New Therapies Are Reshaping Treatment for Relapsed Aggressive Lymphoma

DLBCL is the most common aggressive non-Hodgkin lymphoma, curable in approximately 60–70% of patients with frontline rituximab-based immunochemotherapy such as R-CHOP. For the remaining 30–40% who develop primary refractory disease or relapse, outcomes have historically been devastating—the Scholar-1 benchmark study reported a median overall survival of only 6.3 months for patients refractory to their last therapy. Prior to 2017, only autologous stem cell transplant (auto-SCT) offered curative potential in the relapsed setting, benefiting fewer than 20% of patients.

The landscape has shifted dramatically over the past five years. CD19-directed CAR-T therapy with axicabtagene ciloleucel (axi-cel) demonstrated an ORR of 82%, CR rate of 58%, and 5-year OS of 42.6% in third-line or later settings. By 2021, both axi-cel and lisocabtagene maraleucel (liso-cel) received FDA approval as preferred second-line options for patients with primary refractory disease or relapse within 12 months, supplanting auto-SCT in this high-risk population.

Among non-cellular therapies, bispecific antibodies (BsAbs) targeting CD20×CD3 represent the most active new drug class. Epcoritamab (subcutaneous, continuous until progression) achieved ORR/CR of 59%/41% in heavily pretreated patients including 38% with prior CAR-T; among CR patients, median duration of CR was 36.1 months with median OS not yet reached at 31 months follow-up. Glofitamab (fixed 12-cycle IV regimen) showed ORR/CR of 52%/40%, with 57.3% of CR patients still in remission at 24 months. Odronextamab (EMA-approved) showed similar efficacy with a median CR duration of 36.3 months. All BsAbs carry risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), managed through step-up dosing and corticosteroid premedication.

Antibody-drug conjugates also play important roles: polatuzumab-vedotin with bendamustine-rituximab (Pola-BR) demonstrated ORR/CR of 56.6%/52.8% with a median OS of 12.5 months; loncastuximab-tesirine (CD19-targeted) yielded ORR/CR of 48.3%/24.8% with a median DOR of 13.4 months in 3L+ patients. Tafasitamab plus lenalidomide achieved ORR/CR of 57.5%/40% with impressive 24-month OS of 90.6% among CR patients. Selinexor (XPO1 inhibitor) provides an oral option with modest ORR of 28% but durable responses in responders.

The review emphasizes that no head-to-head trials exist among these newer agents, and optimal treatment sequencing remains uncertain. The authors recommend CAR-T as the preferred curative approach for eligible patients with early relapse, with BsAbs and ADCs serving as bridges to CAR-T or as definitive therapy for CAR-T–ineligible patients. Reliable predictive biomarkers are still lacking, and response to therapy remains the strongest prognostic indicator. Emerging combination strategies pairing BsAbs with lenalidomide, venetoclax, or checkpoint inhibitors are under active investigation in clinical trials.