The addition of rituximab, a chimeric monoclonal antibody (mAb) targeting CD20, to the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen has created a paradigm shift in the frontline treatment of diffuse large B-cell lymphoma (DLBCL).

This chemoimmunotherapy approach was associated with an improvement in overall survival (OS), leading to a cure in about 60 to 65% of cases. Nonetheless, about a third of patients will be refractory or relapse (r/r) after achieving a response with frontline treatment.

The management of r/r disease has greatly improved in recent years. “There has been a proliferation of immunotherapies for the treatment of DLBCL that have expanded our treatment options for these patients [referring to r/r DLBCL patients], providing the opportunity for durable remissions that were not previously possible,” said Geoffrey Shouse and Alex F. Herrera, from City of Hope’s Department of Hematology & Hematopoietic Cell Transplantation (US).

Traditionally, patients with r/r DLBCL with chemosensitive disease are treated with salvage chemotherapy followed by consolidative autologous stem cell transplantation (ASCT). However, durable remissions are only observed in about half of patients.

If second-line therapy fails, patients are considered for CD19-directed chimeric antigen receptor (CAR) T cell therapy. Currently, there are 3 autologous CD19 CAR T cell products available for patients with r/r DLBCL: axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel) and lisocabtagene maraleucel (liso-cel). The rate of complete responses to CAR T cell therapy is high regardless of the DLBCL subtype, but only about a third of patients achieve durable remission.

The unmet need for therapeutic options capable of providing durable remission and long-term survival for patients with high-risk r/r DLBCL has instigated several studies as more targets are being discovered.

Monoclonal Antibodies

Obinutuzumab (Gazyva®), another anti-CD20 mAb, showed greater antibody-dependent cytotoxicity than rituximab. The combination therapy with obinutuzumab and CHOP was inferior to R-CHOP in improving the outcome of patients with newly diagnosed DLBCL. However, a phase 2 study evaluating obinutuzumab monotherapy reported an overall response rate (ORR) of 37% and found a therapeutic response in 20% of rituximab-resistant patients.

The combination therapy with tafasitamab (Monjuvi®), an anti-CD19 mAb, and lenalidomide (Revlimid®) was approved by the US Food and Drug Administration (FDA) for the treatment of r/r DLBCL in patients ineligible for ASCT.

“Whether it is better to consider tafasitamab in r/r DLBCL prior to CAR T cell therapy or after disease progression remains unknown and most practices take patients to CAR T cell therapy first because of the higher sensitivity of CAR T cells compared to mAbs,” explained Atallah-Yunes et al in a review article published in Frontiers in Immunology. Also, the effect of the combined therapy in patients with high-risk disease (eg, double- and triple-hit and primary refractory disease) is yet to be determined.

Magrolimab, an investigational mAb against CD47, showed promising results in combination with rituximab in r/r DLBCL, as it seems to potentiate its antibody-dependent cytotoxicity.

Antibody–Drug Conjugates

Polatuzumab vedotin (Polivy®, PV) reunites the most robust data among the antibody-drug conjugates (ADCs) evaluated in r/r DLBCL. It was approved by the FDA to treat patients with r/r DLBCL after at least 2 prior therapies. PV contains an anti-CD79b mAb covalently linked to the chemotherapeutic agent monomethyl auristatin E.

Two other ADCs showed promise as therapeutic approaches in r/r DLBCL: brentuximab vedotin (Adcetris®, BV), which carries the same chemotherapeutic agent of PV but the covalently linked mAb targets the CD30 antigen, and loncastuximab tesirine (Zynlonta®, LT), which contains an anti-CD19 mAb linked to a pyrrolobenzodiazepine dimer toxin.

BV may have a particularly important role in r/r CD30-positive disease and has been heavily explored in combination therapy. LT may have a role in treating patients with r/r DLBCL who are not candidates for or who have progressed after cellular therapies. It has been evaluated either as monotherapy or in combination with other agents with promising results.

CD22-targeted ADCs, including pinatuzumab vedotin, inotuzumab ozogamicin (Besponsa®), and Trph-222, have not proved to be as efficient as other ADCs in treating r/r DLBCL.

Bispecific T Cell Engager Antibodies

Many CD20-targeted bispecific T cell engager (BiTE) antibodies have shown efficacy in r/r DLBCL. These include mosunetuzumab, odronextamab, epcoritamab, and glofitamab. Among them, mosunetuzumab reunites the most robust clinical data so far.

“The efficacy of these agents either after failure of rituximab and/or failure of cellular therapy gives hope for patients with an otherwise very challenging disease to treat,” said Shouse and Herrera.

Blinatumomab (Blincyto®), a BiTE directed against CD19 and CD3, has also been studied in r/r DLBCL with some promising results. A phase 2 trial suggested a remarkable performance for blinatumomab as consolidation strategy after the rituximab-chemotherapy-based first-line, as it was able to convert positive minimal residual disease to negativity. However, most phase 3 trials were held due to modest activity and more encouraging results for other immunotherapeutic agents.

CAR T Cell Therapy

Deciding which FDA-approved CAR T cell product to use can be challenging. However, according to Shouse and Herrera, some particularities may help in this task. As they mentioned, liso-cel and tisa-cel may have more favorable severe toxicity rates. Also, liso-cel is the only agent with proven efficacy in patients with secondary central nervous system lymphoma (the other 2 excluded these patients from the trials).

In addition to the approved products, other CAR T cell products are currently under investigation. These include allogeneic, autologous, and bispecific products. “Beyond the FDA-approved therapies, allogeneic CAR T cell products appear efficacious and may have a role in patients unable to await the manufacturing times associated with autologous products, and novel targets may play a role in CD19 CAR T cell refractory disease,” wrote Shouse and Herrera.

Final Considerations

Immunotherapy has conquered a place in r/r DLBCL treatment The choices are multiple, which brings other challenges. “The plethora of novel agents leaves patients with more therapeutic options, but leaves the practitioner faced with challenging decisions regarding the timing and indications for use of these immunotherapies,” said Shouse and Herrera.

Despite the options, including as second and third-line treatment, durable remission remains a mirage for certain patients. Hence, more therapeutic choices are expected in the coming years.


Shouse G, Herrera AF. Advances in immunotherapy for diffuse large B cell lymphoma. BioDrugs. Published online July 15, 2021. doi:10.1007/s40259-021-00491-w

Atallah-Yunes SA, Robertson MJ, Davé UP, Ghione P, Perna F. Novel immune-based treatments for diffuse large B-cell lymphoma: the post-CAR T cell era. Front Immunol. Published online June 1, 2022. doi:10.3389/fimmu.2022.901365

Gambella M, Carlomagno S, Raiola AM, et al. CD19-targeted immunotherapies for diffuse large B-cell lymphoma. Front Immunol. Published online February 24, 2022. doi:10.3389/fimmu.2022.837457