Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma, representing 40% of the total cases reported. This cancer originates from the germinal center and represents a widely heterogenous group of diseases. 

DLBCL used to include primary mediastinal B-cell lymphoma, high-grade B-cell lymphoma, Epstein-Barr virus associated with positive DLBCL, and T-cell histiocyte-rich B-cell lymphoma. A recent revision of the definition of DLBCL by the World Health Organization has resulted in all these diseases being classified as their own entities. This is a welcome step because it clarifies the contours of what constitutes DLBCL, allowing medical researchers to essentially communicate in the same language. 

Read more about DLBCL etiology

Gene expression profiling allowed researchers to distinguish 2 distinct subtypes of DLBCL: germinal B-cell-like (GCB) DLBCL and activated B-cell like (ABC) DLBCL; around 15% of cases remain unclassified. Molecular biologists have since reported additional molecular subtypes within and beyond GCB and ABC DLBCL. 

Because DLBCL is an aggressive disease, patients often present with rapidly enlarging lymphadenopathy and constitutional symptoms. This means that immediate medical attention is often needed. 

“The most common upfront treatment is chemoimmunotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), which leads to a cure in approximately 50% – 60% of patients,” Liu and Barta wrote in the American Journal of Hematology. 

R-CHOP is universally accepted as the standard therapy for untreated DLBCL. Medical researchers have investigated the possibility of adding a sixth drug to this 5-drug cocktail, only to achieve mixed results. A recent trial failed to achieve clinically meaningful improvements; another trial added the antibody-drug conjugate polatuzumab-vedotin and significantly improved progression-free survival in patients with untreated DLBCL.

“Overall, while roughly two-thirds of DLBCL patients can be cured by first-line therapy, one-third of the patients will be primary refractory or will relapse (R/R DLBCL) after an initial response,” Frontzek and colleagues wrote in Therapeutics Advances in Hematology. 

Unfortunately, many patients who do not respond well to first-line therapy eventually deteriorate, resulting in early death. However, clinicians have designed treatment algorithms to better characterize these patients’ needs and ensure that subsequent management plans follow the latest and best evidence in this field. In addition, we also have a number of novel agents available that may improve the clinical condition of these patients. 

Second-Line Treatment 

We will now consider a distinct category of patients: individuals who are considered transplant-eligible after failing first-line therapy. 

“At the time of progression or disease relapse, the standard treatment for transplant-eligible patients remains salvage chemotherapy followed by consolidative autologous stem cell transplantation (ASCT) in chemotherapy-sensitive disease,” Liu and Barta wrote. 

As of today, patients who are considered transplant-eligible will normally receive the following combinations of chemoimmunotherapy drugs: 

  • Rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP)
  • Rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP)
  • Rituximab, ifosfamid, carboplatin, and etoposide (R-ICE)

These 3 regimens have been assessed for their efficacy and have been found to achieve very similar outcome parameters. 

The current standard therapy — a combination of high-dose therapy (HDT) and ASCT — has been the standard second-line approach in treating patients with refractory or relapsed DLBCL. Nevertheless, a novel approach has emerged as an alternative to this treatment combination — chimeric antigens receptor (CAR) T-cell therapies. 

CAR T-cell therapies have emerged as a viable, even desirable, alternative to the ASCT approach. Recent trials suggest that CAR T-cell therapy is superior to the HDT/ASCT approach for patients who do not respond well to first-line therapy. 

“CAR-T presents a viable and very promising therapy in RR DLBCL . . . and is an area of active research,” Liu and Barta wrote. 

One of the reasons that oncologists are increasingly turning to CAR T-cell therapy as their second-line treatment of choice is that there is mixed evidence regarding the efficacy of ASCT. Studies indicate that patients with double-hit lymphoma (DHL) who undergo ASCT have poorer outcomes than their non-DHL peers. Another study demonstrates that patients with RR DLBCL who underwent ASCT had poorer 4-year progression-free survival if they had DHL compared to their peers who did not have DHL. 

Read more about DLBCL treatment 

The field of DLBCL is constantly evolving — from how the disease is defined, to the expanding treatment options on offer. Part of what makes the field of DLBCL so exciting is the heterogeneous nature of the disease and the variety of drugs that can make a difference. We have made notable progress in identifying the various subtypes of the disease and refined our understanding of the complex pathogenesis of these subtypes. 

The expansion of knowledge in a given medical field allows researchers to explore different angles from which to approach treatment. In addition, new medical technologies, such as next-generation sequencing, will help us understand the different subtypes of DLBCL in even greater detail. 

“Advancements in bioinformatics and gene-editing technologies in translational medicine will lead to significant progress in . . . the next decade,” Liu and Barta wrote. “All of this runs in parallel to the development of cellular therapy and bispecific T-cell engager therapy.” 


Frontzek F, Karsten I, Schmitz N, Lenz G. Current options and future perspectives in the treatment of patients with relapsed/refractory diffuse large B-cell lymphomaTher Adv Hematol. Published online June 28, 2022. doi:10.1177/20406207221103321

Liu Y, Barta SK. Diffuse large B cell lymphoma: 2019 update on diagnosis, risk stratification, and treatmentAm J Hematol. Published online March 11, 2019. doi:10.1002/ajh.25460