Key Clinical Summary

• Interim PET and circulating tumor DNA (ctDNA) assessments show prognostic value in diffuse large B-cell lymphoma (DLBCL), but their clinical utility for guiding treatment modifications remains investigational.
• CAR T-cell therapies and bispecific antibody–based combinations are redefining sequencing in relapsed/refractory (R/R) DLBCL, especially for patients who are ineligible for transplant.
• Molecular and microenvironmental subtyping may soon inform frontline and subsequent therapy decisions, with multiple subtype-directed trials underway.

At the 67th ASH Annual Meeting and Exposition, leading investigators presented new data and frameworks aimed at improving outcomes in DLBCL. The session focused on integrating early response assessment tools, optimizing treatment sequencing amid rapid therapeutic expansion, and applying molecular subtypes to tailor strategies for diverse patient populations. Collectively, the presentations illustrated a rapidly evolving treatment landscape poised to reshape oncology clinical pathways.

Session Highlights

Early Response–Adapted Strategies

Jennifer Crombie, MD, Dana-Farber Cancer Institute, explored whether interim PET and ctDNA could meaningfully guide frontline DLBCL therapy. While PET-complete response in the GOYA study correlated with improved progression-free survival (PFS), she noted limitations in predictive accuracy and a high false-positive rate. Interim PET similarly demonstrated prognostic significance but remains unreliable for treatment escalation.

Dr Crombie reviewed 3 ctDNA methodologies—immunoglobulin (IG) sequencing, CAPP-Seq, and PhasED-Seq—showing that early molecular response strongly predicted event-free and overall survival in multiple datasets. Small exploratory studies demonstrated minimal residual disease (MRD) conversion following addition of glofitamab, suggesting a potential future role for MRD-guided intensification. Phase-adapted frameworks combining interim PET and MRD may eventually enable early escalations or de-escalations of therapy, though clinical adoption is limited by assay availability, lack of standardization, and insufficient prospective evidence.

Sequencing Novel Therapies in R/R DLBCL

Franck Morschhauser, MD, PhD, Centre Hospitalier Régional Universitaire De Lille, addressed optimal sequencing for relapsed/refractory disease. Historically, transplant-ineligible patients were limited to low-intensity regimens with modest outcomes. CAR T-cell products such as axi-cel and liso-cel now provide complete response rates near 80% and 1-year PFS around 50% in high-risk populations.

He highlighted emerging bispecific antibody–based regimens, including glofitamab plus gemcitabine and oxaliplatin (GemOx), mosunetuzumab-polatuzumab, and polatuzumab-chemotherapy, which in phase 3 studies have achieved complete response (CR) rates and PFS outcomes approaching those of CAR T-cell therapy, with fewer logistical constraints. Dr Morschhauser emphasized the dynamic nature of CAR T eligibility and noted limited but encouraging data showing that prior exposure to bispecific antibodies does not preclude CAR T efficacy.

Molecular Subtypes and Personalized Therapy

Sarah Rutherford, MD, Weill Cornell Medicine, reviewed evolution from cell-of-origin classification to genetically defined subtypes, including MCD, BN2, EZB, A53, and ST2. She underscored that MCD (cluster 5) disease represents the highest-risk group, with potential benefit from BTK inhibitor–based approaches. She noted that Pola-R-CHP continues to demonstrate a PFS advantage at 5 years, particularly in activated B-like (ABC)/non-germinal center B-like (GCB) phenotypes.

Dr Rutherford described ongoing subtype-directed clinical trials, including LymphoMATCH, which integrates targeted agents such as BTK, EZH2, and JAK2 inhibitors depending on genetic cluster. She also reviewed early data suggesting that microenvironment-defined profiles (gene expression profiling [GEP] hot vs cold) may predict response to bispecific antibodies such as mosunetuzumab.

Dr Crombie highlighted that interim imaging remains useful for identifying clear progressors but cannot yet reliably guide treatment modifications. Dr Morschhauser reiterated that CAR T eligibility—not transplant status—should drive decision-making and noted that age alone should not exclude candidates. Dr Rutherford emphasized that genetic subtyping is poised to enhance frontline therapy design, particularly for high-risk groups such as MCD. Panelists collectively agreed that bispecific antibodies, ctDNA-guided approaches, and molecular stratification will increasingly influence oncologic pathways as evidence matures.

Implications for Practice

The session underscores a shift toward biology-driven, response-adapted management in DLBCL. Although not yet practice-changing, interim MRD and PET assessments may soon help identify candidates for early intensification with CAR T or bispecific antibodies, or those suitable for de-escalation. Molecular subtyping is expected to guide therapy selection in both clinical trials and future standard-of-care pathways.

Conclusion

Rapid advances in response assessment tools, novel therapeutics, and molecular characterization are reshaping the DLBCL treatment paradigm. Ongoing randomized trials will determine how these innovations can be incorporated into clinical practice, with significant implications for oncology decision-makers and pathway optimization.

Reference

Morschhauser F, Crombie J, Rutherford S. Now Is the Time to Improve Outcomes in Diffuse Large B-Cell Lymphoma. Presented at: ASH 2025; December 6-9; Orlando, FL.