Improving Outcomes in Diffuse B-Cell Lymphoma Requires Multidisciplinary Evolution

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and common form of cancer that impacts thousands of individuals globally. In recent years, the treatment landscape of DLBCL has shifted rapidly due to evolutions in molecular profiling, immunotherapy, and response-adapted monitoring. During the 67th American Society of Hematology Annual Meeting and Exposition, held December 6-9, 2025, in Orlando, Florida, experts discussed how emerging modalities and novel research insights are powering the next frontier of DLBCL care.¹

Presenters at the session “Now Is the Time to Improve Outcomes in Diffuse Large B-Cell Lymphoma” included Sarah Rutherford, MD, an associate professor of clinical medicine in the Division of Hematology/Oncology at Weill Cornell Medicine in New York, New York; Jennifer Crombie, MD, a senior physician at Dana-Farber Cancer Institute in Boston, Massachusetts; and Franck Morschhauser, PhD, of the Centre Hospitalier Universitaire de Lille in France. The presenters outlined a series of innovations helping to inform personalized treatment strategies, as well as the challenges associated with these methods.¹

Early Response Assessment Could Lead to Treatment Modification, Improved Outcomes in DLBCL

Improving outcomes in patients with DLBCL begins with earlier response assessments that can be analyzed to determine therapy modifications, according to Crombie. She detailed opportunities for improving prognosis and early detection, including the use of PET scans and measuring circulating tumor DNA (ctDNA) to detect minimal residual disease (MRD). Crombie explained why utilizing ctDNA can be particularly effective at identifying patients who may benefit from a treatment alteration.¹

After frontline chemotherapy, often consisting of treatment with rituximab (Rituxan; Genentech), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), or polatuzumab (Polivy; Genentech) with the R-CHOP regimen, many patients will achieve significant improvements in their disease. For patients who do not exhibit a complete response following cycles of therapy, a PET scan at the end of treatment or an interim PET (iPET) scan during treatment will determine the state of the cancer and the impact of treatment.¹

Crombie described numerous challenges with PET scans that can hamper efforts to assess the patient’s cancer. These include imperfections in end-of-treatment PET, which, despite predicting progression-free survival (PFS) and overall survival (OS) after first-line treatment, may miss patients who relapse.¹

In addition, she noted, “There is a high false-positive rate. It makes you worry about potentially changing the therapy of someone who may be driving benefit [from their current regimen].”¹

Moreover, investigators of response-adapted trials have attempted to derive a clinical benefit with intensive chemotherapy using iPET with little success. In a 10-year follow-up of the phase 3 PETAL trial (NCT00554164), for example, although iPET predicted outcomes in aggressive lymphoma, iPET-based treatment alterations did not improve outcomes.^2-4

Crombie highlighted molecular testing using ctDNA assessments as a more productive avenue, asking the crowd, “Can we do better?” She outlined a series of next-generation sequencing assays for MRD, including clonoSEQ (Adaptive Biotechnologies), CAPP-Seq (Roche), and PhasED-Seq (Foresight Diagnostics). Recent studies have demonstrated improved personalized cancer profiling and heightened sensitivity with these novel diagnostic assays. Roschewski et al demonstrated that PhasED-Seq can be prognostic at both interim and end-of-therapy assessments.^1,5,6

Barriers remain in place against the use of interim MRD in clinical practice, including workflow and turnaround time considerations, as well as a lack of commercial availability of diagnostic assays. However, Crombie envisions a future where frontline induction—whether it be chemotherapy or a novel agent—could be followed by iPET and interim ctDNA assessment, with results that can guide future treatment plans. These interim assessments could play a complementary role in future DLBCL treatment.¹

“We’re not there yet, but this is, I think, an attractive potential strategy to consider for the future,” Crombie explained. “And I hope clinical trials start to answer these types of questions, as to whether or not we can use MRD and PET scans in this fashion.”¹

Optimizing Treatment Sequencing in Second and Third Lines

Novel modalities of response assessments, such as ctDNA MRD, could transform how patients with DLBCL are treated. But how do health care professionals determine exactly which treatments to utilize in each patient with relapsed or refractory disease, especially given the myriad novel therapies and regimens now available? Morschhauser explained how this consideration has come to the forefront of a shifting field, which is transitioning from defining patients after the first line based on their transplant eligibility to defining them by their eligibility for chimeric antigen receptor (CAR) T-cell therapy.¹

CAR T-cell therapies have transformed the paradigm of second-line treatment in DLBCL. In phase 2 trials such as ALYCANTE (NCT04531046) and PILOT (NCT03483103), agents such as axicabtagene ciloleucel (axi-cel; Yescarta; Gilead Sciences) and lisocabtagene maraleucel (liso-cel; Breyanzi; Bristol Myers Squibb) have demonstrated strong PFS rates within 1 year. CAR T-cell therapy offers numerous advantages compared with autologous stem cell transplantation, including not requiring a response from a prior line of therapy and not necessitating a referral to a specialty setting. Still, Morschhauser cautioned providers that “eligibility for CAR T-cell therapy is a dynamic process,” noting that older adults and patients with comorbidities face a higher risk of neurotoxicities.^1,7-10

Although new CAR T-cell therapies are becoming standard-of-care options, bispecific antibodies (BsAbs) and combination agents with antibody-drug conjugates are further advancing treatment capabilities. Investigators have tested regimens such as glofitamab (Columvi; Genentech) plus gemcitabine and oxaliplatin; mosunetuzumab (Lunsumio; Genentech) plus polatuzumab vedotin; and polatuzumab vedotin, rituximab, gemcitabine, and oxaliplatin. The sheer number of combinations provides countless new ways to better treat patients with DLBCL in the relapsed or refractory setting, Morschhauser explained.^1,11-13

Still, Morschhauser noted that data on the impacts of prior BsAb exposure on CAR T-cell outcomes remain limited. He told the audience, “We should be very cautious…before making a decision to shift the sequence in the other direction.” Given the unanswered questions that remain in the field, Morschhauser expressed his preference for CAR T-cell therapy in the second-line setting. However, in the third line—following the failure of CAR T-cell therapy—Morschhauser discussed the merits of treatment with BsAbs. Research by Topp et al previously demonstrated the effectiveness of monotherapy with the BsAb odronextamab in patients with disease progression after CAR T-cell therapy.^1,14

“Patients experiencing disease progression after CAR T and bispecifics still have [significant] unmet need, and we should focus our research on those patients,” Morschhauser concluded.¹

REFERENCES

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

2. Kostakoglu L, Martelli M, Sehn LH, et al. End-of-treatment PET/CT predicts PFS and OS in DLBCL after first-line treatment: results from GOYA. Blood Adv. 2021;5(5):1283-1290. doi:10.1182/bloodadvances.2020002690

3. Dührsen U, Bockisch A, Hertenstein B, et al; PETAL Trial Investigators. Response-guided first-line therapy and treatment of relapse in aggressive lymphoma: 10-year follow-up of the PETAL trial. Blood Neoplasia. 2024;1(3):100018. doi:10.1016/j.bneo.2024.100018

4. Positron emission tomography guided therapy of aggressive non-Hodgkin’s lymphomas (PETAL). ClinicalTrials.gov. Updated May 5, 2017. Accessed December 6, 2025. https://www.clinicaltrials.gov/study/NCT00554164

5. Falchi L, Jardin F, Haioun C, et al. Glofitamab (Glofit) plus R-CHOP has a favorable safety profile and induces high response rates in patients with previously untreated (1L) large B-cell lymphoma (LBCL) defined as high risk by circulating tumor DNA (ctDNA) dynamics: preliminary safety and efficacy results. Presented at ASH 2023; December 9-12, 2023; San Diego, CA. Accessed December 6, 2025. https://ash.confex.com/ash/2023/webprogram/Paper173953.html

6. Roschewski M, Kurtz DM, Westin JR, et al. Remission assessment by circulating tumor DNA in large B-cell lymphoma. J Clin Oncol. 2025;43(34):3652-3661. doi:10.1200/JCO-25-01534

7. Houot R, Bachy E, Cartron G, et al. Axicabtagene ciloleucel as second-line therapy in large B cell lymphoma ineligible for autologous stem cell transplantation: a phase 2 trial. Nature Medicine. 2023;29:2593-2601. doi:10.1038/s41591-023-02572-5

8. Axi-cel as a 2nd line therapy in patients with relapsed/refractory aggressive B lymphoma ineligible to autologous stem cell transplantation. ClinicalTrials.gov. Last Updated October 9, 2024. Accessed December 6, 2025. https://clinicaltrials.gov/study/NCT04531046

9. Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Lancet Oncol. 2022;23(8):1066-1077. doi:10.1016/S1470-2045(22)00339-4

10. Lisocabtagene maraleucel (JCAR017) as second-line therapy (TRANSCEND-PILOT-017006). ClinicalTrials.gov. Updated December 20, 2023. Accessed December 6, 2025. https://clinicaltrials.gov/study/NCT03483103

11. Abramson JS, Ku M, Hertzberg M, et al. Glofitamab plus gemcitabine and oxaliplatin (GemOx) versus rituximab-GemOx for relapsed or refractory diffuse large B-cell lymphoma (STARGLO): a global phase 3, randomised, open-label trial. Lancet. 2024;404(10466):1940-1954. doi:10.1016/S0140-6736(24)01774-4

12. Westin J, Zhang H, Kim W, et al. Mosunetuzumab plus polatuzumab vedotin is superior to R-GemOx in transplant-ineligible patients with R/R LBCL: primary results of the phase III SUNMO trial. Presented at: 2025 International Conference on Malignant Lymphoma Annual Meeting; June 17-21, 2025; Lugano, Switzerland. Accessed December 6, 2025. https://medically.gene.com/global/en/unrestricted/haematology/ICML-2025/icml-2025-presentation-westin-mosunetuzumab-plus-polatu.html

13. Matasar M, Li ZM, Vassilakopoulos TP, et al. Polatuzumab vedotin, rituximab, gemcitabine and oxaliplatin (Pola-R-GemOX) for relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL): results from the randomized phase III POLARGO trial. Presented at : European Hematology Association 2025 Congress; June 12-15, 2025; Milan, Italy. Accessed December 6, 2025. https://library.ehaweb.org/eha/2025/eha2025-congress/4159178/matthew.matasar.polatuzumab.vedotin.rituximab.gemcitabine.and.oxaliplatin.html

14. Topp MS, Matasar M, Allan JN, et al. Odronextamab monotherapy in R/R DLBCL after progression with CAR T-cell therapy: primary analysis of the ELM-1 study. Blood. 2025;145(14):1498-1509. doi:10.1182/blood.2024027044