A Systematic Literature Review of Clinical Outcomes in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Treated in the Third-Line or Later Setting

Introduction: While many patients with diffuse large B-cell lymphoma (DLBCL), an aggressive non-Hodgkin lymphoma and common large B-cell lymphoma subtype, are cured with standard first-line therapy, ~40% develop relapsed/refractory (R/R) disease and require additional therapy (Sehn LH, Salles G. N Engl J Med 2021;384(9):842-58. Susanibar-Adaniya S, Barta SK. Am J Hematol 2021;96(5):617-29. Coiffier B, et al. Blood 2010;116(12):2040-5.). Progression-free survival (PFS) and overall survival (OS) worsen with each additional line of therapy (LOT). Results from a real-world analysis (January 2010-March 2022) showed that median survival was <1 year for patients with R/R DLBCL receiving >2 lines of therapy (Ip, et al. Adv Ther 2024; 41(3):1226-44). As of 2024, there is a lack of standard of care in the third-line setting for patients with DLBCL. This systematic literature review (SLR) aims to evaluate clinical outcomes for R/R DLBCL treatments administered as a third or later LOT.

Methods: An SLR was conducted via PubMed (MEDLINE), Embase, and Cochrane Library from January 1, 2014 - May 17, 2024. Relevant conference abstracts were included from January 1, 2020 - May 17, 2024 to capture contemporary publications. Studies were reviewed in 2 phases, title/abstract and full text. Clinical trials included those evaluating Food and Drug Administration-approved or guideline-recommended R/R DLBCL therapies, providing information on patients treated with a third or later LOT, and reporting on efficacy and safety outcomes such as OS, PFS, objective response rates (ORRs), and adverse events (AEs).

Results: In total, 1,301 unique articles and abstracts were screened; 11 unique clinical trials (phase Ib/II randomized controlled trial [RCT], n=1; single-arm studies, n=10) described in 17 publications (original publication, n=11; longer-term follow-up, n=6) were included. Treatments included bendamustine + rituximab (BR; n=1), bispecific antibodies (epcoritamab, n=1; glofitamab, n=1), CAR T-cell therapies (axicabtagene ciloleucel, n=1; tisagenlecleucel, n=1; lisocabtagene maraleucel, n=1), loncastuximab tesirine (n=2), polatuzumab + BR (n=1), selinexor (n=2), and tafasitamab (anti-CD19 monoclonal antibody) + lenalidomide (n=1). Baseline characteristics such as DLBCL subtype and treatment history varied among trials. For the 11 original publications, median follow up ranged from 7.8 - 27.7 mo; median OS ranged from 9.1 mo - not reached, with 6 trials reporting a median OS of <12 mo. Three trials reported an OS of ≥12 mo; interventions included CAR T-cell therapy (n=2) and a bispecific antibody (n=1). Median PFS ranged from 1.9 - 7.4 mo; 7 trials reported a median PFS of <6 mo. ORR ranged from 21.7% - 82.0%; complete response (CR) rates were <50% in 10 studies. The frequency of any AE of grade ≥3 was 56.0% - 95.3%. Grade ≥3 AEs of special interest were neutropenia, febrile neutropenia, and cytokine release syndrome, which were experienced by 14.6% - 78.0%, 3.0% - 31.0%, and 2.5% - 22.0% of patients.

For the 6 single-arm studies with longer-term results (axicabtagene ciloleucel, n=1; epcoritamab, n=1; polatuzumab + BR, n=1; tafasitamab + lenalidomide, n=1; loncastuximab tesirine, n=1; and tisagenlecleucel, n=1) median follow up was 20.0 - 63.1 mo, OS was 11.1 - 25.8 mo, and PFS was 2.9 - 7.6 mo. ORR ranged from 42.5% - 83.0%; 5 studies reported a CR rate of <50%. AEs were similar to those reported in the original publications.

Conclusions: Most data in the third-line setting reported in this review are from single-arm studies, highlighting a need for RCTs in this population. This review was limited by heterogeneity in interventions, baseline characteristics, and trial eligibility, and a lack of comparative studies. While interventions identified were evaluated in patients receiving a third or later LOT, treatments such as CAR T-cell therapies, bispecifics, and polatuzumab are now recommended or being studied in earlier LOT, leaving limited third-line options and a lack of standard of care. RCTs such as the ECHELON-3 trial, comparing brentuximab vedotin vs placebo, both in conjunction with lenalidomide and rituximab, in patients with R/R DLBCL, are needed to evaluate the efficacy and safety of new third-line treatment options for patients with R/R DLBCL.

Bandy:Aesara: Current Employment; Pfizer: Consultancy. Wu:Pfizer: Consultancy; Aesara: Current Employment. Gratie:Pfizer: Consultancy; Aesara: Current Employment. Horblyuk:Pfizer: Consultancy; Aesara: Current Employment. Repetny:Pfizer: Current Employment, Current holder of stock options in a privately-held company. Fanale:Seagen: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months; Pfizer: Current Employment, Current holder of stock options in a privately-held company. Mitchell:Pfizer: Current Employment, Current holder of stock options in a privately-held company. Liu:Pfizer: Current Employment, Current holder of stock options in a privately-held company.