The R-CHOP regimen (consisting of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone) has revolutionized the treatment of diffuse large B-cell lymphoma (DLBCL). Improvements in patient outcomes have become widely known, with long-term disease-free survival rates increasing to 60%-70%. However, some patients (up to 40%) develop relapsed or refractory disease (rrDLBCL), which has a poor prognosis.

Several factors have been shown to contribute to treatment resistance in DLBCL. These include tumor heterogeneity, tumor microenvironment, and host variabilities, such as age, sex, body weight, pharmacokinetics, and polymorphisms.

Patients with DLBCL have a high degree of tumor heterogeneity. “It is one of the most obvious causes of treatment resistance because the spatial and temporal genetic and/or epigenetic diversity in cancer cells is often associated with resistance to cancer therapy,” said He and Kridel in Leukemia.

Both intra- and interpatient heterogeneity have been described. Sources of interpatient variability include the genetic subtype and the cell of origin of the tumor. Regarding the latter, most pretreatment DLBCLs (80-85%) can be classified into germinal center B-cell-like (GCB) or activated B-cell-like (ABC). The remaining cases are “unclassified”. Generally, ABC-DLBCLs have a poorer prognosis and a higher incidence of treatment resistance.

Tumor heterogeneity may also manifest in rrDLBCL after R-CHOP treatment. Several studies suggest that mutations in TP53, as well as in oncogenes and genes involved in immune surveillance and epigenetic regulation, among other cellular processes, are contributing factors. However, the underlying molecular mechanisms are not completely understood.

In addition, nonmutational modifications, such as epigenetic alterations, might support the development of resistance to treatment in DLBCL.

Despite the scarcity of tumor microenvironment in DLBCL, it too has been shown to contribute to treatment resistance. For instance, alterations in the tumor immune microenvironment have been correlated with poorer overall survival after R-CHOP treatment.

Clinical studies have demonstrated that among patients who received R-CHOP, elderly male patients (>60 years of age) had poorer clinical outcomes than elderly females.

“This therapeutic disadvantage was shown to stem from the differential rituximab clearance rates and serum concentrations: an age-dependent reduction of rituximab clearance only occurred in elderly females but not in males and the higher body weight of males also contributed to their faster drug clearance,” He and Kridel explained. Accordingly, increasing the dose of rituximab in an R-CHOP regimen in elderly male patients seems to improve outcomes.

The Prediction and Monitoring of Treatment Response

Predicting and monitoring treatment response in DLBCL is key for therapeutic success. A study showed that positron emission tomography-computed tomography (PET-CT) scans might allow the identification of patients with early-stage DLBCL with excellent outcomes, without radiation. However, the role of PET-CT scans in advanced disease is uncertain.

Therefore, efforts have been made to identify predictive biomarkers to aid patient stratification, though a long road is ahead. The expression of the germline polymorphism Denovo Genomic Marker 1, for example, was shown to correlate with the response to the protein kinase C beta inhibitor enzastaurin.

Moreover, the classification of DLBCLs by their cell of origin might have predictive value, as the B-cell receptor signaling inhibitors ibrutinib, lenalidomide, and bortezomib have demonstrated superior response rates in ABC-DLBCL, compared to GCB-DLBCL.

Real-time monitoring of treatment response can provide the possibility of implementing early therapeutic changes. However, this requires the implementation of novel monitoring systems. Circulating tumor DNA-based methods as well as novel risk assessment tools (eg, the Continuous Individualized Risk Index) have emerged as potential alternatives to conventional methods.

Treating Refractory Disease

Although the R-CHOP regimen is the current standard of care in DLBCL, several other strategies have been evaluated and shown varying degrees of success. For instance, single-agent novel therapies, including the selective BCL-2 inhibitor venetoclax and checkpoint inhibitors, have shown potential for treating rrDLBCL but only a few patients have responded, with short remissions.

Chimeric antigen receptor T (CAR-T) cell therapy is available for patients who experience progressive disease after 2 or more prior therapies. Importantly, 40% of patients remained in remission at 1 year and were eventually cured after CAR-T cell therapy.

“Based on the excellent activity of CAR-T cells in patients with chemotherapy-resistant disease, there is enthusiasm for using CAR-T cells earlier in the course of disease and currently, there are several ongoing studies comparing high dose therapy and autologous stem cell transplant in first relapse,” Goldfinger and Cooper wrote in Clinical Lymphoma, Myeloma and Leukemia.

Bispecific T cell engagers (BiTEs) and antibody-drug conjugates (ADC) have also emerged as potential therapeutic approaches in DLBCL. The most studied BiTEs target the CD20 protein, which facilitates sequential treatment with CD19-directed CAR-T cell therapy if needed. In the case of ADCs, brentuximab was shown to be effective in recurrent DLBCL if at least some of the tumor cells are CD30+.

A strategy to overcome treatment resistance to single-agent novel therapies in DLBCL is combination therapy. Several combinations have been investigated in clinical settings, with some showing encouraging results. For instance, the combination of venetoclax, ibrutinib, lenalidomide, and obinutuzumab had an overall response rate of 56% and a complete response rate of 37%, with durable responses observed in heavily pretreated patients, including those who had failed CAR-T cell therapy.

According to Goldfinger and Cooper, “it seems likely that R-CHOP will remain the backbone of treatment for DLBCL but may eventually be combined with ADC or BiTEs depending on the results of ongoing studies.”


He MY, Kridel R. Treatment resistance in diffuse large B-cell lymphoma. Leukemia. 2021;35(8):2151-2165. doi:10.1038/s41375-021-01285-3

Goldfinger M, Cooper DL. Refractory DLBCL: challenges and treatment. Clin Lymphoma, Myeloma Leuk. 2022;22(3):140-148. doi:10.1016/j.clml.2021.09.011