Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, is an aggressive and heterogeneous disease. Since the late 1990s, six to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has been the standard of care (1). More than 60% of patients are cured with this regimen. There have been different trials trying to improve the results of R-CHOP without success, as those in which targeted therapies are added to the R-CHOP backbone: bortezomib (REMoDL-B trial) (2), ibrutinib (PHOENIX trial) (3), or lenalidomide (ROBUST trial) (4), or the trial in which rituximab is replaced by obinutuzumab (a glycoengineered, type II anti-CD20 monoclonal antibody, GOYA trial) (5). Nevertheless, in a recently published phase 3 trial, a modified regimen of R-CHOP (pola-R-CHP), in which vincristine was replaced by polatuzumab vedotin (anti-CD79b antibody-drug conjugate), was compared with the standard R-CHOP, in patients with previously untreated intermediate-risk or high-risk DLBCL, and progression-free survival (PFS) was significantly higher in the pola-R-CHP group than in the R-CHOP group (76.7% vs. 70.2% at 2 years, hazard ratio 0.73), with a similar safety profile in the two groups, although overall survival did not differ significantly (6).

Salvage high-dose chemotherapy with autologous stem cell transplant (ASCT) remains the standard second-line treatment for relapsed or refractory (R/R) patients. However, few patients are cured with this intensive approach, and applicability is limited by comorbidities and advanced age (7). Moreover, patients with refractory disease or relapse within 12 months of ASCT have poor outcomes even with this intense strategies, as it is shown in the SCHOLAR-1 multicenter retrospective study, in which the objective response rate (ORR) to the next line of therapy in such patients was 26% (CR, 7%), with a median overall survival (OS) rate of 6.3 months (8).

Recent novel immunotherapy approaches are changing the treatment landscape for these patients. CD19 chimeric antigen receptor T cells (CARTs), are autologous T cells that have been genetically reengineered using viral transduction to express an anti-CD19 single- chain variable fragment for antigen recognition. Three CD19 CART products have been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) [axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel)], for the treatment of R/R aggressive B-cell lymphomas, including DLBCL, high-grade B-cell lymphoma, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma, after ≥ 2 prior lines of systemic therapy, and they show high response rates with durable remissions (9–11). The most up-to-date data with axi-cel demonstrates an OS rate at 4 years of 44% (12).

Due to these impressive results beyond two lines of therapy, several trials tested CART therapy in second line in high risk DLBCL patients. Three randomized phase 3 clinical trials compared the second line treatment with high-dose chemotherapy followed by ASCT (standard arm), with CART therapy (experimental arm), in high-risk patients with DLBCL, refractory or in early relapse (during the first year after finishing the first line treatment) (13–15). An improvement in event-free survival compared with ASCT was demonstrated in 2 of them (13, 15). As a result of these trials, FDA has approved on April 1^st, 2022, the use of axi-cel in second line for adult patients with DLBCL refractory or relapsed within 12 months after first-line chemoimmunotherapy. Therefore, CARTs have changed the treatment paradigm for R/R aggressive B-cell lymphomas, although significant toxicities are associated with this therapy, such as cytokine release syndrome (CRS) and immune effector cell-associated neurologic syndrome (ICANS).

Nevertheless, despite the high efficacy of CART therapy, many patients do not respond or relapse, representing a new unmet clinical need. Results from retrospective studies show a median survival for these patients of around 6 months (16–18). There are no standard treatment options. Check points inhibitors have been used in early relapses, resulting In ORR of 40%, as well as lenalidomide based regimens, chemotherapy and radiotherapy (17). Loncastuximab tesirine, a humanized anti-CD19 antibody drug conjugated, has been used in the LOTIS 2 trial, in 13 patients after CART failure, with an ORR of 46% (19). For those patients who achieve a response, a consolidation with allogeneic transplantation should be considered (17).

Other new targeted approaches for R/R DLBCL have been recently approved, as the combination of tafasitamab (anti-CD19 monoclonal antibody) and lenalidomide (20), the combination of polatuzumab vedotin with bendamustine and rituximab (21), and selinexor, an oral inhibitor of exportin 1 (approved by the FDA but not by the EMA) (22). Each of these options should be considered for patients who are poor candidates for ASCT or for CARTs.

The observations that CART cells are capable of achieving very durable remissions supported the T cell‐mediated approach to therapy. With this in mind, a new type of monoclonal antibodies called bispecific antibodies (BsAbs) has been designed. BsAbs combine two different monospecific antigen‐binding regions from different antibodies to achieve a single antibody‐derived molecule with bispecific antigen binding. Currently, there are under development BsAbs that target CD20 on B cells and engage CD3 on T cells in a 1:1 or 2:1 CD20:CD3 antigen binding fragment (Fab) format, to treat B‐cell lymphomas ( Table 1 ). There are different types of BsAbs, those that are IgG-like are large, and contain the fragment crystallizable (Fc) region linking the two antibody binding domains, which is an advantage as they have pharmacokinetic profiles that allow intermittent dosing. Thus, BsAbs have emerged as a novel class of off-the-shelf immunotherapies with clear efficacy in R/R aggressive B-cell lymphomas, including for those patients relapsing after CART therapy. This review describes updated data on the toxicity and efficacy of the IgG-like BsAbs that are currently being studied in lymphomas, especially in DLBCL.

Clinical data available of the four BsAbs that are in clinical development for DLBCL will be discussed, as well as the clinical trials that are ongoing.

Fortunately, new therapeutic strategies are available today to treat high risk R/R DLBCL patients. Three CD19 CART products, axi-cel, tisa-cel, and liso-cel, have been approved by FDA and EMA, to treat R/R DLBCL patients beyond 2 lines, and axi-cel has been recently approved by FDA as second line for adult patients with DLBCL refractory or relapsed within 12 months after first-line chemoimmunotherapy.

On the other hand, BsAbs have shown very promising preliminary results in the first published trials. Advantages and disadvantages of each of these strategies will be discussed, and a treatment algorithm is proposed for the treatment of R/R DLBCL (Figure 1).

CARTs have to be engineered for each individual patient, with a potential for logistical delays from the time of patient identification to CART infusion, as well as a risk of manufacturing failure (9–11). Moreover, CARTs may not be feasible for patients with rapidly progressive disease. These patients need bridging therapy during the manufacturing period, but it is not known what treatments are the best to be used. On the other hand, BsAbs, as an off-the-shelf option, allow immediate treatment. These agents are administered in an ease way, every 1 to 4 weeks either IV or even SC, and most can be administered in an outpatient basis. However, CART therapy consists in only one IV infusion, while treatment duration with BsAbs is prolonged.

Side effects associated with CARTs include CRS and ICANS, prolonged cytopenia, and impairment of humoral immunity with increased risk of infection (9–11). CRS is the most common and has been described in 42% to 93% of patients, with grade ≥3 events occurring in 2% to 22% of patients. BsAbs can also produce CRS and neurologic toxicities, seemingly at lower frequencies and severity, although toxicity data are not yet mature. Rates of CRS for BsAbs range from 27% (mosunetuzumab) to 62% (odronexamab), with grade ≥3 events in 0% (epcoritamab) to 7% (odronexamab) of patients (23, 29–31). Most of the CRS events occurred during the first 2 cycles. To mitigate CRS, different strategies are being employed, as the step-up dosing (23), the use SC formulation (24, 31), or the use a cytoreductive anti-CD20 monoclonal antibody before the BsAb infusion (29). Rates of ICANS of grade ≥3 range from 1% (glofitamab) to 4% (mosunetuzumab and odronexamab) with BsAbs. Additional toxicities described for BsAbs with an incidence of ≥10% include pyrexia, reaction at the injection site, and cytopenia. Like CARTs, BsAbs have been used safely in older patients and in patients with comorbidities (25).

Response rates for CARTs in patients with DLBCL range from 52% to 82%, with CR rates of 40% to 54%, and these responses are durable (9–12). For axi-cel, the CART product with a longer follow-up, with a median follow-up greater than 4 years, the OS at 4 years is 44% (12). For liso-cel, with a median follow-up of 40 months, the PFS at 3 years is 31%. For BsAbs, response rates in aggressive lymphomas range from 35% to 88%, with CRs of 19% to 60%, for those patients not exposed to prior CART. Nevertheless, follow-up with BsAbs is still very short, and most of the data regarding efficacy come from phase 1 trials. Therefore, efficacy data, although promising, are still immature, and the results of the new trials that are ongoing are needed to confirm them. Although CARTs offer durable responses, some patients will still relapse. BsAbs have been used in patients relapsed after CARTs, and durable responses have been observed (23, 31).

BsAbs have emerged as a novel class of off-the-shelf immunotherapies with a manageable safety profile, and clear efficacy in R/R aggressive B-cell lymphomas, including in those patients relapsing after CART therapy. There are still many open questions, and new trials are currently ongoing to confirm BsAbs efficacy and tolerability, as well as to explore its efficacy in different lines of therapy or in combination with other drugs.

EG performed the review, critically analyzed the data and wrote the manuscript.

We thank CERCA Programme/Generalitat de Catalunya for institutional support.

EG declares having received lecture fees and advisory board fees from Janssen, Abbvie, Gilead, Kiowa, EUSAPharma, Incyte, Lilly, Beigene, Novartis, Abbvie, Takeda, and Roche.

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