Fifteen percent of DLBCL patients are refractory to the first line of therapy, while 25% experience relapse after response. The management of these patients is planned according to the patient's suitability for high-dose chemotherapy and whether the disease is refractory/early relapse (BSH guideline, 2025). While HSCT provides long-term survival in patients who are suitable for treatment and are chemosensitive (CORAL study), long-term survival compared to HSCT has been achieved in non-chemosensitive patients with CAR-T therapies ZUMA-7 and TRANSFORM studies. CAR-T therapies are approved as first-line treatment for patients with refractory/early relapse.

However, some r/r DLBCL patients are not suitable for HSCT and CAR-T treatments due to age and comorbidities, and some are resistant to these treatments or relapse after these treatments. Tafasitamab – Lenalidomide combination is approved for patients with relapsed DLBCL, NOS who are not eligible for HSCT or CAR-T therapies (L-MIND study). The efficacy of Glofitamab – GemOx has also been proven in patients with relapsed DLBCL, NOS who are not suitable for HSCT or CAR-T therapy in the STARGLO study. Loncastuximab is a single-agent ADC used in r/r DLBCL. Due to its cumulative toxicity, long-term use is not suitable, and a one year treatment was planned in the LOTIS-2 study. This study also included a significant number of patients with refractory and high-grade lymphoma, making it one of the limited treatment options in this high-risk patient group. Polatuzumab-BR was compared with BR in a phase II trial. Pola-BR demonstrated superiority in r/r DLBCL patients who were not suitable for HSCT and CAR-T therapies, and it should be considered an option, particularly in patients with < 60 years, IPI<2, ABC phenotype, non-bulky, and relapsed patients.Glofitamab and epcoritamab are a treatment option for r/r DLBCL patients. CAR-T therapies are costly and have high side effects, leading to treatment delays, especially in patients with rapid progression, and requiring specialized centers. BiTE therapies, with fewer side effects, lower costs, and easier access, may be an alternative for patients unable to access CAR-T therapies. The inclusion of high-grade lymphoma cases in trials provides an alternative in this group with limited treatment options. Its use will also increase as an important part of combination treatments.

The XPO1 inhibitor Selinexor has been tested in SADAL study in patients with R/R DLBC lymphoma who have no treatment options. Although response rates are low, it may increase the effectiveness of these treatments as part of combination therapies. The SADAL study demonstrated greater efficacy in the GCB phenotype.

Since there are no randomized studies of TL, Loncastixumab, BiTE treatments, Pola-BR and XPO1 inhibitors with each other, the choice of these treatments can be determined based on subgroup analyses in the studies.

Allogeneic stem cell transplantation, a treatment with high NRM and morbidity, remains an alternative treatment for DLBCL patients. Although prospective studies have not compared it with CAR-T therapies, retrospective studies have not found any significant differences (Blood 2020, Dreger et al)