Bispecific Antibodies in DLBCL: Navigating the Evolving Treatment Landscape
Welcome to this Clinical Case Series learning module!
Here's how it works:
- Read these 3 case studies on the AP role in managing relapsed/refractory DLBCL.
- Answer the poll next to each case to see how your colleagues are treating these patients. You'll see results in real time.
- Continue your learning by watching a recording of a webinar presented by Jacklyn Gideon, MSN, AGNP-BC.
Epcoritamab for the Management of DLBCL
Clinical Pearl: Epcoritamab is effective in patients who have failed multiple lines of therapy and can be safely given to elderly patients with comorbidities.
EV is a 76-year-old woman with a history of relapsed DLBCL arising from follicular lymphoma (FL). Her ECOG performance status is a 1. Her past medical history is significant for hypertension, atrial fibrillation, and deep vein thrombosis. She was initially diagnosed with grade 1-2 FL in 2017 and received rituximab monotherapy followed by six cycles of bendamustine and rituximab (BR). End of treatment (EOT) PET scan after BR was consistent with a partial response (PR), and she continued on close clinical observation. In 2018 EV presented with significant right leg swelling and bulky inguinal adenopathy. A right inguinal excisional lymph node biopsy revealed diffuse large B-cell lymphoma (DLBCL), and flow cytometry revealed CD19+, CD20+, CD10+ (dim), CD5-. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) was given for six cycles. Her treatment course was complicated by recurrent hospitalizations and infectious complications, leading to dose reductions for Cycles 2 to 4. EOT PET scan was consistent with progressive disease. EV went on to receive multiple lines of treatment including an investigational therapy on a clinical trial, axicabtagene ciloleucel (axi-cel) CAR T-cell therapy, and tafasitamab in combination with lenalidomide. Her disease was either refractory to these therapies, or she experienced a short remission duration. Treatment with a CD3 x CD20 T-cell engaging bispecific antibody was recommended for her next line of therapy.
Epcoritamab is a bispecific antibody that directs cytotoxic T cells to produce an immune response toward target cells that express CD20 and is indicated for the treatment of adult patients with relapsed or refractory DLBCL, not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma, after two or more lines of systemic therapy failure. The NCCN recommends epcoritamab as a treatment option for patients with DLBCL in the third line and beyond.1 Patients treated on the EPCORE-NHL-1 study, which was the pivotal trial leading to FDA approval of epcoritamab, had a median age of 64 years and received a median of three prior lines of therapy. Of 157 patients, 61.1% had primary refractory disease, and 75.8% had disease that was refractory to two or more consecutive lines of therapy. Many of the patients on this study were heavily pre-treated and refractory to multiple lines of therapy like the patient in this case. However, despite this challenging-to-treat patient population, the overall response rate (ORR) seen on EPCORE-NHL-1 was 63.1% with a 38.9% complete response rate. Epcoritamab is administered subcutaneously, with step-up dosing during Cycle 1 to minimize the risk of cytokine release syndrome (CRS). Cycles 1-3 are weekly, Cycles 4-9 are every 2 weeks, and Cycles 10 and beyond are every 4 weeks—until progressive disease or unacceptable toxicity.2
EV had a history of grade 2 CRS and grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) with axi-cel, so her care team was vigilant about monitoring for these potential toxicities following initiation of epcoritamab. CRS occurred in 49.7% of patients treated on EPCORE NHL-1; of these, 47.15% were grade 1 and 2. ICANS only occurred in 6.4% of patients. The majority of CRS occurred during Cycle 1, following full-dose administration on Day 15.2 Epcoritamab carries a Black Box warning given the risk of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), which is discussed in more detail in Case 3.
EV began treatment with epcoritamab and experienced grade 1 CRS during cycle 1, day 15 of treatment as evidenced by a fever of 38.5°C. She was in the hospital during this time for the required 24-hour observation, and CRS was managed with antipyretics and supportive care with symptom resolution. She had no recurrence of CRS and experienced no ICANS. Another notable toxicity she experienced with epcoritamab was grade 2 thrombocytopenia. Of note, EV had grade 1 thrombocytopenia at baseline with a platelet count of 90,000 prior to treatment initiation. She had no evidence of lymphomatous involvement in her bone marrow, and thrombocytopenia was likely related to her prior treatment history including chemotherapy and lenalidomide. It should be noted that epcoritamab can be continued as long as the patient’s absolute neutrophil count (ANC) is > 500 and platelet count is > 50,000. This is an important consideration in a heavily pre-treated population that may have baseline cytopenias.
Because of her history of atrial fibrillation, EV has been treated with long-term anticoagulation; despite grade 2 thrombocytopenia, she maintained a platelet count > 50,000 on epcoritamab and has not required any interruptions to her anticoagulation therapy nor had any bleeding complications while on treatment. However, her anticoagulation therapy was held while she was receiving other anti-lymphoma therapies.
Despite EV’s history of poorly tolerating therapy in the past, she has tolerated epcoritamab well overall, with manageable toxicities, and has responded to treatment. PET imaging following two cycles of treatment demonstrated a complete response. EPCORE-NHL-1 showed a median time to response of 1. 4 months, with a median time to complete response of 2.7 months.2 EV will remain on treatment as long as she continues to respond and tolerate therapy.
Future Study
Given the effectiveness of epcoritamab as demonstrated in the EPCORE NHL-1 study for DLBCL in the relapsed/refractory setting, a phase III clinical trial is currently underway evaluating epcoritamab in combination with R-CHOP vs. R-CHOP alone in the front-line setting. Optimal sequencing of therapy continues to be an area of study, given the evolving treatment landscape for DLBCL management both in the front-line and relapsed/refractory settings.
References
- Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 4.2023. Accessed June 28, 2023. https://bit.ly/44VJO83
- Karimi Y, Ghesquieres H, Jurczak W, et al. Effect of follow-up time on the ability of subcutaneous epcoritamab to induce deep and durable complete remissions in patients with relapsed/refractory large B-cell lymphoma: Updated results from the pivotal EPCORE NHL-1 trial. J Clin Oncol. 2023;16:7525.
Epcoritamab Use for Relapsed/Refractory DLBCL After CAR T-cell Therapy Failure
Clinical Pearl: Bispecific antibody therapy is an effective treatment strategy for relapsed/refractory DLBCL, even after CAR T-cell therapy failure.
KB is a 54-year-old active man with a history of relapsed diffuse large B-cell lymphoma (DLBCL) not otherwise specified. His ECOG score was 0, and his medical history is significant for hypertension and prior tobacco use.
His prior treatment history includes:
- Rituximab with etoposide phosphate, prednisone, and vincristine sulfate (R-EPOCH) for 6 cycles
- Rituximab with gemcitabine, dexamethasone, and cisplatin (R-GDP) for 2 cycles
- Autologous stem cell transplantation with carmustine, etoposide, cytarabine, and melphalan (BEAM) conditioning chemotherapy
- Rituximab plus polatuzumab vedotin for 1 cycle
- Lisocabtagene maraleucel CAR T-cell therapy with fludarabine and cyclophosphamide lymphodepleting chemotherapy
KB presented to clinic in May 2023 with new palpable cervical adenopathy approximately 5 months following CAR T-cell therapy. PET imaging demonstrated new hypermetabolic cervical and axillary adenopathy. Clinically he felt well and had no B symptoms (fevers, drenching night sweats, and loss of > 10% of body weight over 6 months). He underwent an excisional biopsy of an FDG avid left cervical lymph node, and pathology was consistent with recurrent DLBCL; flow cytometry revealed CD10+, CD20+, CD5-. The advanced practitioner discussed possible treatment options for relapsed/refractory DLBCL with KB, including bispecific antibody therapy with epcoritamab or glofitamab, clinical trial, the monoclonal antibody conjugate loncastuximab, and tafasitamab in combination with lenalidomide.
Through shared decision making with the patient and care team the decision was made to proceed with bispecfic antibody therapy with epcoritamab. This decision was based on the encouraging response rates seen from the EPCORE NHL-1 study in relapsed/refractory DLBCL.1 This is a challenging patient population to treat, with 18% of patients receiving prior autologous stem cell transplant and 38.9% prior CAR T-cell therapy; 75.4% of those patients had progressed within 6 months of CAR T.1 These characteristics are similar to our patient KB.
KB began treatment in early June with step-up-dosing in order to reduce the risk of CRS. He was admitted to the hospital on Cycle 1, Day 15 for a 24-hour observation period following dose escalation and administration of full-dose epcoritamab. He developed neutropenia without fever on day 16, as evidenced by a neutrophil count of 650. He was given 300 mg of subcutaneous granulocyte colony-stimulating factor (G-CSF and started on antibacterial and antifungal prophylaxis. He was educated on neutropenic precautions by the advanced practitioner and discharged home. He returned to clinic on day 22 for treatment. He reported new grade 1 fatigue, but neutropenia had resolved with a neutrophil count of 1600. Antibacterial and Antifungal prophylaxis were discontinued. In the EPCORE NHL-1 trial, 21.7% of patients developed neutropenia and 22.9% experienced fatigue .1 The most common grade 3 or 4 adverse event was neutropenia (14.6%). His restaging PET scan following Cycles 2 and 4 of treatment were consistent with a CR. KB continues to tolerate treatment well, with grade 1 fatigue and anemia. He will continue to receive epcoritamab every 2 weeks through Cycle 9 of treatment and then monthly thereafter. Treatment is continued until progression of disease or unacceptable toxicity.
References
- Karimi Y, Ghesquieres H, Jurczak W, et al. Effect of follow-up time on the ability of subcutaneous epcoritamab to induce deep and durable complete remissions in patients with relapsed/refractory large B-cell lymphoma: Updated results from the pivotal EPCORE NHL-1 trial. J Clin Oncol. 2023;16:7525.
Managing Side Effects Associated with Bispecific Antibody Therapy
Clinical Pearl: Epcoritamab has a manageable side-effect profile.
CB is a 63-year-old woman with a history of relapsed high-grade B cell lymphoma (HGBL). Her past medical history is significant for insulin-dependent diabetes mellitus (DM), hypertension, and obesity. She has an ECOG score of 1. She failed two prior lines of therapy before treatment with the bispecific antibody epcoritamab was recommended. The most common side effects of epcoritamab include cytokine release syndrome (CRS), fatigue, muscle and bone pain, injection site reactions, fever, abdominal pain, nausea, and diarrhea. Epcoritamab carries a Black Box warning given the risk of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS); however, data from EPCORE NHL-1 demonstrated that these toxicities are manageable, and the majority of the adverse events were low grade and occurred in the first 12 weeks of therapy.2 CRS occurred in 49.7% of patients and ICANS in 6.4%. CRS occurred most commonly following the administration of full-dose epcoritamab (48 mg) on Cycle 1, Day 15. For this reason, hospital admission is required for patients for 24 hours following the first full dose. The predictability of CRS onset with epcoritamab provides a reasonable strategy for patient safety requiring a 24-hour observation period when the likelihood of CRS incidence is highest, while limiting unnecessary hospital admissions. Patients should be educated on the required hospital admission prior to treatment initiation.
Epcoritamab is administered with step-up dosing and premedication with steroids, acetaminophen, and diphenhydramine with Cycle 1 to minimize the risk of CRS. Prednisolone 100 mg or dexamethasone 15 mg is given prior to administration of epcoritamab and once daily for 3 days following each dose with Cycle 1 for a 28-day cycle. Acetaminophen and diphenhydramine are administered pre-dose. Premedications beyond Cycle 1 are not required unless the patient experienced grade 2 or higher CRS with their prior dose. Antiviral and pneumocystis jirovecii pneumonia prophylaxis are also recommended to reduce the risk of infection while on treatment.1 CB received prophylaxis with acyclovir and sulfamethoxazole/trimethoprim. Additional antibacterial and antifungal prophylaxis should be considered, as applicable in the setting of neutropenia.2
CB began treatment as an outpatient with step-up dosing on Cycle 1, Days 1 and 8. She received her first full dose of epcoritamab (48 mg) on Cycle 1, Day 15 as an outpatient and was admitted following administration for observation and close monitoring. She experienced grade 2 CRS (fever of 39°C and hypotension) 12 hours after the dose. She received antipyretics, IV fluids, and a dose of tocilizumab for CRS management, with symptom resolution. She was hospitalized for 36 hours. In the EPCORE-NHL-1 trial the median time to onset of CRS was 20 hours following Cycle 1, Day 15, with a median time to resolution of 48 hours.2 Epcoritamab should be held in the event of ongoing CRS or ICANS.1 CB also experienced intermittent grade 1 injection site reactions that were managed with topical steroids as needed for pruritus.
Given that high-dose steroids are required for all patients with Cycle 1 and, in some instances, beyond Cycle 1, it is important to recognize if a patient receiving epcoritamab has a history of DM or steroid-induced hyperglycemia. The advanced practitioner should take a detailed history and perform a medication reconciliation. These patients should also be educated on the importance of close glucose monitoring and the potential need for temporary medication adjustments. CB had well-controlled DM but did briefly require an increase in her basal insulin dose and sliding-scale insulin during Cycle 1. She experienced no CRS beyond Cycle 1; therefore, premedication was no longer required. She experienced no ICANS with treatment.
Discontinuation of epcoritamab on EPCORE-NHL-1 due to adverse events only occurred in 7.6% of patients.2 CB continues to receive epcoritamab treatment as an outpatient and has experienced no grade 3 or 4 toxicities. Epcoritamab has demonstrated promising response rates in a relapsed/refractory patient population with a favorable safety profile. Treatment is continued on a 28-day cycle until disease progression or unacceptable toxicity. Dosing changes to monthly for Cycle 10 and beyond. In addition to the demonstrated effectiveness of epcoritamab in a challenging-to-treat patient population, the administration route and tolerable safety profile make this a favorable and appealing treatment option for relapsed/refractory DLBCL.
References
- Epcoritamab prescribing information. Accessed October 11, 2023. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761324s000lbl.pdf
- Karimi Y, Ghesquieres H, Jurczak W, et al. Effect of follow-up time on the ability of subcutaneous epcoritamab to induce deep and durable complete remissions in patients with relapsed/refractory large B-cell lymphoma: Updated results from the pivotal EPCORE NHL-1 trial. J Clin Oncol. 2023;16:7525.
Meet the Faculty
Jacklyn Gideon
MSN, AGNP-BC
Nurse Practitioner
University of Chicago
Jacklyn is a nurse practitioner in the Hematopoietic Cellular Therapy Program at the University of Chicago. She specializes in the care of patients with lymphoma using novel agents and cellular and immunotherapy approaches including CAR T-cell therapy, Bispecific antibodies, stem cell transplantation, and investigational therapies. She has over 13 years of experience in hematology oncology and completed her graduate degree at Loyola University in Chicago.
Let us know what you'd like to learn more about at jadpro-editor@broadcastmed.com