Introduction: Diffuse large B-cell lymphoma (DLBCL) is one of the most aggressive non-Hodgkin lymphoma, known for its invasive nature and distant metastasis. Relapsing/refractory DLBCL represents a therapeutic challenge owing to its unsatisfactory response to first lines of treatment. There several modalities of treatment proposed for such cohort with variable response rates. Historically, salvage chemotherapy followed by autologous stem cell transplantation was the approach for patients with chemo-sensitive relapsing/refractory DLBCL. However, new immunotherapeutic modalities have recently evolved for the management of such challenging disease. There has been no systematic reporting of recent data on the management of relapsing/refractory DLBCL. We conducted a systematic literature review to evaluate efficacy of current therapeutic modalities in the treatment of relapsing/refractory DLBCL.

Methods: A literature search was performed in June 28, 2025, in PubMed and Scopus Database using the term ‘CAR-T cell therapy in refractory diffuse large B-cell lymphoma’. The search was further limited to English articles published between the years 2024-2025. These articles were then screened through a pre-defined inclusion criteria. Data pertaining to number of participants, treatment group, comparative group, 1-year overall survival (OS), 1-year progression free survival (PFS), all grade cytokine release syndrome (CRS), grade ≥3 CRS, all grade immune-effector cell-associated neurotoxicity syndrome (ICANS), and grade ≥3 ICANS was further extracted and analyzed.

Results: After exclusion of duplicate articles, a total of 36 articles were screened, and 9 publications were included in the review analysis. These articles consisted of retrospective observational studies and randomized controlled trials. 75% of the studies were conducted in the United States. All clinical trials examined chimeric antigen receptor T-cell therapy (CAR-T) using either axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), or tisagenlecleucel (tisa-cel). At 1-year, liso-cel demonstrated statistically significant improvements in OS and PFS when compared to second line conventional chemotherapy regimens. Furthermore, there was no significant difference in 1-year OS and PFS when liso-cel delivered in the outpatient setting was compared with the inpatient setting. However, the occurrence of grade ≥3 ICANS was three times more likely when liso-cel is administered in the outpatient compared to inpatient setting (13% vs. 4%, respectively). Although there were no significant differences if 1-year OS and PFS when axi-cel and tisa-cel was compared in adults ≥70 years and <70 years of age, there was a significantly increased incidence of grade ≥3 CRS in cohorts ≥70 years of age (5% vs. 15%; p=0.013). Moreover, the administration of CAR-T as second line of treatment has been associated with a significant improvement in 1-year OS (82% vs. 71%; p=0.036) and a lower incidence of grade ≥3 CRS (2.5% vs. 7%; 0.031) when compared to its initiation after two or more prior lines of treatment have been utilized.

Conclusion: CAR-T cell therapy with either axi-cel, liso-cel, or tisa-cel have demonstrated superior outcomes to conventional chemotherapy. Additionally, our review has outlined that the risk of adverse effects including CRS and ICANS was higher in elderly cohorts ≥75 years, in the outpatient setting, as well as when CAR-T cell initiation is delayed. Further research is warranted to evaluate the long-term outcomes of CAR-T to further optimize the management approach to patients with relapsing/refractory DLBCL.

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2025
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