The DLBCL Treatment Algorithm in 2025

John Leonard, MD NYU Langone Health

Key Points

• PET and laboratory evaluations are the main workup tools to confirm diffuse large B-cell lymphoma (DLBCL) and determine the International Prognostic Index score.

• R-CHOP and Pola-R-CHP are the primary treatments for fit patients with newly diagnosed DLBCL.

• In the relapsed or refractory setting, eligibility for chimeric antigen receptor T-cell (CAR-T) therapy or autologous stem cell transplant (ASCT) is a major factor in treatment selection and sequencing.

Introduction

Joined by John Leonard, MD, of Perlmutter Cancer Center, Rahul Gosain, MD, MBA, and Rohit Gosain, MD—hosts of the Oncology Brothers podcast—dove into the treatment algorithm for patients who have DLBCL.

The doctors covered the initial workup for a new patient with DLBCL, the approved treatments for both newly diagnosed and relapsed or refractory DLBCL, and current considerations for CAR-T therapy and bispecific antibody agents.

Initial Workup for DLBCL in 2025

According to Dr. Leonard, PET is the test of choice when DLBCL is suspected. An elevated standardized uptake value may indicate a more aggressive histology like DLBCL, whereas lower values suggest a more indolent lymphoma.

Dr. Leonard said other tests include a complete blood count, lactate dehydrogenase (LDH), hepatitis serologies, human immunodeficiency virus testing, and serum immunoelectrophoresis. A good core needle biopsy is also important because fine needle aspiration biopsies are often insufficient.

Patients with confirmed DLBCL are stratified with the International Prognostic Index, which is informed by age, performance status, LDH elevation, extranodal disease, and stage III or IV disease. The two major DLBCL subtypes are defined by cell of origin—germinal center B-cell (GCB) and activated B-cell (non-GCB). To determine the subtype, many centers are analyzing immunohistochemistry with the Hans algorithm as a “reasonable surrogate marker,” Dr. Leonard said.

DLBCL Treatments for Newly Diagnosed Patients

In fit patients with previously untreated stage I/II disease, the established frontline standard of care is six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by radiation. If a patient is PET-negative after completing three cycles, data show that abbreviating the remaining cycles and delaying radiation does not compromise survival.

More recently, a modified regimen of Pola-R-CHP (polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone) showed a progression-free survival benefit in the POLARIX trial. Based on those findings, most patients receive Pola-R-CHP, Dr. Leonard said; however, because POLARIX primarily enrolled patients with stage III/IV DLBCL, it’s unclear whether Pola-R-CHP can be adapted based on PET status for stage I/II disease.

Notably, follow-up analyses have suggested that polatuzumab has a greater benefit in non-GCB DLBCL. “The takeaway message is, if you see a non-germinal center subtype patient, you definitely want to use polatuzumab,” Dr. Leonard said.

Tailoring therapy based on individual tolerability is key for patients who are frail, are older, or have comorbidities. Regimens like mini–R-CHOP and mini–Pola-R-CHP (reduced doses of CHOP and CHP, respectively) may be preferable.

CHOP and CHP combinations are contraindicated in patients with cardiac risk features such as poor ejection fraction. In these cases, alternative regimens like R-CEPP (rituximab, cyclophosphamide, etoposide, prednisone, and procarbazine), R-CEOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), and DA-EPOCH (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) should be considered.

Treatment Options for Relapsed or Refractory Patients 

For patients with relapsed or refractory DLBCL, the treatment algorithm can vary based on when the most recent line of therapy was completed. Patients who relapse early—typically defined as within 12 months—are considered chemotherapy-resistant, whereas those who relapse later are considered chemotherapy-sensitive.

For early-relapse patients, the evidence favors the two approved CAR-T therapies, axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel), Dr. Leonard said. “Whether or not the patient needs bridging therapy with some sort of chemotherapy-based approach to get to CAR-T is a clinical judgement,” he added.

For later-relapse patients, alternative chemotherapy regimens and ASCT or regimens like Pola-BR (polatuzumab, bendamustine, and rituximab) and tafasitamab plus lenalidomide may still be effective. Bispecific antibodies or CAR-T therapies could also be considered.

“My takeaway is that you have to decide if the patient going to be a CAR T-cell or an ASCT candidate,” Dr. Leonard said. “If the patient is eligible, you really want to get the patient to those approaches, because those are the best established and still potentially curative options, albeit in a smaller fraction of patients.” 

Rounding up the discussion, Dr. Leonard offered some thoughts for community oncologists regarding choosing between approved bispecific antibodies and CAR-T therapies. In his experience, he said, axi-cel has been more practical and faster to obtain than liso-cel but tends to have a little more toxicity. For bispecifics, he noted that epcoritamab is approved for both follicular lymphoma and DLBCL indication, so it may be easier to implement in a community practice.