For those patients deemed not to be candidates for CAR T-cell therapy (because of an underlying neurological condition or other comorbid condition) or who are unwilling to travel to a tertiary center to receive care, second- or third-line treatment options, according to the National Comprehensive Cancer Network (NCCN) guidelines version 1

For those patients deemed not to be candidates for CAR T-cell therapy (because of an underlying neurological condition or other comorbid condition) or who are unwilling to travel to a tertiary center to receive care, second- or third-line treatment options, according to the National Comprehensive Cancer Network (NCCN) guidelines version 1.2024, including bispecific antibodies (BsAb) which should be considered on a case-by-case basis. treatment of R/R DLBCL after two or more lines of systemic therapy. These bispecific antibodies have demonstrated overall response rates exceeding 50% and durable remissions at >2 years of follow-up. Additionally, a notable treatment advantage of bispecific antibodies is their ability to be administered in the community setting, making treatment more accessible for patients. The development and advancement of these novel therapies raise questions regarding the ongoing role of HSCT in the management of R/R DLBCL and the best sequence of cellular and bispecific therapies to optimize patients outcomes. == Introduction == Non-Hodgkin lymphoma is a heterogeneous group of lymphoid neoplasms that originate from B cells, T cells, or natural killer cells.1Mature B-cell lymphomas rank as the 11thmost common cancer CNA1 worldwide, with more than 80,000 new cases diagnosed in the United States each year, and accounting for >60% of all hematopoietic neoplasms.2,3Diffuse large B-cell lymphoma (DLBCL) is the most common and prototypical aggressive B-cell lymphoma accounting for approximately 30% of cases.1In the rituximab era, administration of anti-CD20-containing chemoimmunotherapy regimens, such as R-CHOP, DA-R-EPOCH, and POLA-R-CHP, has become the standard-of-care, front-line treatment for DLBCL with complete response rates ranging from 75-80%.4-6However, 30-40% of these patients will be refractory to front-line treatment or experience relapse within 5 years.7 Since 1995, management for relapsed or refractory (R/R) DLBCL has been second-line chemotherapy, followed by high-dose chemotherapy and consolidative autologous (auto) hematopoietic stem cell transplantation (HSCT), resulting in durable remission rates in 30-40% of patients.8,9However, Silymarin (Silybin B) auto-HSCT is associated with acute and long-term treatment-related toxicities and many patients are thought not to be good candidates for transplantation due to advanced age or other pre-existing comorbid conditions.10Novel therapies such as chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies (BsAb) have demonstrated durable treatment responses in the management of R/R DLBCL with tolerable side-effect profiles, even for those patients of advanced age or with comorbidities. These developments in cellular therapy raise questions regarding the role of HSCT in the management of R/R DLBCL going forward and how to integrate these novel therapies into clinical practice. == Autologous stem cell transplantation == The PARMA study, published by Philipet al. inThe New Eng land Journal of Medicinein 1995, demonstrated superior overall response rates for patients treated with intensive chemotherapy followed by consolidative auto-HSCT compared to those given four additional cycles of chemotherapy (84%vs. 44%). Long-term follow-up data showed a superior 5-year overall survival of 53% in the auto-HSCT group compared with 32% in the group treated with intensive chemotherapy alone, and established auto-HSCT as the standard of care for chemotherapy-sensitive, relapsed non-Hodgkin lymphoma.9The CORAL study further validated these findings in 2010 2010, albeit in the post-rituximab era, and demonstrated a 3-year progression-free survival of 37% and a 3-year overall survival of 49% in patients with R/R DLBCL treated with second-line chemotherapy followed by auto-HSCT. However, this study showed an inferior 3-year progression-free survival of 23% in those patients whose disease relapsed early, defined as relapse within less than 12 months after diagnosis, treated with second-line chemotherapy followed by auto-HSCT.8,11Hamadaniet al. further investigated the use of auto-HSCT in those patients with early relapsed disease in a large, multicenter, retrospective analysis of 516 patients with R/R DLBCL treated with second-line chemotherapy followed by auto-HSCT. This study demonstrated inferior progression-free and overall survival in those patients with early relapsed disease compared with patients who relapsed >12 months after diagnosis.12In addition, studies examining the use of auto-HSCT in patients with DLBCL harboring aMYCgene rearrangement withBCL2and/orBCL6gene rearrangements, also referred to as high-grade B-cell lymphomas, have demonstrated particularly bad outcomes with a 2-year overall survival <10%.13These studies highlight Silymarin (Silybin B) the limitations of second-line chemotherapy + auto-HSCT for the management of R/R DLBCL in higher risk groups of patients. == Chimeric antigen receptor T-cell therapy == In 2017, CAR T-cell therapy changed the Silymarin (Silybin B) landscape of treatment for patients with refractory DLBCL or relapse following auto-HSCT. The ZUMA-1, JULIET, and TRANSCEND NHL 001 clinical trials, targeting patients who progressed after at least two lines of therapy, including auto-HSCT, demonstrated overall response rates of 52-83%, with complete responses in 40-58%, and long-term.