Frontline treatment for diffuse large B-cell lymphoma in 2026: Lessons from targeted and immune-based approaches

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in the USA and Western Europe.^1,2 DLBCL is treated with curative intent given the aggressive nature of the disease. Rituximab (R), cyclophosphamide (C), doxorubicin (H), vincristine (O) and prednisone (P) (R-CHOP) has been the bedrock of therapy for patients with DLBCL since the pivotal study by Coiffier et al.³ This was the first study in DLBCL that introduced an immunotherapeutic agent (rituximab) into the treatment of lymphoma. Although highly effective for most patients, approximately one-third of those who receive this regimen will have primary refractory disease or experience a late relapse. Additionally, patients must have adequate cardiac function to safely receive doxorubicin, which is one of the most effective components of this regimen.

Attempts at improving outcomes in frontline DLBCL have mostly focused on the R-CHOP + X model, which is rooted in the belief that adding novel treatments (X) that have demonstrated single-agent activity in DLBCL could further enhance the efficacy of R-CHOP. This approach led to the enrollment and completion of several studies, as illustrated in Table 1, including a cooperative study from the USA that sought to establish rituximab (R), dose-adjusted etoposide phosphate (E), prednisone (P), vincristine sulfate (Oncovin; O), cyclophosphamide (C), doxorubicin hydrochloride (Hydroxydaunomycin; H) or R-DA-EPOCH as the new standard of care.^4–11 Unfortunately, with the exception of small, selected populations in some of these studies, these trials failed to demonstrate any benefit over R-CHOP, despite the great initial enthusiasm for some of the regimens that demonstrated impressive phase II data.

This metric changed with the completion of the POLARIX study (A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial Comparing the Efficacy and Safety of Polatuzumab Vedotin in Combination With Rituximab and CHP [R-CHP] Versus Rituximab and CHOP [R-CHOP] in Previously Untreated Patients With Diffuse Large B-Cell Lymphoma; ClinicalTrials.gov identifier: NCT03274492), which substituted the antibody–drug conjugate (ADC) polatuzumab (pola) for vincristine.⁵ This study enrolled 879 patients who were subsequently randomized in a 1:1 ratio to receive either polatuzumab vedotin (Pola), rituximab (R), cyclophosphamide (C), doxorubicin (H), prednisolone (P) (Pola-R-CHP) or R-CHOP. This study demonstrated a progression–free survival (PFS) benefit over R-CHOP. The most recent update, after a median follow-up of 64.1 months, reported a 64.9% PFS in the Pola-R-CHP group versus 59.1% in the group treated with R-CHOP, with a corresponding hazard ratio (HR) of 0.78.^5,12 Despite the PFS benefit, even with longer follow–up, this study has yet to demonstrate an overall survival (OS) benefit with Pola-R-CHP. Data continue to suggest that the regimen is most effective in patients diagnosed with the nongerminal center B-cell (non-GCB)/activated B-cell (ABC) subtype and has an equivalent outcome to R-CHOP in those with a germinal center (GC) subtype of DLBCL. Those in favor of Pola-R-CHP have often raised the issue of the difficulty of accurately classifying all patients based on cell of origin (COO). The gold standard for determining COO, gene expression profiling (GEP), is seldom, if ever, used outside of Canada. Currently, the most widely used method to determine COO in most other countries, immunohistochemical staining, has an approximately 20% discordance rate compared with GEP. As such, treating all patients with Pola-R-CHP would provide a benefit to all patients with the non-GCB/ABC subtype while providing equivalent efficacy to those with the GC subtype. This approach is further supported by the similar toxicity profiles between the two regimens, despite the inclusion of pola. Further subgroup analysis indicates that several other patient subsets appear to obtain a PFS benefit over R-CHOP when treated with Pola-R-CHP. The argument against utilization of Pola-R-CHP in all patients has centered on the lack of an OS benefit despite several years of follow–up, as well as the cost–effectiveness of the regimen versus R-CHOP. The latter has been evaluated in three studies, whose results have mostly supported the role of Pola-R-CHP in frontline DLBCL, with the data indicating that it would continue to be cost-effective as long as it maintained at least a 5% PFS benefit over R-CHOP.

The combination of tafasitamab (tafa), a CD19 monoclonal antibody, and lenalidomide (len), an immunomodulatory agent, (tafa-len), was shown to be an effective regimen in the L-MIND study (A Phase II, Single-Arm, Open-Label, Multicentre Study to Evaluate the Safety and Efficacy of Lenalidomide Combined With MOR00208 in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma [R-R DLBCL]; ClinicalTrials.gov identifier: NCT02399085), which enrolled patients with relapsed DLBCL.¹³ Given the results of this study, especially in those treated after only one prior line of therapy, the tafa-len regimen was further explored in combination with R-CHOP in patients with newly diagnosed DLBCL. The frontMIND study (A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial Comparing the Efficacy and Safety of Tafasitamab Plus Lenalidomide in Addition to R-CHOP Versus R-CHOP in Previously Untreated, High-intermediate and High-risk Patients With Newly-diagnosed Diffuse Large B-cell Lymphoma [DLBCL]; ClinicalTrials.gov identifier: NCT04824092) enrolled patients aged 18–80 years with high–risk DLBCL and an International Prognostic Index (IPI) score of 3–5 or patients aged 60 years or younger with an age-adjusted IPI score of 2–3.⁶ In this double-blind study, patients were randomized to receive either R-CHOP plus placebo or R-CHOP in combination with 25 mg of len on days 1–10 and 12 mg/kg of intravenous (IV) tafa on days 1, 8 and 15. With 899 patients randomized, tafa-len-R-CHOP demonstrated a 3-year PFS rate of 71.1% versus 62.9% for those who received R-CHOP, with a corresponding HR of 0.79. At this early readout, this regimen has not yet demonstrated an OS benefit but currently appears to be agnostic to COO. Like Pola-R-CHP, the frontMIND regimen presents some unique challenges that might limit universal adoption. The inclusion of len is covered differently from the IV medicines, must be obtained through a specialty pharmacy and is therefore subject to patient-to-patient variability in copay costs. The regimen also introduces additional treatment burden compared with Pola-R-CHP and R-CHOP, as tafa is given weekly throughout the entirety of treatment. Lastly, unlike Pola-R-CHP, the toxicity profile of tafa-len-R-CHOP raises some concerns about tolerability in older patients.

The POLARIX and frontMIND regimens have demonstrated that immunotherapy-based treatments may improve the efficacy of R-CHOP in patients aged 80 years or younger. Several studies building upon this theme have completed enrollment in phase III trials and are awaiting formal results. These studies have incorporated T-cell–engaging antibodies, which have recently made an impact on the management of relapsed/refractory DLBCL. Epcoritamab and glofitamab have received accelerated approval based on phase I/II studies in the USA (both are approved in the European Union [EU]), whereas odronextamab has approval in the EU and Asia based on the ELM-2 study.^14–17 These three agents, combined with a CHOP, R-CHOP or Pola-R-CHP backbone, are being evaluated in separate randomized studies in frontline DLBCL, in comparison with R-CHOP or Pola-R-CHP.^18–20 Given the single-agent activity of these molecules in third-line or later DLBCL, there is an expectation that these studies will usher in the next advancement in frontline therapy for DLBCL. To this point, the EPCORE DLBCL-2 study (A Phase 3, Randomized, Open-Label Study to Evaluate Safety and Efficacy of Epcoritamab in Combination With R-CHOP Compared to R-CHOP in Subjects With Newly Diagnosed Diffuse Large B-Cell Lymphoma [DLBCL]; ClinicalTrials.gov identifier: NCT05578976) has reported a 51% reduction in the risk of progression or death (HR, 0.49; p<0.001) with epcoritamab plus R-CHOP compared with R-CHOP. We look forward to further details being reported to fully assess the role of this regimen in frontline DLBCL.

Efforts to improve outcomes in this patient population are not limited to immunotherapeutic modalities. ESCALADE (Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Acalabrutinib in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone [R-CHOP] in Subjects ≤75 Years With Previously Untreated Non-GCB DLBCL; ClinicalTrials.gov identifier: NCT04529772) and GOLSEEK-1 (A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study Comparing the Efficacy and Safety of Golcadomide Plus R-CHOP Chemotherapy vs Placebo Plus R-CHOP Chemotherapy in Participants With Previously Untreated High-risk Large B-cell Lymphoma; ClinicalTrials.gov identifier: NCT06356129) are active studies aimed at improving upon the results reported in PHOENIX (PHOENIX DDR/Anti-PD-L1 Trial: A Pre-surgical Window of Opportunity and Post-surgical Adjuvant Biomarker Study of DNA Damage Response Inhibition With or Without Anti-PD-L1 Immunotherapy in Patients With Neoadjuvant Treatment Resistant Residual Triple Negative Breast Cancer; ClinicalTrials.gov identifier: NCT03740893) and ROBUST (Phase 3 Randomized, Double-Blind, Placebo Controlled, Multicenter Study to Compare the Efficacy and Safety of Lenalidomide [CC-5013] Plus R-CHOP Chemotherapy [R2-CHOP] Versus Placebo Plus R-CHOP Chemotherapy in Subjects With Previously Untreated Activated B-cell Type Diffuse Large B-cell Lymphoma; ClinicalTrials.gov identifier: NCT02285062), respectively, through the incorporation of novel second–generation agents related to ibrutinib and len, respectively.^8,9,21,22 The ESCALADE study will randomize patients aged 65 years or younger with non-GCB DLBCL (the ABC subtype will be centrally confirmed after enrollment) to acalabrutinib 100 mg twice a day (BID) + R CHOP versus R-CHOP, with PFS as the primary endpoint. The GOLSEEK-1 study will randomize patients with newly diagnosed DLBCL to golcadomide, a novel cereblon E3 ligase modulatory drug (CELMoD) reported to promote the degradation of Ikaros and Aiolos more effectively than len, at a dose of 0.4 mg on days 1–7 of each cycle in conjunction with R-CHOP versus R-CHOP. This study will also have PFS as its primary endpoint. A list of all on-going randomized studies in frontline DLBCL is provided in Table 2.^18–25

Using an alternative approach from the group at MD Anderson has slowly adapted a series of phase II studies in an attempt to eliminate chemotherapy in patients who achieve a complete response to an induction regimen composed of immunotherapeutic agents and small-molecule inhibitors.^24,25 The most recent iteration, Smart Stop, demonstrated that some patients could achieve remission without having to receive CHOP. Long–term follow-up is needed to determine whether this induction regimen can induce a cure without chemotherapy consolidation.

Although we have had promising changes in the landscape of frontline DLBCL treatment for younger patients, this has not been the case for older patients (>80) and/or those with comorbidities that preclude the use of full-intensity therapy in frontline DLBCL. For this patient population, there has been a heterogeneous mix of regimens used, although none have matched the efficacy of R-CHOP. The most commonly used regimen for this patient population is R-mini-CHOP, which, unfortunately, has not demonstrated OS rates equivalent to that in younger patients treated with R-CHOP.²⁶ Several studies evaluating whether to replace R-mini-CHOP or add novel agents to a mini-CHOP backbone have been hampered by increased toxicity in the experimental arms. Some of this is understandably attributable to the novel agent included, but some of this is undoubtedly due to the frailty of this patient population.

Recent efforts to improve outcomes in this patient population have again used immunotherapeutic approaches. The most mature study is the phase III POLAR BEAR study (R-MINI-CHOP Versus R-MINI-CHP in Combination With Polatuzumab-vedotin, as Primary Treatment for Patients With Diffuse Large B-cell Lymphoma, ≥80 Years, or Frail ≥75 Years – an Open Label Randomized Nordic Lymphoma Group Phase III Trial; ClinicalTrials.gov identifier: NCT04332822), which is evaluating Pola-R-mini-CHP versus R-mini-CHOP.²⁷ Although mature data from this study are not yet available, some of the early data again hint at increased toxicity in the experimental arm.²⁸

As illustrated in Table 3, several other studies have sought to improve outcomes in this patient population using bispecific antibodies alone, in combination with the ADC, pola or mini-CHOP/CVP. The results of these phase II studies have demonstrated promising efficacy and acceptable toxicity.^29–33 The next steps in the development of these regimens will be to evaluate them against R-mini-CHOP in a randomized phase III study. We look forward to seeing whether any of these regimens will provide the first improvement in this population since the introduction of rituximab.

Treatment approaches for frontline DLBCL remain an area of great interest, given the limitations of current standard-of-care regimens. Despite significant progress, approximately one-third of patients will relapse or have primary resistance to R-CHOP or Pola-R-CHP. Unfortunately, despite substantial efforts, only one randomized study had demonstrated a PFS benefit over R-CHOP until the recently reported frontMIND study. Unfortunately, neither the POLARIX nor the frontMIND regimen, despite meeting their prespecified primary endpoints, is likely to completely displace R-CHOP, given the concerns raised about both studies. There is hope that some of the currently on-going studies have the potential, based on their known safety and efficacy profiles, to establish a new standard of care for all patients with newly diagnosed DLBCL.