A Review of Bispecific Antibody Therapy for Relapsed/Refractory Diffuse Large B-Cell Lymphoma and Implementation in a Community Hospital

Abstract

Patients with Relapsed/Refractory Diffuse Large B-cell Lymphoma (R/R DLBCL) harbor a poor prognosis. Novel therapies, such as bispecific antibodies (BsAbs), provide an effective therapeutic option for such patients. BsAbs are studied both as monotherapy and combination therapy for patients with R/R DLBCL with promising results. Unlike cellular therapies, such as autologous stem cell transplant (ASCT) or chimeric antigen receptor therapy (CAR-T), BsAbs are more amenable to administration in a community setting, given the lower incidence and severity of key toxicities, such as cytokine release syndrome (CRS) and immune effector cell-associated neurologic syndrome (ICANS). Deployment of BsAbs in the community setting requires operational considerations and a multidisciplinary team approach. This review will discuss the currently approved BsAb treatment regimens and our community institution’s experience in implementing BsAbs.

1. Introduction

Diffuse Large B-cell Lymphoma (DLBCL) is the most common type of B-cell lymphoma. Polatuzumab, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone are the standards of care [1]. Despite standards of care, 20–40% may have relapsed or refractory (R/R) disease, with a median overall survival of 6 months [2,3]. Risk factors for R/R disease include an elevated International Prognostic Index (IPI) and double-hit or triple-hit lymphomas (DLBCL with MYC and BCL2 and/or BCL6 rearrangements). Specific genetic subtypes, such as MCD (MYD88L265P and CD79B mutations) and N1 (NOTCH1 mutations), are more common in relapsed cases, while BCL2 rearrangements and NOTCH2 mutations also confer higher risk [4].

Novel therapies such as chimeric antigen receptor T-cell (CAR-T), monoclonal antibodies, antibody drug conjugates (ADC), and bispecific antibodies (BsAbs) have emerged as important treatment strategies that improved outcomes in patients with R/R DLBCL [5,6,7].

For patients who have R/R disease to first-line treatment, the current preferred standard of care is CAR-T if R/R occurs within 12 months and if the patient is an appropriate candidate. If a patient relapses more than 12 months after first-line standard of care, then autologous stem cell transplant (ASCT) is preferred if the patient is considered eligible. If ineligible, then CAR-T may still be an option [8,9,10]. However, this leaves a group of patients who are not candidates for either CAR T or ASCT.

CAR-T may not be feasible for many patients. First of all, CAR-T can only be administered in specialized centers and requires additional procedures of apheresis and manufacturing, which makes it not practical for patients with rapidly progressing disease.

Secondly, there are significant socioeconomic barriers to receiving CAR-T and ethnic biases for enrolling in CAR-T clinical trials [11,12].

BsAbs act by binding to both the patient’s T-cells and target tumor cells, and in doing so, they recruit the patient’s immune system to attack the target tumor cells via cell-mediated cytotoxicity [1]. Once the BsAb binds to the T-cell’s CD3 subunit and the tumor’s target antigen, which is CD20 for R/R DLBCL, this forms a synapse that activates T-cells, leading to tumor cell killing and more recruitment of T-cell activation [13].

Per current NCCN guidelines, BsAbs are considered appropriate treatment of R/R DLBCL as a second-line or third-line treatment if the patient is not a candidate for CAR-T or if the patient progresses after CAR-T [4].

BsAbs have an advantage over CAR-T since they are “off the shelf”, readily available for use, and can be accessible to patients in the community setting.

The first BsAb for the treatment of lymphoma was blinatumomab, a CD19 × CD3 conjugate; however, several trials documented significant neurotoxic adverse effects, and blinatumomab is not used for R/R DLBCL when compared to other BsAbs [14,15,16,17].

The following BsAbs are considered therapeutic options as monotherapy and/or combination therapy for R/R DLBCL: glofitamab, mosunetuzumab, and epcoritamab [4].

The aim of this manuscript is to provide an overview of the current available BsAbs and to highlight the experience of successfully implementing BsAbs in the community care setting.

2. Glofitamab

2.1. Glofitamab Monotherapy, Third Line

Glofitamab is a CD20 × CD3 BsAb, with an IgG1-based structure of 2:1 bivalently binding to CD20 and monovalent binding to CD3, which was studied as a third-line therapy in R/R DLBCL and as a monotherapy, including transformed Follicular Lymphoma [18]. In a phase I/II study, 171 patients with R/R DLBCL received glofitamab monotherapy in a step-up dosing regimen administered over 21-day cycles for 12 total cycles (Table 1). Premedication with antihistamines, acetaminophen, and corticosteroids was given prior to obinutuzumab and glofitamab to mitigate infusion-related toxicities.

At a median follow-up of 12.6 months, the complete response (CR), assessed by an independent review committee (IRC), was 39%, and the objective response (ORR) was 52%. In a subgroup analysis, there was a similar rate of CR among patients previously treated by CAR-T compared to CAR-T-naïve patients. Median overall survival (OS) was 11.5 months, and median progression-free survival (PFS) was 3.8 months.

CRS was the most common adverse effect, at 63%. Most CRS events were grade 1 (47%) and grade 2 (12%). ICANS occurred in 8% of patients, and all cases were resolved. Other common side effects included infections, which occurred in 39% of patients [19].

The results of this study led to the accelerated FDA approval of glofitamab for R/R DLBCL in June 2023 [20].

Table 1. Comparison of BsAb agents.

BsAbs per NCCN Guidelines	Line of Therapy per NCCN Guidelines	Bispecific Antibody Structure	Administration	ORR	CR	PFS	OS	CRS	ICANS	Number of Previous Lines of Therapy	Previous CAR-T	Double-/Triple-Hit Lymphoma	Reference
Glofitamab Monotherapy (n = 155)	≥3rd line	Humanized Mouse IgG1-based, 2xCD20:1xCD3	IV, 21-day cycles, 12 total cycles C1D8, C1D15: dose escalation C2D1-C12D1: target dose	52%	39%	3.8	11.5	63%	8%	2 previous lines: 40% ≥3 previous lines: 60%	40%	13%	Dickinson et al., 2022 [19]
Glofitamab + Gemcitabine/Oxaliplatin (n = 183)	≥2nd line		Glofitamab 21-day cycles, 12 total cycles C1D8, C1D15: dose escalation C2D1C12D1: target dose GemOx 21-day cycles, 8 total cycles C1D2, C2D1-C8D1	68.30%	58.50%	13.8	25.5	44%	2%	1 previous line: 63% ≥2 previous lines: 37%	7%	excluded	Abramson et al., 2024 [21]
Mosunetuzumab Monotherapy (n = 88)	≥3rd line	Humanized Mouse IgG1-based CD20:CD3	IV, 21-day cycles, up to 17 total cycles C1D1, C1D8, C1D15, C2D1: dose escalation C3D1 onward: target dose	42%	32%	3.2	11.5	26.10%	2.30%	2 previous lines: 35.2% 3 previous lines: 31.8% >3 previous lines 33%	35.20%	19.30%	Bartlett et al., 2023 [22]
Mosunetuzumab + Polatuzumab (n = 120)	≥2nd line		Mosunetuzumab IV, 21-day cycles, up to 17 total cycles C1D1, C1D8, C1D15, C2D1: dose escalation C3D1 onward: target dose Polatuzumab D1 each cycle	59.20%	45.90%	11.4	23.3	17%	5%	1–2 previous lines: 52.5% ≥3 previous lines: 47.5%	35%	20.2% (n = 22/109)	Budde et al., 2024 [23]
Epcoritamab Monotherapy (n = 157)	≥3rd line	Humanized Mouse IgG1-based CD20:CD3	Subcutaneous, 28-day cycles, until progression/intolerable toxicity C1: dose escalation C2–C3: once weekly C4–C9: once every other week C10 onward: once every 4 weeks	63.10%	40.10%	4.4	18.5	51%	6.40%	2 previous lines: 29.9% 3 previous lines: 30.6% ≥4 previous lines 39.5%	38.90%	8.28%	Thieblemont et al., 2024 [24]
Epcoritamab + Gemcitabine/Oxaliplatin (n = 103)	≥2nd line		Epcoritamab Subcutaneous, 28-day cycles, until progression/intolerable toxicity C1: dose escalation C2–C3: once weekly C4–C9: once every other week C10 onward: once every 4 weeks Gemox Every 2 weeks C1–C4, 8 total cycles	85%	61%	11.2	21.6	52%	2.90%	1 previous line: 37.9% 2 previous lines: 26.2% ≥3 previous lines: 35.9%	28.20%	10.3% (n = 6/58)	Brody et al., 2025 [25]

Table 1. Comparison of BsAb agents.

BsAbs per NCCN Guidelines	Line of Therapy per NCCN Guidelines	Bispecific Antibody Structure	Administration	ORR	CR	PFS	OS	CRS	ICANS	Number of Previous Lines of Therapy	Previous CAR-T	Double-/Triple-Hit Lymphoma	Reference
Glofitamab Monotherapy (n = 155)	≥3rd line	Humanized Mouse IgG1-based, 2xCD20:1xCD3	IV, 21-day cycles, 12 total cycles C1D8, C1D15: dose escalation C2D1-C12D1: target dose	52%	39%	3.8	11.5	63%	8%	2 previous lines: 40% ≥3 previous lines: 60%	40%	13%	Dickinson et al., 2022 [19]
Glofitamab + Gemcitabine/Oxaliplatin (n = 183)	≥2nd line		Glofitamab 21-day cycles, 12 total cycles C1D8, C1D15: dose escalation C2D1C12D1: target dose GemOx 21-day cycles, 8 total cycles C1D2, C2D1-C8D1	68.30%	58.50%	13.8	25.5	44%	2%	1 previous line: 63% ≥2 previous lines: 37%	7%	excluded	Abramson et al., 2024 [21]
Mosunetuzumab Monotherapy (n = 88)	≥3rd line	Humanized Mouse IgG1-based CD20:CD3	IV, 21-day cycles, up to 17 total cycles C1D1, C1D8, C1D15, C2D1: dose escalation C3D1 onward: target dose	42%	32%	3.2	11.5	26.10%	2.30%	2 previous lines: 35.2% 3 previous lines: 31.8% >3 previous lines 33%	35.20%	19.30%	Bartlett et al., 2023 [22]
Mosunetuzumab + Polatuzumab (n = 120)	≥2nd line		Mosunetuzumab IV, 21-day cycles, up to 17 total cycles C1D1, C1D8, C1D15, C2D1: dose escalation C3D1 onward: target dose Polatuzumab D1 each cycle	59.20%	45.90%	11.4	23.3	17%	5%	1–2 previous lines: 52.5% ≥3 previous lines: 47.5%	35%	20.2% (n = 22/109)	Budde et al., 2024 [23]
Epcoritamab Monotherapy (n = 157)	≥3rd line	Humanized Mouse IgG1-based CD20:CD3	Subcutaneous, 28-day cycles, until progression/intolerable toxicity C1: dose escalation C2–C3: once weekly C4–C9: once every other week C10 onward: once every 4 weeks	63.10%	40.10%	4.4	18.5	51%	6.40%	2 previous lines: 29.9% 3 previous lines: 30.6% ≥4 previous lines 39.5%	38.90%	8.28%	Thieblemont et al., 2024 [24]
Epcoritamab + Gemcitabine/Oxaliplatin (n = 103)	≥2nd line		Epcoritamab Subcutaneous, 28-day cycles, until progression/intolerable toxicity C1: dose escalation C2–C3: once weekly C4–C9: once every other week C10 onward: once every 4 weeks Gemox Every 2 weeks C1–C4, 8 total cycles	85%	61%	11.2	21.6	52%	2.90%	1 previous line: 37.9% 2 previous lines: 26.2% ≥3 previous lines: 35.9%	28.20%	10.3% (n = 6/58)	Brody et al., 2025 [25]

2.2. Glofitamab + Gemcitabine/Oxaliplatin

Glofitamab was investigated in combination with gemcitabine and oxaliplatin in the global phase III STARGLO trial for ASCT-ineligible patients with R/R disease who had previously received 1–2 previous lines of systemic therapy. Patients were randomized 2:1 to receive glofitamab plus gemcitabine/oxaliplatin (Glofit-GemOx; n = 183) or rituximab plus GemOx (R-GemOx; n = 91).

At a median follow-up of 20.7 months, OS was significantly improved with Glofit-GemOx over R-GemOx (25.5 months vs. 12.9 months; HR 0.62). After a median follow-up of 15.7 months, PFS was also superior, with Glofit-GemOx vs. R-GemOx (13.8 months vs. 3.6 months; HR 0.4). Both CR and ORR favored the Glofit-GemOx group, 58.5% vs. 25.3% and 68.3% vs. 40.7%, respectively.

The most common adverse events of Glofit-GemOx included thrombocytopenia (48%), CRS (44%), neutropenia (42%), anemia (41%), nausea (39%), peripheral neuropathies (36%), diarrhea (34%), and elevated liver enzymes (33%). CRS occurred mostly after the first dose of glofitamab, and most CRS events were either grade 1 (31%) or grade 2 (10%), with only 2% being grade ≥ 3 events. ICANS occurred in four patients (2%), concurrently with CRS, and was grade 3 in only one patient. A total of 78% experienced at least one grade ≥ 3 adverse event in the Glofit-GemOx group, and this led to discontinuation of the study treatment in 48 patients (27%) [21].

The STARGLO study supports the use of Glofit-GemOx in ASCT-ineligible patients and represents an effective treatment option, especially for patients who are not candidates for CAR-T due to poor access or rapid progression of disease. It is listed as a treatment option in the NCCN guidelines as a second-line or later treatment for R/R DLBCL.

While the trial faced limitations in the United States due to poor accrual, leading to the absence of FDA approval, regulatory agencies in Europe, Canada, and China granted approval for Glofit-GemOx in these regions.

3. Epcoritamab

3.1. Epcoritamab Monotherapy, Third Line

Epcoritamab is a subcutaneous CD20 × CD3 IgG-based BsAb, which was studied in the EPCORE NHL-1 trial, a single-arm phase I–II multiregional trial in which adult patients who had R/R LBCL after two or more lines of systemic therapy were enrolled, including patients who had prior failure or ineligibility for ASCT.

A total of 157 patients were enrolled. At a median follow-up of 25.1 months, 130 patients had discontinued therapy, most commonly due to disease progression (n = 89), followed by adverse events (n = 23) or transition to ASCT (n = 7). At data cutoff, 27 patients remained on treatment.

At a median follow-up of 20.3 months, CR and ORR were 40.1% and 63.1%, respectively. Median PFS was 4.4 months, with an estimated 24-month PFS rate of 27.8%. Median OS was 18.5 months, with an estimated 24-month OS rate of 44.6%.

The most common adverse event was CRS, which occurred in 80 patients (51%), predominantly grade 1 (n = 50) or grade 2 (n = 25). There were n = 5 grade 3 events, and there were no grade 4 or 5 events. ICANS occurred in ten patients (6.4%), one of which was a fatal event, the only grade ≥ 3 ICANS event. There were three total epcoritamab-related fatal adverse events, one due to ICANS, the second to COVID-19 pneumonia, and the third to bacterial pneumonia [24,26].

Epcoritamab was granted FDA accelerated approval for third-line treatment in DLBCL in May 2023 [27].

3.2. Epcoritamab + Gemcitabine/Oxaliplatin

In the EPCORE NHL-2 phase 1b/2 single-arm trial, epcoritamab was studied in combination with GemOx (Epco-GemOx) in 103 patients with R/R DLBCL with at least one prior line of therapy. The study included both de novo and transformed DLBCL patients not eligible for ASCT.

At a median follow-up of 13.2 months, ORR was 85%, and CR was 61% by IRC assessment. Median PFS and OS were 11.2 months and 21.6 months, respectively. CRS occurred in 52% of patients, and ICANS occurred in 2.9%; only one patient experienced grade ≥ 3 CRS and ICANS. Cytopenias (anemia 43%, neutropenia 57%, and thrombocytopenia 59%) were the most common grade ≥ 3 adverse events [25].

Of the fifty-nine patients who discontinued treatment, thirty-two had disease progression, twenty had adverse events, three died, three withdrew, and one had maximum clinical benefit and proceeded to ASCT.

3.3. Epcoritamab in Other Combinations

Epcoritamab is also being studied in combination with other regimens, such as R-DHAX/C, R-ICE, and lenalidomide for patients with R/R DLBCL, with promising results [28,29,30,31,32,33].

4. Mosunetuzumab

4.1. Mosunetuzumab Monotherapy, Third Line

Mosunetuzumab is a humanized mouse CD20 × CD3 IgG-based BsAb. It was studied by Bartlett et al. as a third-line monotherapy for R/R DLBCL. Patients were enrolled, regardless of whether or not their tumor cells expressed CD20 [22].

Of 88 treated patients, 37 (42%) achieved ORR, including 21 (24%) with CR. The median OS was 11.5 months, and the median PFS was 3.2 months at a median follow-up of 10.1 months. Notably, none of the four patients with <35% CD20 expression responded.

The most common grade 3–4 side effects included neutropenia, hypophosphatemia, anemia, and febrile neutropenia. CRS was a common adverse event (26.1%), though mainly low grade 23.9%, with only two patients experiencing grade 3 CRS. Two patients (2.3%) experienced ICANS, and both were grade 1 [22].

Mosunetuzumab is currently not approved for DLBCL by the FDA [34].

4.2. Mosunetuzumab + Polatuzumab Vedotin

Mosunetuzumab was studied in combination with polatuzumab vedotin, the CD79B antibody–drug conjugate, as a treatment for R/R LBCL in a phase 1b/2 trial. Twenty-two patients were enrolled in the phase 1b cohort. In the phase 2 portion of the trial, 98 patients with R/R LBCL, with 75 of them having DLBCL, were treated with mosunetuzumab + polatuzumab vedotin (Mosun-Pola).

Patients were planned to receive eight cycles of mosunetuzumab and six cycles of polatuzumab vedotin, with 42 (42.9%) patients having completed treatment. Among the patients who did not complete treatment, forty-two patients had progressive disease, six discontinued due to adverse events, and two died.

At a median follow-up of 23.9 months, ORR was 59.2%, and CR was 45.9%. The median OS and PFS were 23.3 months and 11.4 months, respectively. The median duration of completeness was not reached.

Safety data was analyzed among the 120 patients across both phase 1b and 2 cohorts. The most common grade 3–4 adverse events were neutropenia (25%) and fatigue (6.7%). CRS occurred in twenty patients (16.7%), in which three patients had grade 3 events, but none had grade 4. ICANS occurred in six patients (5%); one had grade 3 and one had grade 4 [23].

5. Other BsAbs Under Investigation

5.1. Plamotamab

Plamotamab is a CD20 × CD3 BsAb and is currently being studied in an ongoing phase 1 study in heavily pretreated patients with R/R Non-Hodgkin’s Lymphoma (NHL), with a median of four prior lines of therapy (NCT02924402) [35].

5.2. Odronextamab

Odronextamab is a CD20 × CD3 BsAb studied in a single-arm phase 1 trial, which enrolled patients with CD20-positive R/R B-cell Lymphoma (BCL) that were heavily pretreated with a median of three prior lines of therapy [36].

Odronextamab monotherapy was studied in R/R DLBCL following progression after CAR-T in the expansion cohort of the ELM-1 study, at a median of 6.5 months since prior CAR-T. Sixty patients were enrolled. A total of 71.7% were refractory to CAR-Ts, and 48.3% relapsed within 90 days of CAR-T therapy. Odronextamab was administered in 21-day cycles with step-up dosing during cycle 1 and target dose cycles 2–4. Thereafter, patients received odronextamab 320 mg every 2 weeks until progression of disease or unacceptable toxicity. Patients who had a sustained CR of at least 9 months received odronextamab at 320 mg every 4 weeks.

ORR and CR were 48.3% and 31.7%, respectively. The median duration of response was 14.8 months, and the median duration of CR was not reached. The most common adverse event was CRS, and there were no grade 3 or grade 4 CRS events. There were no cases of ICANS. PFS and OS were 4.8 months and 10.2 months, respectively [37].

This study illustrates the efficacy of odronextamab after previous CAR-T, with patients achieving CR and some lasting for >9 months.

5.3. IGM-2323

IGM2323 is a CD20 × CD3 BsAb studied in a phase 1 trial as monotherapy for R/R NHL [38,39].

6. Comparing Agents

BsAbs represent effective treatment options for second- and third-line treatments for R/R DLBCL. All currently available BsAbs target CD20 and engage CD3, though their differing molecular structures may influence both efficacy and toxicity profiles.

Across the pivotal phase 2 monotherapy trials, epcoritamab was evaluated in the most heavily pretreated population, with 70.1% of patients having received ≥3 prior lines of therapy, compared with 60% in the glofitamab trial and 64.8% in the mosunetuzumab study. Epcoritamab also had the highest proportion of patients previously exposed to CAR-T therapy (38.9%) versus 33% for glofitamab and 29.5% for mosunetuzumab. All three trials enrolled patients with double- or triple-hit lymphoma; however, efficacy outcomes for these subgroups were reported only in the mosunetuzumab (ORR 41%, CR 6%) and epcoritamab studies (CR 25%). Notably, despite enrolling in a more heavily pretreated cohort, epcoritamab demonstrated comparatively favorable overall survival. Data for double-expressor lymphoma were available only in the epcoritamab trial, where CR was substantially lower in double expressors (20%) versus non-double expressors (41%).

In combination regimens, Glofit-GemOx remains the only BsAb chemotherapy backbone with phase 3 data. Unlike Glofit-GemOx, both Epco-GemOx and Mosun-Pola enrolled patients with double- or triple-hit disease. Mosun-Pola was studied in a more heavily pretreated cohort and included a greater proportion of patients with prior CAR-T exposure [21,23,25].

Toxicity patterns also varied across agents, although cross-trial comparisons should be interpreted cautiously. Mosunetuzumab consistently demonstrated lower rates of CRS, whereas both glofitamab monotherapy and Glofit-GemOx were associated with higher CRS incidence. This difference may reflect glofitamab’s unique 2:1 bivalent CD20 monovalent CD3 structure, which may enhance T-cell activation compared with the 1:1 CD20:CD3 configuration of mosunetuzumab and epcoritamab.

Practical administration requirements further distinguish between these agents. Mosunetuzumab can be delivered fully in the outpatient setting without mandated hospitalization. Glofitamab generally requires inpatient monitoring during step-up dosing, particularly for early CRS events. Epcoritamab requires hospitalization for the initial 48 mg step-up dose, although ongoing trials (e.g., EPCORE NHL-6) are evaluating the safety of entirely outpatient administration [27,40].

6.1. Sequencing BsAbs with CAR-T Therapy

There is no current standard of care for sequencing BsAbs and CAR-T for R/R DLBCL. CAR-T is currently the preferred second-line treatment in patients with R/R DLBCL within 12 months of initial treatment based on phase III studies showing CR of 40–58% and long-term disease-free survival of >40% [38,39,40,41,42]. Patients who relapse after CAR-T have a poor outcome; however, BsAbs have shown efficacy in this setting. BsAbs can be considered in second-line treatment in patients who have poor access to CAR-T or who have rapid disease progression and cannot wait for the process of apheresis and manufacturing of CAR-T. Nonetheless, the overlapping mechanisms of action raise concerns regarding resistance to immune-mediated killing following BsAb exposure, as well as the potential for T-cell exhaustion, which may adversely impact subsequent CAR-T efficacy [41,42].

6.2. BsAbs Prior to CAR-T

The process for CAR-T therapy is time-consuming. The process of insurance authorization, leukapheresis, and manufacturing CAR-T can take several weeks [11]. While waiting for CAR-T, there is emerging evidence that patients may receive BsAbs without diminished response to CAR-T in the future.

A recent retrospective study by Crochet et al. reviewed 47 patients with R/R LBCL who had previously received BsAbs, excluding those who received CD19 × CD3 BsAbs, and evaluated their responses to CD19-targeted CAR-T. ORR to CAR T was 85%, and CR was 43%. The median follow-up was 10.5 months, the median PFS was 6.6 months, and the median OS was not reached. The median duration between BsAbs and leukapheresis for CAR-T was 51 days, and the median duration between leukapheresis and CAR-T was 43 days. Notably, patients who received BsAbs less than 50 days prior to leukapheresis had similar ORR and CR to patients beyond 50 days between treatments (82% vs. 84% and 32% vs. 52%, p = 0.36) [43].

This study, although limited by the small number and the retrospective nature, suggests that CAR-T remains effective after exposure to BsAbs. Further studies are needed to assess BsAbs as a potential bridge to CAR-T.

6.3. Efficacy of BsAbs After CAR-T

An important clinical question is whether previous CAR-T therapy diminishes the efficacy of BsAbs. The median OS for patients with LBCL who relapse after CAR-T is 5.2 months, underscoring the urgent need for effective salvage strategies [44]. Emerging evidence suggests that prior CAR-T may not substantially impair response to BsAbs, although outcomes appear modestly lower compared with CAR-T-naïve patients.

In the glofitamab monotherapy trial, similar CR was noted among patients who had received prior CAR-T (36 patients), with a median of 127 days between previous CAR-T administration and obinutuzumab pretreatment [20]. In the STARGLO trial, 13 patients (7%) in the Glofit-GemOx group had prior CAR-T, and those had a CR of 53.8% and a median PFS of 8.4 months, which were lower compared to the overall CR of 58.5% and PFS of 13.8 months [21].

In the Epco-GemOx combo therapy trial, 29 patients (28%) had previously received CAR-T, with an ORR of 76% and a CR of 45%, which was lower than the ORR and CR without prior CAR-T (89% and 68%, respectively), though not statistically significant.

Although one cannot compare across trials, these findings are consistent with the ELM-1 study, which reported lower ORR, CR, PFS, and OS after CAR-T. Nevertheless, these findings provide promising evidence of response to BsAbs after CAR-T [37].

It is unclear how much this decrease in BsAb effectiveness is due to it occurring after CAR-T vs. decreased efficacy with each subsequent line of therapy. Since a significant proportion of patients relapse after CAR-T, BsAbs are currently being explored as a consolidation strategy. There is an ongoing SWOG trial studying the use of mosunetuzumab consolidation after CAR-T [45].

6.4. Resistance to BsAbs

BsAb resistance arises through diverse mechanisms.

Antigen loss is one tumor escape mechanism, which can occur after BsAb treatment. Loss of CD20 has been identified among patients who relapsed after CD20-directed BsAbs [46]. In the four patients with CD20 loss identified by Duell et al., genomic alteration appears to be the mechanism behind the loss of CD20 [47].

Re-biopsy to confirm CD20 positivity is recommended prior to initiating bispecific antibody therapy.

Philip et al. studied T-cell exhaustion as another potential mechanism of resistance. They found that extracted T-cells from B-cell acute lymphoblastic leukemia patients had decreased T-cell activity after one cycle of blinatumomab. They also found that a treatment-free interval led to improved T-cell function in previously exhausted T-cells in mice [48].

T-cell exhaustion in R/R DLBCL was also identified in two patients by Duell et al. [47].

In addition, tumor-intrinsic alterations (e.g., TP53 mutations and MYC amplifications) and immunosuppressive influences from the tumor microenvironment play a role. More investigation in larger numbers of patients is required to further elucidate these mechanisms of resistance.

7. Implementing BsAbs in Community Care Settings

There are many logistical considerations that require multidisciplinary planning to implement BsAbs in the community care setting. An international panel of experts provided a framework of consensus recommendations for managing BsAbs in the community care setting. Recommended key features of implementation of BsAbs include proper inpatient/outpatient facilities, trained staff, and patient/caregiver education [49].

The Community Cancer Institute (CCI) is affiliated with Community Medical Centers and is located in the Central Valley of California. As we planned the deployment of BsAbs in 2021, we took into consideration the requirement of hospitalization, risk evaluation, and mitigation strategy (REMS) programs, the management of prophylaxis to avoid toxicities, and the overall coordination of care. We started by building our management team that included a physician, an advanced practice provider, nurse champions at the cancer center and the hospital, a pharmacist, and a social worker.

Key steps in implementation included the following:

• Training the staff. A physician, APP, and pharmacist held several sessions educating the nursing staff in the cancer center, inpatient oncology unit, emergency room, and intensive care unit on the mechanism of action, recognition of CRS and ICANS, and grading per ASTCT consensus grading.
• Emergency preparedness. Order sets in EMR for the management of CRS and ICANS were implemented.
• Selection of patients. Patients were presented at the multidisciplinary team conference for a comprehensive assessment of comorbidities, prior therapies (especially CAR-T or ASCT), and performance status. They were assessed for caregiver availability, compliance with monitoring vitals, and understanding of the side effects.
• Site preparation. We partnered with the hospital system for inpatient admission when indicated during dose escalation of epcoritamab and the first dose of glofitamab, or if the patient developed grade 2 CRS or any grade of ICANS. A group that included inpatient oncology nursing, ER nursing, and ICU nursing managers was created in the EMR messaging system and informed when a patient needed admission. The pharmacist ensured the availability of at least two doses of tocilizumab for every patient. The patients were provided with wallet cards to present to the ED to help expedite care through the pathway implemented for treatment of CRS and ICANS. Standard operative procedures and protocols were implemented to facilitate rapid escalation to higher care when needed.
• Patient education. The patient and caregiver were educated on monitoring vital signs at home and when to call, emphasizing early reporting of symptoms.

Since some community practices do not have affiliation with hospitals, it is important for these practices to build a collaborative care model with academic centers to admit patients for doses that need to be given inpatient care and to establish referral pathways for complex cases.

There are other challenges that can be encountered when implementing BsAbs, including financial issues.

BsAbs carry substantial upfront costs, encompassing drug acquisition, step-up dosing administration, hospitalization during early cycles, toxicity management (including CRS and ICANS), and the need for frequent clinic visits in the first several weeks of therapy. These cumulative expenses create variability in payer authorization, with coverage decisions differing widely across commercial plans. Delays in insurance approval can be particularly consequential for R/R DLBCL, where rapid disease progression is common. Early involvement of specialty pharmacy teams, financial counselors, and patient navigators is, therefore, essential to avoid treatment interruptions and ensure timely initiation.

Insurance-related challenges may disproportionately affect patients with lower socioeconomic status, limited English proficiency, or restricted transportation options. As such, with BsAbs, financial toxicity remains a real concern. Patients may face significant copays due to emergency room evaluations and hospital admissions that can carry high out-of-network costs. Community centers must, therefore, anticipate these challenges by establishing clear financial navigation pathways and collaborating closely with payers.

Health equity considerations are critical when implementing BsAbs in underserved regions, such as California’s Central Valley. Rural populations, migrant workers, uninsured or underinsured patients, and individuals from racial or ethnic minority groups—populations historically underrepresented in CAR-T trials—may experience delays in diagnosis, limited specialty access, and reduced continuity of care. To ensure equitable delivery, we trained our navigators on culturally sensitive education on BsAbs in addition to providing language services and transportation assistance.

Collectively, addressing cost, insurance variability, and structural inequities is essential to achieving broad and equitable access to BsAbs.

Nevertheless, there is emerging evidence that BsAbs in R/R DLBCL may save money compared to other agents in this setting. A budget impact model study by Mahmoudjafari et al. demonstrated that utilization of glofitamab saves an estimated USD 728,697 over 3 years in a hypothetical 1,000,000-patient health plan compared to other treatments in R/R DLBCL [50].

Since launching our BsAb program in 2021, our institution has treated a growing cohort of patients with R/R DLBCL using glofitamab-, epcoritamab-, and mosunetuzumab-based regimens. Among our initial patients, we observed clinical outcomes comparable to those reported in pivotal clinical trials. Our real-world toxicity profile aligns with the published literature. Most CRS events were grade 1–2 and occurred during step-up dosing, with only a minority requiring inpatient transfer. No cases of grade ≥ 3 CRS or ICANS were observed. Importantly, implementation of pre-specified EMR order sets, standardized grading tools, and early tocilizumab availability allowed rapid intervention, resulting in prompt resolution of CRS events and no treatment-related discontinuations. Most patients were able to continue subsequent doses entirely in the outpatient setting. The involvement of nurse navigators, pharmacists, and emergency department staff proved essential in minimizing delays, ensuring toxicity recognition, and optimizing patient flow. BsAbs can be implemented safely, efficiently, and with outcomes comparable to those seen in academic trial settings—even within a community hospital serving an underserved region.

8. Current Trials and Future Directions

There are several currently ongoing trials using BsAbs in the first-line treatment of DLBCL, including glofitamab + Pola-R-CHP (Polatuzumab Vedotin + Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone), odronextamab + R-CHOP, and epcoritamab + R-CHOP [51,52,53].

Other trials are evaluating several combinations of BsAbs with other novel therapies, such as the LOTIS-7 trial, which is investigating the activity of novel antibody drug conjugate loncastuximab tesirine with other agents, including in combination with glofitamab or mosunetuzumab [54].

There are also newer studies optimizing the CRS toxicity in BsAbs, such as NCT06806033, which seeks to evaluate CRS in Glofit-Gemox, and EPCORE NHL-6, which is evaluating the safety of administration of outpatient epcoritamab [40,55]. These studies will likely further facilitate the uptake of BsAbs in the community setting.

9. Conclusions

BsAbs are effective and accessible treatment options for R/R DLBCL and can be implemented in the community setting. Our center’s experience can serve as a model for other community practices to both participate in BsAb clinical trials and successfully administer standard-of-care BsAbs.