

Looking ahead, studies incorporating ctDNA-guided surveillance, biomarker stratification, and combination regimens may help clarify treatment selection criteria and sequencing strategies in relapsed DLBCL. Until then, optimizing care in relapsed DLBCL will require balancing efficacy, access, and patient-specific goals while navigating an increasingly crowded and complex therapeutic landscape.

Reference:
Bock AM, Epperla N. Therapeutic landscape of primary refractory and relapsed diffuse large B-cell lymphoma: recent advances and emerging therapies. J Hematol Oncol. 2025;18(1):68. doi:10.1186/s13045-025-01702-5