Diffuse large B-cell lymphoma (DLBCL) exemplifies how lymphoma therapy has advanced on three fronts: better frontline chemoimmunotherapy, off-the-shelf bispecific antibodies, and CAR T-cell therapy moving earlier in the course.
Frontline therapy
The POLARIX trial added the antibody-drug conjugate polatuzumab vedotin to a modified R-CHOP backbone (pola-R-CHP), improving progression-free survival versus R-CHOP in previously untreated DLBCL — establishing a new frontline option. Peripheral neuropathy, from the monomethyl auristatin E payload, is the characteristic toxicity to monitor.
Relapsed/refractory disease: bispecifics and CAR-T
Two CD20×CD3 bispecific antibodies — glofitamab (given for a fixed duration) and epcoritamab — are approved for relapsed or refractory DLBCL after two or more lines, producing complete responses in roughly 40% of heavily pretreated patients, including some who have failed CAR-T. Cytokine release syndrome is the main adverse event, mitigated by step-up dosing and premedication; their off-the-shelf availability complements CAR-T.
On CAR T-cell therapy, an important nuance corrects a common misconception. While tisagenlecleucel did not beat salvage chemotherapy in the second-line BELINDA trial, the other two products succeeded: axicabtagene ciloleucel (ZUMA-7) and lisocabtagene maraleucel (TRANSFORM) were superior to salvage chemotherapy and transplant in primary-refractory or early-relapsing large B-cell lymphoma, and are now standard second-line therapy. The lesson is that this is a difference between products, not a failure of the class.
Molecularly directed combinations
Fixed-duration targeted combinations such as ViPOR (venetoclax, ibrutinib, lenalidomide, prednisone, and obinutuzumab) are active in specific molecular subtypes of relapsed DLBCL, offering a chemotherapy-sparing, biology-driven approach; tumour lysis syndrome (from venetoclax) and cytopenias require attention. Bispecifics such as mosunetuzumab have also become important in follicular lymphoma.
Further reading: POLARIX pola-R-CHP (Tilly et al., NEJM 2022); glofitamab (Dickinson et al., NEJM 2022); ViPOR combination (Melani et al., NEJM 2024); ZUMA-7 and TRANSFORM second-line CAR-T trials.