Précis
This article reviews the efficacy and safety data for bispecific T-cell engagers and the practical considerations for their implementation across various types of practice sites for the historically difficult-to-treat relapsed/refractory B-cell lymphoma population.
Abstract
The treatment landscape for relapsed/refractory B-cell lymphomas has evolved rapidly with the advent of immune cell–engaging therapies, including bispecific T-cell engagers (TCEs). In the past 2 years, the FDA has approved bispecific TCEs for the treatment of relapsed/refractory follicular lymphoma (mosunetuzumab-axgb [Lunsumio; Genentech, Inc] and epcoritamab-bysp [Epkinly; Genmab US, Inc]) and diffuse large B-cell lymphomas (epcoritamab and glofitamab-gxbm [Columvi; Genentech, Inc]). Additionally, odronextamab (Regeneron Pharmaceuticals, Inc), another bispecific T-cell–engaging antibody, is being investigated in both follicular and diffuse large B-cell lymphomas. These bispecific TCEs provide novel, non–chemotherapy-based treatment options for a historically difficult-to-treat relapsed/refractory B-cell lymphoma population. This article reviews the efficacy and safety data behind these treatments and highlights practical considerations for implementing these bispecific TCEs across various types of practice sites.
Introduction
The treatment landscape for patients with diffuse large B-cell lymphoma (DLBCL) who are refractory to treatment or relapse after achieving remission with first-line chemoimmunotherapy has shifted with the availability of chimeric antigen receptor (CAR) T-cell therapies for refractory disease or early relapse, and the historical second-line standard of care—salvage chemotherapy followed by autologous stem cell transplant (ASCT)—continues to be an option for eligible patients.1 However, outcomes remain poor for patients who are not candidates for aggressive second-line treatment, are unable to proceed with ASCT, or relapse shortly after ASCT. Additionally, due to the indolent and incurable nature of follicular lymphoma (FL), patients with FL will often require multiple lines of therapy throughout their lifetime.2 Therefore, treatments with novel, non–chemotherapy-based mechanisms have been developed, including an array of T-cell–based immunotherapies such as bispecific T-cell engagers (TCEs).
Bispecific TCEs are antibodies engineered with 2 active domains: a domain that promotes T-cell activity (eg, via CD3) and a domain that targets a tumor-specific marker or antigen. TCEs recruit endogenous T cells to tumor-expressed antigens on cancer cells to enact cytotoxic effects, resulting in T-cell activation and proliferation, which also leads to the hallmark toxicities of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS).3
For relapsed or refractory (R/R) BCLs, CD20 × CD3 bispecific TCEs—including epcoritamab-bysp (Epkinly; Genmab US, Inc) and glofitamab-gxbm (Columvi; Genentech, Inc) for R/R DLBCL and mosunetuzumab-axgb (Lunsumio; Genentech, Inc) and epcoritamab for R/R FL—have been developed and approved for use,4-6 increasing treatment options for patients with R/R LBCL and R/R FL who have received 2 or more lines of systemic therapy. In addition, odronextamab (Regeneron Pharmaceuticals, Inc), another CD20 × CD3 bispecific TCE, is being investigated in both FL and DLBCL, and ongoing research into other B-cell non-Hodgkin lymphomas (NHLs) and usage of TCEs in earlier lines of therapy will continue to expand the therapeutic role of TCEs.
This article reviews the efficacy and safety data from the pivotal trials that support the use of these TCEs as well as the practical considerations for—and challenges of—operationalizing these therapies across various types of practice sites for the historically difficult-to-treat R/R BCL population.
Overview of TCEs for R/R BCLs
odronextamab are all bispecific TCEs that bind to CD20 on B cells and CD3 on T cells. The structures of mosunetuzumab, epcoritamab, and odronextamab enable monovalent binding to CD20, whereas glofitamab has a 2:1 (CD20:CD3) configuration, allowing bivalent binding to CD20.7 Glofitamab was found to be more potent than odronextamab and mosunetuzumab in tumor lysis experiments in vivo and ex vivo.8 Also noteworthy, epcoritamab exhibited similar in vitro potency for inducing T-cell activation and T-cell–mediated cytotoxicity compared with an experimental 2:1-format TCE and higher potency than 3 other 1:1-format TCEs in clinical development.9
The trials that led to the accelerated approvals for mosunetuzumab, glofitamab, and epcoritamab were GO29781, NP30179, and EPCORE NHL-1, respectively. The drugs’ indications are as follows:
- Mosunetuzumab is approved for adult patients with R/R FL after 2 or more lines of systemic therapy.6
- Glofitamab is approved for adult patients with DLBCL not otherwise specified (NOS) or LBCL arising from FL after 2 or more lines of systemic therapy.5
- Epcoritamab is approved for adult patients with DLBCL NOS, including DLBCL arising from indolent lymphoma, and high-grade BCL after 2 or more lines of systemic therapy and R/R FL after 2 or more lines of systemic therapy.4
In June 2024, epcoritamab received accelerated approval from the FDA for treatment of adult patients with R/R FL after 2 or more lines of systemic therapy,4 with the National Comprehensive Cancer Network guidelines for BCLs supporting epcoritamab as a category 2A recommendation for FL as a third-line and subsequent therapy.10
Mosunetuzumab and glofitamab are fixed-duration treatments, whereas epcoritamab is a continuous therapy. After 8 cycles of mosunetuzumab, patients who achieve a complete response (CR) require no further treatment; patients who have a partial response (PR) or stable disease should be administered an additional 9 cycles (for a total of 17 cycles). Glofitamab is administered for up to 12 cycles or until intolerable toxicity. Epcoritamab is administered until disease progression but is being investigated in various combinations as a fixed-duration treatment.11,12 The administration schedules, including step-up dosing, for mosunetuzumab, glofitamab, epcoritamab, and odronextamab are summarized in Table 1. Safety data about CRS and ICANS are summarized in Table 2.
As previously noted, odronextamab is an emerging CD20 × CD3 bispecific TCE being investigated in both FL and DLBCL. In late 2023, the FDA granted priority review of the biologics license application (BLA) for odronextamab for adult patients with R/R FL and R/R DLBCL who have progressed after 2 or more lines of systemic therapy.13 The BLA was supported by data from the phase 1 ELM-1 trial and phase 2 ELM-2 trial.13 On March 25, 2024, however, the FDA declined approval of the BLA, citing issues related to the enrollment status of the confirmatory trials.14 No issues were raised by the FDA related to the efficacy or safety of odronextamab.14 Regeneron Pharmaceuticals is expected to resubmit the application for odronextamab after the completion timelines of the confirmatory trials are agreed upon with the FDA.14
Of note, mosunetuzumab, glofitamab, and epcoritamab are being investigated for other B-cell NHLs—such as mantle cell lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and Richter syndrome—in various combinations and earlier lines of therapy beyond their current approvals.15-32
Pivotal TCE Trials for R/R BCL
The following section summarizes the efficacy and safety data from the pivotal trials that support the use of mosunetuzumab, epcoritamab, glofitamab, and odronextamab in the R/R BCL population.
GO29781 for mosunetuzumab
The open-label, multicenter, multicohort phase 1/2 GO29781 trial (NCT02500407) evaluated mosunetuzumab monotherapy in patients with R/R FL who had received at least 2 prior therapies, including an anti-CD20 monoclonal antibody and an alkylating agent. Of the 90 enrolled patients, the median age was 60 years (range, 29-90), 61% were men, and 82% were White. The median number of prior therapies was 3 (range, 2-10).33
The primary end point was CR, which was achieved in 60% of patients (95% CI, 49%-70%). The median times to first response and CR were 1.4 and 3 months, respectively. The overall response rate (ORR) was 80%, and the PR rate was 20%. The median duration of response (DOR) was 35.9 months (95% CI, 20.7-not reached [NR]), the duration of CR was NR (95% CI, 33-NR), and the median progression-free survival (PFS) was 24 months (95% CI, 12.0-NR).33,34
CRS was the most common adverse event (AE) (44%), was predominantly grade 1 (26%) and grade 2 (17%), and was primarily confined to cycle 1. The median duration of CRS was 3 days (IQR, 2-4). To manage CRS, 8% of patients received tocilizumab (Actemra; Genentech, Inc), 15% received corticosteroids, and 10% received both tocilizumab and corticosteroids. Hospitalizations due to CRS occurred in 21% of patients, with a median duration of hospitalization of 5 days (range, 0-30). All CRS events fully resolved. ICANS occurred in 5% of participants, was limited to grade 1 or 2, and resolved in all patients.33
Extended analysis with a data cutoff of January 3, 2022, showed that fixed-duration mosunetuzumab induced durable responses in these heavily pretreated patients and that those who achieved a CR had durable responses. The investigators did not identify any new safety concerns or delayed toxicities.35
Extended analysis also addressed patients who received time-limited mosunetuzumab, had an initial response followed by recurrence, and received mosunetuzumab retreatment. Of 8 patients with FL who received mosunetuzumab retreatment, 5 (62.5%) achieved a CR. Notably, none of these 8 patients who had recurrence had received the recommended phase 2 dose as their initial dose of mosunetuzumab.35
The positive results from this trial led to the accelerated approval of mosunetuzumab in adult patients with R/R FL after 2 or more lines of systemic therapy.6
EPCORE NHL-1 for epcoritamab
In the dose-expansion phase of the open-label, multicenter, multicohort phase 1/2 EPCORE NHL-1 trial (NCT03625037), 157 patients with R/R DLBCL who had received at least 2 prior lines of therapy, including CD20-directed treatment and an anthracycline, were treated with epcoritamab. The median age was 64 years (range, 20-83). Notably, the study population included heavily pretreated patients with 4 or more lines of prior therapy (38.9%), primary refractory disease (61.1%), and disease refractory to the most recent line of therapy (82.8%), as well as patients who had received prior anti-CD19 CAR T-cell therapy (38.9%).36-38
The ORR and CR were 63.1% (95% CI, 55.0%-70.6%) and 38.9% (95% CI, 31.6%-46.9%), respectively. The median time to initial response was 1.4 months (IQR, 1-8.4), and median time to CR was 2.7 months (range 1.2-11.1 months), although some patients with a PR had a deepening response even at 36 weeks or more. At the 20-month median follow-up, median duration of response for patients who achieved a CR was 20.8 months (95% CI, 17.3-NR) and median overall survival (OS) was 18.5 months (95% CI, 11.7-NR). Notably, CRS occurred most often after the cycle-1, day-15 dose and occurred overall in 51% of patients (grades 1 or 2, 48%; grade 3, 3%). ICANS occurred in 6% of patients, with 1 grade 5 ICANS event with confounding factors.37,38
The trial also included patients with R/R FL who had received 2 or more prior systemic therapies. Among the 128 patients with R/R FL who received epcoritamab, the ORR and the CR rates were 82% and 63%, respectively, with a median time to first response of 1.4 months. At the 17.4-month median follow-up, median PFS was 15.4 months.25
Based on the results of this trial, in May 2023, the FDA granted accelerated approval to epcoritamab for R/R DLBCL NOS, including DLBCL arising from indolent lymphoma, and high-grade BCL after 2 or more lines of systemic therapy. In June 2024, epcoritamab was granted accelerated approval for R/R FL after 2 or more lines of systemic therapy.4
Additionally, the phase 2 EPCORE-NHL-6 trial (NCT05451810) is evaluating the safety of epcoritamab in the outpatient setting without mandatory hospitalization after the first full dose and the use of a dose-optimization schedule with a third step-up dose as an additional CRS mitigation strategy.25,39 The findings from this trial may impact the operationalization of epcoritamab.
NP30179 for glofitamab
The multicenter, open-label phase 1/2 NP30179 trial (NCT03075696) assessed the efficacy and safety of glofitamab (with a dose of obinutuzumab [Gazyva;
Genentech, Inc] given before glofitamab) in patients with R/R DLBCL, including LBCL arising from FL, who had received at least 2 lines of prior therapy. The study included 154 patients—58% with primary refractory disease, 60% who had received 3 or more lines of therapy, and 30% who had received prior CAR T-cell therapy.40,41
As assessed by an independent review committee and at a median of 12.6 months of follow-up, the ORR was 52% and the median DOR was 18.4 months (95% CI, 13.7-NR). Thirty-nine percent of patients achieved a CR, with a median time to CR of 42 days (range, 31-308) and a median duration of CR of 24.1 months (95% CI, 19.8-NR). The CR rate was similar between patients who had and had not received prior CAR T-cell therapy (37% vs 39%, respectively). The median PFS was 4.9 months, and the 12-month PFS rate was 37%. The estimated 12-month and 18-month OS rates were 50% and 41%, respectively.40-42
Trial investigators concluded that glofitamab continued to demonstrate durable responses,42 supporting the FDA’s accelerated approval of glofitamab in adult patients with DLBCL NOS or LBCL arising from FL after 2 or more lines of systemic therapy.5
ELM-2 for odronextamab
The multicenter, open-label, multicohort phase 2 ELM-2 trial (NCT03888105) assessed the efficacy and safety of odronextamab in 141 patients with R/R DLBCL who had received at least 2 prior lines of therapy (median, 2 prior lines; range, 2-8), with 57% having primary refractory disease.43-45 Of the 127 patients evaluable for efficacy at a median follow-up of 26.2 months, the ORR was 52% and the CR rate was 31%, with a median DOR of 10.2 months (95% CI, 5-NR).43 In patients achieving a CR, the median CR duration was 17.9 months (95% CI, 9.2-NR).43
The incidence of any-grade CRS was 55%. Among the 74 patients who received an optimized step-up dose of 0.7, 4, and 20 mg, most CRS events were grade 1 or 2 (98%), with 1 grade 3 event; 26% of these patients received tocilizumab for CRS management. No cases of ICANS were reported in these 74 patients. In the overall population, serious infections occurred in 37% of patients; 11% were fatal.43
Additionally, 44 patients with R/R DLBCL who had previously received CAR T-cell therapy and were treated with odronextamab monotherapy had similar response rates and AE profiles as patients without prior CAR T-cell therapy (ORR, 48% vs 52%, respectively; CR, 30% vs 31%; CRS, 52% vs 55%; serious infections, 22% vs 37%).43,46
In the R/R FL cohort of the ELM-2 trial at a median 26.6-month follow-up, 140 adults with R/R FL (grades 1-3a) who had progressed after 2 or more lines of therapy and received odronextamab monotherapy achieved an ORR of 80% and a CR rate of 72%, with a median DOR of 21.7 months.47,48 The median PFS was 20.7 months (95% CI, 16.7-26.5). The incidence of any-grade CRS was 55%.48 Among the 72 patients who received the optimized step-up dose (0.7, 4, and 20 mg), most CRS events were grade 1 or 2 (98%), with 1 grade 3 event; 18% of patients received tocilizumab for CRS management.48 Only 1 ICANS case was reported among the 72 patients who received the step-up regimen.48 Serious infections occurred in 36% of patients in the R/R FL cohort (10% fatal).48
In both the R/R DLBCL and R/R FL cohorts of the ELM-2 trial, odronextamab induced responses in these heavily pretreated patients—including in those with R/R DLBCL who had previously received CAR T-cell therapy—and demonstrated manageable AEs with the optimized step-up dosing schedule.43-46,48
These findings, along with those from the ELM-1 trial (NCT02290951), led to the FDA granting priority review of the BLA for odronextamab for adult patients with R/R FL and R/R DLBCL who have progressed after 2 or more lines of systemic therapy. Based on the ELM-2 data, Regeneron Pharmaceuticals has been actively enrolling patients in multiple phase 3 confirmatory trials for odronextamab as part of its extensive OLYMPIA program, including the OLYMPIA-3 trial (NCT06091865) for patients with previously untreated DLBCL and the OLYMPIA-4 trial (NCT06230224) for patients with relapsed/refractory B-cell NHL.13
Retreatment With TCEs
Treatment with epcoritamab for R/R DLBCL is continued until disease progression or unacceptable toxicity. However, treatment with mosunetuzumab for R/R FL and glofitamab for R/R DLBCL is of fixed duration, which may allow for retreatment in patients who experienced a CR with initial treatment, completed treatment, and had subsequent disease progression.4-6
Retreatment data may be available in the future with epcoritamab because, as noted, it is being investigated in various combinations as a fixed-duration treatment.11,12 Retreatment data with glofitamab are limited, but early data with mosunetuzumab retreatment in patients with R/R B-cell NHL suggest that this strategy may be efficacious and have a manageable safety profile similar to that with initial treatment.15,21,34 Longer follow-up and additional data are needed to inform the potential role for retreatment with TCEs as a monotherapy and, in the future, as part of a combination therapy.
Practical Considerations for CRS and ICANs
Heightened T-cell activity induced by TCEs results in immune system hyperactivity, massive inflammatory cytokine release, and subsequent downstream effects that can be as serious as organ failure and death.49 The cytokine-mediated hallmark toxicities of CRS and neurotoxicity, including ICANS, are AEs commonly seen with bispecific TCEs and CAR T-cell therapies.50
CRS is a potentially life-threatening AE resulting from overactivation of immune effector cells, leading to a surge of systemically released pro-inflammatory cytokines.51 CRS can present with a variety of symptoms, ranging from mild (fever, myalgia, and fatigue) to severe (acute respiratory distress syndrome, hypotension, disseminated intravascular coagulation, and potential renal and hepatic toxicities).52,53
Inflammation also leads to increased blood-brain barrier permeability, which allows circulating cytokines to cross into the central nervous system, resulting in neurotoxicity and ICANS. ICANS may manifest as neuropsychiatric symptoms, including tremor, dysgraphia, expressive aphasia, impaired attention, lethargy, headache, myoclonus, tremor, and a depressed level of consciousness that may progress to obtundation or coma. ICANS may occur concurrently with CRS or after CRS.50
Due to these risks, many bispecific TCEs incorporate mitigation strategies in clinical practice, including, but not limited to, patient counseling, pre- and post-medication prophylactics, step-up dosing strategies, and close monitoring after dose administration—sometimes in inpatient settings. Information about onset and duration of CRS and ICANS for each bispecific TCE is summarized in Table 2.
CRS and ICANS risk mitigation
- Routes of administration: The occurrence of CRS is associated with the peak plasma concentration (Cmax) of TCEs following administration.54 Cmax is reached rapidly after intravenous (IV) administration of TCEs, whereas subcutaneous (SQ) administration is associated with a longer time to Cmax due to slower absorption. Thus, SQ administration provides longer drug exposure with lower peak drug concentrations, decreasing the incidence and severity of CRS and ICANS.55 For example, SQ administration of mosunetuzumab resulted in a lower Cmax and a higher trough concentration compared with IV administration and demonstrated a lower incidence of grade 2 and 3 CRS.56 Although the only CD20-directed bispecific TCE currently available as an SQ injection is epcoritamab, investigations into mosunetuzumab and glofitamab as SQ injections are ongoing.4-6,16,17,32
- Step-up dosing: This CRS prevention strategy is common with TCEs and involves giving an initial dose of drug that is lower than the target dose, with subsequent doses increased in a stepwise manner until the target dose is reached.55 The step-up increase in peak drug levels after each dose escalation primes the immune system for following doses and has been shown to reduce the incidence or severity of CRS during clinical trials.55
Step-up dosing often is accompanied by a recommendation to closely monitor the patient (sometimes in the hospital) for a time period after they receive the dose most often associated with CRS.4,5 For R/R FL, mosunetuzumab and epcoritamab have no requirements for hospitalization after administration; for R/R DLBCL or high-grade BCL, hospitalization is recommended with the first step-up dose of glofitamab (2.5 mg on day 8 of cycle 1) and the first full dose of epcoritamab (48 mg on day 15 of cycle 1).4-6 Data on outpatient administration of step-up dosing with epcoritamab and glofitamab are being generated through clinical trials and real-world experiences and will inform how broadly outpatient step-up dosing may be implemented.
Further optimizing step-up dosing to reduce the incidence and severity of CRS is an area of interest. As mentioned previously, an optimized step-up dosing schedule for epcoritamab is being evaluated using dexamethasone for CRS prophylaxis and administering a third step-up dose of 3 mg on cycle 1, day 15 and the first full dose on cycle 1, day 22.39 Preliminary results suggest that this optimized step-up dosing schedule for patients with R/R DLBCL and R/R FL not only decreases the incidence and severity of CRS but also results in fewer patients requiring tocilizumab.39,57
Accelerated step-up dosing schedules are also of interest, particularly in select patients with rapidly progressing disease. Although evidence is currently limited on these types of dosing schedules, the French phase 2 BiCAR study of glofitamab evaluated accelerated dosing in patients with B-cell NHL and suboptimal response to or R/R disease after CAR T-cell therapy. Obinutuzumab was administered 3 days prior to the first step-up dose of glofitamab, and glofitamab was escalated to full dose over 8 days (step-up dose 1 on day 1, step-up dose 2 on day 3, and full dose on day 8), resulting in comparable CRS (grades 1 or 2, 14.3%; ≥ grade 3, 0%) and neurological events (grades 1 or 2, 3%; ≥ grade 3, 0%) vs standard glofitamab escalation dosing.5,58
- Premedications—All FDA-approved TCE therapies for BCLs include recommendations for premedications, including corticosteroids, to reduce the risk of CRS and infusion- or injection-related reactions.4-6,59-61 Although clinical trials initially included corticosteroids other than dexamethasone as premedications, it is now clear that dexamethasone is superior to nondexamethasone corticosteroids, such as prednisone, for CRS prophylaxis.24,60 Of note, the epcoritamab prescribing information recommends dexamethasone 15 mg (the equivalent of prednisolone 100 mg), but the dose of dexamethasone 16 mg is commonly used in clinical practice due to available tablet sizes.4 In glofitamab specifically, obinutuzumab pretreatment is administered prior to glofitamab step-up dosing as a CRS mitigation strategy.5 Required premedications and CRS- and ICANS-related safety end points are summarized in Tables 1 and 2.
- Postmedications—Currently, epcoritamab is the only FDA-approved TCE for BCL with a recommendation for posttreatment corticosteroids; mosunetuzumab and glofitamab do not utilize posttreatment corticosteroids as a CRS mitigation strategy.4-6 After treatment with epcoritamab, corticosteroids are given for 3 days following administration during cycle 1 and cycle 2—and beyond cycle 2 if patients experience grade 2 or 3 CRS with the previous dose.4 The optimal dosing of posttreatment dexamethasone has yet to be determined, specifically whether lower doses may be similarly efficacious at decreasing the risk for CRS and corticosteroid-related AEs.
Treating CRS and ICANS
Preventive methods are key to reducing CRS and neurotoxicity/ICANS, but they do not eliminate the risks. Consensus definitions and grading systems for CRS and ICANS are available from the American Society for Transplantation and Cellular Therapy.53 More specific consensus recommendations supported by the Lymphoma Research Foundation on managing toxicity associated with CD20 × CD3 bispecific antibody therapy are now available.62 Treatments for CRS and ICANS include interventions targeting circulating cytokines (including agents targeting IL-6) and various supportive measures such as antipyretics, hydration, vasopressors, oxygen supplementation, antiepileptic drugs, and management of concurrently occurring conditions such as febrile neutropenia.62
Corticosteroids are used to both prevent and treat CRS and ICANS. They exert their effects via nonspecific systemic cytokine suppression. The grade of CRS or ICANS determines the dose, route, frequency, and duration of corticosteroid treatment.62
IL-6 is a key cytokine associated with CRS. Consequently, monoclonal antibodies that block IL-6, including tocilizumab, have shown rapid effectiveness in reversing life-threatening CRS.54 The dose of tocilizumab—an antibody targeting soluble and membrane-bound IL-6 receptors—for treating patients with CRS weighing less than 30 kg is 12 mg/kg; for patients weighing 30 kg or more it is 8 mg/kg, with a dose cap of 800 mg when tocilizumab is used for CRS.63 Further doses may be given based on continued CRS severity, with 4 doses maximum within a 24-hour period.63 If effective, tocilizumab is expected to rapidly improve CRS symptoms.50 Tocilizumab also may be administered in conjunction with corticosteroids based on the duration and severity of CRS.63
Even though approved TCE therapies for BCLs do not have Risk Evaluation and Mitigation Strategy programs that require the immediate availability of tocilizumab for prompt administration in the event of CRS, treatment centers providing TCE therapy should be prepared to treat CRS and ICANS and have tocilizumab immediately available.
Supportive Care Considerations
Although the incidence of grade 3 or 4 neutropenia ranges from 26% to 40% for available TCEs and the incidence of febrile neutropenia is low (2.5%-3.4%), the potential for grade 3 or 4 infections (10%-17%) and fatal infections (0.9%-4.8%) warrants considerations for anti-infective prophylaxis and monitoring for infections during treatment.4-6,44,46
Support with granulocyte colony-stimulating factors should be considered for patients receiving treatment with TCEs who develop neutropenia.4,6,61,62 Consult product-specific labeling for recommendations on when to hold therapy for cytopenias or infection.
Whenever possible, patients should receive vaccinations appropriate for their age and risk factors, including but not limited to annual influenza vaccines, pneumococcal vaccines, and COVID-19 vaccinations and boosters. These vaccines should be inactivated because live vaccines are contraindicated in patients receiving CD20 x CD3 bispecific TCEs. In addition, vaccinating prior to TCE treatment is advised because the impact of TCEs on immune response to vaccines is unclear.61
Anti-infective prophylaxis recommendations were not uniform in the registrational trials and deferred to institutional practices, resulting in varied policies and differing recommendations on the labeling for anti-infective prophylaxis specific to each TCE (Table 1).33,36,40,44 However, prophylaxis for Pneumocystis jirovecii pneumonia and varicella-zoster virus is recommended based on consensus recommendations. Because there is no consensus on duration, clinicians may consider continuing prophylaxis for 6 months after treatment discontinuation based on a nonconsensus recommendation.4-6,62 Additionally, immunoglobulin replacement should be considered in patients with hypogammaglobulinemia.61
Risk assessment for tumor lysis syndrome (TLS) should be conducted for all patients, and supportive care with IV or oral hydration and antihyperuricemics should be employed per standard of care.64 TLS is uncommon with available TCEs (glofitamab in NP30179 trial: n = 2/154; epcoritamab in EPCORE NHL-1 LBCL cohort: n = 2/157; mosunetuzumab in GO29781 FL cohort: n = 1/90).38,40,65 Nevertheless, decision-making on TLS monitoring and prophylaxis should be informed by patient-specific risk factors such as tumor burden, histologic subtype, and organ function (eg, renal, cardiac, pulmonary).64
Clinicians also should be aware of and counsel patients on the possibility of tumor flare, which may manifest as localized pain or swelling at sites with lymphoma involvement and becomes more worrisome if it occurs near vital organs. Tumor flare more commonly occurs during the initial cycle of treatment and can recur. Corticosteroids may be used to treat tumor flare.62
Operational Considerations
Complicated dosing and infusion schedules (eg, specific pre- and postmedications), hospitalization requirements, and novel toxicities can make operationalizing TCEs challenging. During this process, pharmacists and the interdisciplinary team should complete an assessment of the TCE package insert, toxicity profile, and site-of-care resources in anticipation of creating processes for drug preparation, drug administration, triaging, and managing toxicity.
It is necessary to determine site-of-care resources for monitoring and managing CRS, neurotoxicity, and other regimen-specific AEs. First, however, institutions must determine in what care setting the step-up doses of TCEs will be administered (hospital, ambulatory clinic, or community site), particularly doses associated with the highest incidence and severity of CRS. Recommendations for observation and hospitalization for FDA-approved TCEs for R/R BCL are described in Table 1. Thereafter, it is necessary to consider when patients can be transitioned to hospital outpatient and community settings and, eventually, which patients can receive step-up dosing in these settings. Emerging data and protocols are exploring fully outpatient step-up dosing,39 so institutions should reassess site-of-administration protocols when those data become available.
Additionally, because TCE dosing and infusion schedules are complex and have specific supportive care medications and monitoring requirements, creating order templates for each TCE that incorporate any institution-specific protocols will maximize consistency and decrease the likelihood of accidental omissions.
Sites should also ensure that they have the requisite medications to treat TCE toxicities (eg, infections, CRS, and ICANS) and a clear referral/triage plan if they cannot manage the toxicity there. Any sites caring for patients receiving TCEs should ensure that team members seeing these patients are appropriately educated about the TCE and any institution-specific processes and procedures for it. Additionally, sites should clearly designate the responsibility of providing patients with required resources, including counseling, a drug-specific wallet card, and a treatment calendar.4-6
Because of the availability of TCEs targeting the same tumor antigen and overlapping indications, institutions need to consider which TCEs to operationalize across oncologic disease states. Total cost of care with TCEs is an important consideration, and institutional capacity related to the availability of inpatient monitoring and scheduling constraints for outpatient infusions also is a factor.66,67 Furthermore, drug-specific considerations currently focus on the efficacy and safety of these agents as monotherapy, but these will continue to evolve as competing TCE-based combinations become available.
When institutions are creating standard operating procedures to guide TCE administration, monitoring, toxicity management, and supportive care, the scope of these guidelines should not only consider available CD20 x CD3 TCEs but also other TCEs, notably blinatumomab (Blincyto; Amgen Inc) for B-cell acute lymphoblastic leukemia; tebentafusp-tebn (Kimmtrak; Immunocore Limited) for uveal melanoma; tarlatamab-dlle (Imdelltra; Amgen Inc) for small cell lung cancer; and teclistamab-cqyv (Tecvayli; Janssen Biotech, Inc), elranatamab-bcmm (Elrexfio; Pfizer Inc), and talquetamab-tgvs (Talvey; Janssen Biotech, Inc) for multiple myeloma.
Given the complexity of drug- and antigen-specific considerations—which will continue to grow with approvals of TCEs for both hematologic and solid tumor malignancies—a multidisciplinary team of those participating in the care of patients receiving TCEs will be vital to formulate and update institutional guidelines that reflect the demographics and needs of patients while being cognizant of institutional resources. Operational considerations that can be harmonized among TCEs available at the institution should be consolidated, and drug-specific considerations also should be addressed.
Epcoritamab dose preparation safety considerations
About the Authors
Uvette Lou, PharmD, BCOP, is a clinical pharmacy specialist at Massachusetts General Hospital in Boston.
Brenna Rowen, PharmD, BCOP, is a clinical pharmacy specialist and clinical pharmacy manager at Massachusetts General Hospital’s Danvers and Waltham satellite sites.
Abigail McLaren, PharmD, MS, is a clinical pharmacist at Massachusetts General Hospital in Boston.
E. Bridget Kim, PharmD, BCPS, BCOP, is a clinical pharmacy specialist at Massachusetts General Hospital in Boston.
Mark N. Sorial, PharmD, BCOP, is a clinical pharmacy specialist at Massachusetts General Hospital in Boston.
J. Erika Haydu, MD, PhD, is a medical oncologist and an assistant in medicine at Massachusetts General Hospital, and an assistant professor at Harvard Medical School in Boston.
Matthew M. Lei, PharmD, BCOP, is a clinical pharmacy specialist at Massachusetts General Hospital in Boston.
Notably, safety considerations to prevent dosing errors are necessary when preparing and dispensing initial doses of epcoritamab. Epcoritamab is commercially available in 2 concentrations: 4 mg/0.8 mL and 48 mg/0.8 mL. The 0.16-mg and 0.8-mg doses of epcoritamab are prepared from the 4 mg/0.8 mL vial and require a 2-step and 1-step dilution during preparation, respectively.4 Due to the multiple steps required to prepare epcoritamab step-up doses, utilizing an IV workflow management system or IV room technology-assisted workflow system may decrease the risk of errors.68 If such technology is not available, consider hard stops after each dilution to review accuracy. And when integrating dilutions into the electronic health system, designate distinct medication codes for each dilution.
Conclusion
The development and approval of bispecific TCE therapies create novel treatment strategies for patients with R/R FL or R/R DLBCL. We reviewed the clinical data supporting the use of mosunetuzumab, epcoritamab, glofitamab, and odronextamab. We also described strategies for the unique operationalization challenges arising from complicated bispecific TCE dosing, monitoring, and supportive care, which include clearly delineating site(s) of care and transition plans, creating TCE order sets, developing processes for triaging and treating patients experiencing TCE-related toxicities, educating relevant staff and clearly assigning responsibilities, and ensuring safe preparation of products with complex compounding requirements.
The role of TCEs will continue to grow over time, in part because a key advantage of TCEs is accessibility, especially in the community setting where CAR T-cell therapy may not be feasible. Building a foundational understanding behind the mechanism, hallmark toxicities, and operational intricacies of TCEs is crucial not only to safely treat patients today but also to proactively anticipate any future changes as TCEs move into earlier lines of therapy and are incorporated into combinations and as TCE-related supportive care and dosing schedules are optimized. Sharing real-world data, experiences, and challenges gleaned from institutions that utilized TCEs soon after FDA approval is also essential to improving TCE management outside the highly controlled clinical trial setting and ensuring the best patient care possible.
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The authors have nothing to disclose.
