Review Highlights Multiple Treatment Options Available in DLBCL

Authors from several institutions in Hangzhou, China, have published a comprehensive review of treatment options in diffuse large B-cell lymphoma (DLBCL), ranging from chemoimmunotherapy to bispecific antibodies. The review appears in the March issue of Frontiers in Immunology.¹

“Over the past decade, the advent of novel immunotherapeutic approaches has reshaped the therapeutic paradigm for relapsed/refractory (R/R) DLBCL,” the authors wrote. “Nevertheless, the intrinsic complexity of resistance mechanisms, coupled with the substantial cost and limited accessibility of advanced molecular diagnostics, continues to hinder optimal disease management.”

DLBCL is the most common subtype of non-Hodgkin lymphoma (NHL), representing 30% to 40% of all adult lymphoid malignancies. The authors explain that the aggressiveness of this blood cancer, coupled with its clinical and biological heterogeneity, present both treatment challenges but also opportunity.

Patients are first classified by cell of origin into germinal center B-cell (GCB) and activated B-cell (ABC) subtypes, and further molecular stratification places them into 7 distinct genetic subgroups. “These classifications not only reveal the molecular complexity of DLBCL but also provide a theoretical foundation for developing targeted and immunotherapeutic approaches. Recent progress in immunotherapy have offered new therapeutic options for patients,” they wrote.

Despite the diversity within DLBCL, the backbone of frontline treatment for all patients has been rituximab (Rituxan; Genentech) combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), which achieves durable remission in approximately 60% of patients. The ongoing challenge has been finding options for the 30% to 40% of patients who relapse or develop refractory disease; here, outcomes remain poor. Much of the review addressed how to manage patients who fail to respond to initial treatment. The authors noted the multicenter CORAL study showed that prior rituximab exposure worsens subsequent treatment outcomes,² underscoring the urgent need for novel therapeutic strategies in R/R DLBCL.

CAR T-Cell Therapy

Over the past decade, chimeric antigen receptor (CAR) T-cell therapy has emerged as one of the most transformative advances in the treatment of R/R DLBCL. CAR constructs redirect patient T cells to recognize and destroy CD19-expressing tumor cells via a synthetic receptor comprising an extracellular single-chain variable fragment, a transmembrane hinge, and intracellular signaling domains.

The authors traced the technology’s evolution through 5 generations, with successive iterations improving T-cell persistence, costimulatory signaling, and reduction of toxicity, allowing this therapy to move into earlier lines of care and making it available outside of specialized academic centers.

Axicabtagene ciloleucel, or axi-cel (Yescarta; Kite/Gilead), was the first CAR T-cell therapy product approved for R/R DLBCL, demonstrating an overall response rate (ORR) of 82% and complete response rate (CRR) of 54% in the pivotal ZUMA-1 trial.³ The landmark ZUMA-7 phase 3 trial subsequently confirmed axi-cel's superiority over standard of care as second-line therapy, with a median event-free survival of 8.3 months vs 2.0 months.⁴ Real-world data from the French DESCAR-T registry further validated these outcomes, showing a 1-year overall survival (OS) of 63.5% with axi-cel.⁵

Tisagenlecleucel or tisa-cel (Kymriah; Novartis) offers an alternative CD19-directed CAR-T option with a 4-1BB costimulatory domain. While it demonstrated a 52% ORR in a phase 2 trial, the BELINDA phase 3 study did not show superiority over standard salvage therapy in the second-line setting, highlighting the importance of patient selection.⁶ Lisocabtagene maraleucel or liso-cel (Breyanzi; Bristol Myers Squibb), a defined-composition product with a fixed ratio of CD4+ and CD8+ T cells, achieved an ORR of 87% and CRR of 74% vs 49% and 43% for standard-of-care in the TRANSFORM phase 3 trial,⁷ establishing it as another strong second-line option. Relmacabtagene autoleucel (relma-cel), approved in China, demonstrated an ORR of 77.6% with a favorable safety profile, showing low rates of severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome.⁸

Despite these successes, resistance to CAR T-cell therapy remains an issue. Key mechanisms include CD19 antigen loss or downregulation, T-cell exhaustion, poor in vivo persistence, and an immunosuppressive tumor microenvironment. The authors cited ongoing efforts in multi-antigen targeting, including combination strategies with immunomodulatory agents and next-generation CAR constructs to overcome these barriers.¹

Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) link a tumor-targeting monoclonal antibody to a potent cytotoxic payload via a chemical linker, enabling precise intracellular delivery of cell-killing agents while sparing normal tissue. Several ADCs have demonstrated meaningful efficacy in DLBCL across a range of targets.

Polatuzumab vedotin, or pola (Polivy; Genentech), targeting CD79b with a monomethyl auristatin E payload, is arguably the most impactful ADC in this space. The phase 3 POLARIX trial demonstrated that pola combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) improved 2-year progression-free survival (PFS) to 76.7% vs 70.2% with R-CHOP in previously untreated intermediate- to high-risk DLBCL—marking the first frontline regimen in nearly 2 decades to outperform R-CHOP.⁹ In the R/R setting, pola plus bendamustine and rituximab (pola-BR) achieved a 40% CR rate vs 17.5% for BR alone.

Loncastuximab tesirine, or LT (Zynlonta; ADC Therapeutics SA), a CD19-directed ADC utilizing a pyrrolobenzodiazepine dimer warhead, showed single-agent activity with a 48.3% ORR in heavily pretreated R/R DLBCL. Notably, real-world data demonstrated LT's utility after CAR T-cell therapy failure, with ORRs of 73% to 78% in the third- and fourth-line settings. Brentuximab vedotin or BV (Adcetris; Seagen), targeting CD30, demonstrated significant benefit in the ECHELON-3 phase 3 trial when combined with lenalidomide and rituximab, improving median overall survival to 13.8 months vs 8.5 months in R/R DLBCL patients ineligible for transplant or CAR T therapy.¹⁰ Inotuzumab ozogamicin, a CD22-targeting ADC, did not outperform investigator's choice chemotherapy in a phase 3 trial; however, it showed a longer duration of response and potential benefit in patients with high CD22 expression.¹¹

Bispecific Antibodies

Bispecific antibodies simultaneously engage 2 distinct targets, most commonly a B-cell antigen (CD19 or CD20) and the T-cell coreceptor CD3, physically bridging tumor cells and cytotoxic T cells to enable T cell–mediated tumor killing. Unlike CAR T-cell therapy, bispecific antibodies are off-the-shelf agents requiring no patient-specific manufacturing, making them more accessible. Community practices in the United States are learning to administer these therapies in anticipation that they will be approved in earlier lines of care.

Blinatumomab, the CD19×CD3 bispecific T-cell engager (BiTE) originally approved for B-cell acute lymphoblastic leukemia, has shown activity in R/R DLBCL, with ORRs ranging from 43% to 89% across phase 2 trials, particularly in combination with lenalidomide.

Among CD20×CD3 bispecific antibodies—epcoritamab, glofitamab, and mosunetuzumab—represent the most clinically advanced bispecific antibodies in DLBCL and share a common mechanism while differing meaningfully in their structure, administration, clinical data, and positioning. Epcoritamab and glofitamab have FDA approval for R/R DLBCL, while mosunetuzumab is being studied in this disease.^12,13

Epcoritamab. Administered subcutaneously, epcoritamab (Epkinly; Genmab/AbbVie) offers convenience for patients and allows clinics to free up infusion chair time. In the pivotal EPCORE NHL-1 trial, it achieved an ORR of 63.1% and CR rate of 40.1% in patients with R/R large B-cell lymphoma after at least 2 prior therapies, with 64.2% of complete responders maintaining remission at 24 months. CRS occurred in 51% of patients but was predominantly low-grade.¹⁴ In the EPCORE NHL-2 trial, epcoritamab combined with gemcitabine and oxaliplatin in transplant-ineligible patients produced an ORR of 85% and CR rate of 61%, with a median OS of 21.6 months—among the deepest responses reported for any bispecific antibody combination in this setting.¹⁵ It is currently a preferred regimen for third-line and beyond in DLBCL and is particularly suited to patients in whom subcutaneous delivery and combination flexibility are priorities.

Glofitamab. This therapy is structurally distinct, featuring a 2:1 format with 2 CD20-binding domains and a single CD3-binding domain, which theoretically enhances tumor cell avidity. Glofitamab (Columvi; Genetech/Roche) is administered intravenously and requires obinutuzumab pretreatment to reduce CRS risk—an important logistical consideration. In a phase 2 trial of 155 R/R DLBCL patients who had received at least 2 prior lines of therapy, fixed-duration monotherapy with glofitamab yielded a CR rate of 39% and ORR of 52%, with 12-month PFS and OS rates of 37% and 50%, respectively. Adverse events of grade 3 or higher occurred in 62% of patients.¹⁶ The fixed-duration treatment course (12 cycles) is a distinguishing feature that may appeal to patients and clinicians seeking a defined treatment endpoint, particularly those who have already received CAR T-cell therapy or are ineligible for it.

Mosunetuzumab. A fully humanized IgG1 CD20×CD3 antibody, mosunetuzumab (Lunsumio; Genentech/Roche) is available in both intravenous and subcutaneous formulations. In R/R DLBCL patients after at least 2 prior therapies, intravenous mosunetuzumab monotherapy achieved an ORR of 42% and CR rate of 23.9%, with a median PFS of 3.2 months—somewhat lower efficacy than the other 2 agents in monotherapy. Approved by FDA for follicular lymphoma, it is being studied in a combination with CHOP for DLBCL.¹⁷

The M-CHOP combination showed a striking ORR of 96% and CR rate of 85% in newly diagnosed DLBCL, suggesting a potentially important role in the frontline combination setting. CRS was manageable, predominantly grade 1 to 2, and confined mainly to the first cycle.¹⁸ Mosunetuzumab's dual administration routes and its emerging data in combination with standard chemotherapy distinguish it as particularly versatile, with the authors suggesting a potential role earlier in the treatment course.

The authors concluded that despite the many advances, treatment of DLBCL has many challenges, including “biological complexity of resistance mechanisms, heterogeneity in treatment response, and the absence of standardized molecular stratification across clinical settings.”

“Future efforts should focus on integrating multi-omics data to refine disease classification, optimizing rational combination strategies with acceptable toxicity profiles (such as CAR-T–based combinations), and further incorporating clinically applicable biomarkers to guide patient selection and therapeutic sequencing,” they wrote. “Collectively, these approaches may facilitate more precise and individualized immunotherapeutic strategies for patients with DLBCL.”¹

References

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