Relapsed DLBCL After CAR T-Cell Therapy

History and Presentation

A 74-year-old female retired teacher, who lives in a rural area and has a past medical history of diabetes mellitus, is diagnosed with non–germinal center B-cell (GCB) subtype, stage IV diffuse large B-cell lymphoma (DLBCL). She received six cycles of R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone) as frontline therapy. Her end-of-treatment PET/CT scan demonstrated Deauville 2. 

Second-Line Treatment

Nine months later, the patient reported worsening fatigue and back pain. A PET/CT demonstrated progressive adenopathy at multiple sites above and below the diaphragm, and ureteral obstruction with right-sided hydronephrosis.   

She sought a second opinion at an academic medical center. As she was deemed ineligible for autologous stem cell transplant (ASCT), her treatment options included anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, tafasitamab plus lenalidomide, or polatuzumab vedotin (pola) plus bendamustine (BR) with or without rituximab. She opted for axicabtagene ciloleucel (axi-cel) CAR T-cell therapy. Due to progressive symptoms and concern for the preservation of kidney function, the advanced practitioner (AP) discussed the initiation of bridging therapy. 

The patient began bridging therapy with pola plus rituximab, and then BR was added after leukapheresis. She received axi-cel infusion and experienced grade 1 cytokine release syndrome (CRS) but no immune effector cell-associated neurotoxicity syndrome (ICANS). Supportive care was provided, and her symptoms resolved. After 1 month, she returned home to her local oncologist. Her end-of-treatment PET/CT scan was consistent with Deauville 5. 

Relapsed/Refractory Treatment

Through shared decision-making, the patient and the AP agreed on treatment with a CD3 x CD20 T-cell engaging bispecific antibody. The patient understood that until her local oncologist completed the Risk Evaluation and Mitigation Strategy (REMS) training program, she would have to return to the academic center for administration. She began treatment with a step-up dosing of epcoritamab outpatient and was hospitalized for 24-hour observation for cycle 1, day 15. She experienced grade 2 CRS (fever of 39°C and hypotension) 12 hours after receiving the dose. She received antipyretics, IV fluids, and a dose of tocilizumab for CRS management, with symptom resolution. Her hospitalization was extended to 48 hours. She received prophylaxis acyclovir and sulfamethoxazole/trimethoprim to reduce risk of infection. 

She had no recurrence of CRS and experienced no ICANS. PET imaging following two cycles of treatment demonstrated a complete response (CR). Her local oncologist was able to complete the REMS training, and she is now receiving epcoritamab locally. She is still on therapy and will continue as long as she is responding and tolerating treatment. 

Discussion

DLBCL, the most common type of non-Hodgkin lymphoma, encompasses a highly heterogeneous group of B-cell lymphomas. Despite the efficacy of initial chemoimmunotherapy, 35% to 40% of patients relapse, and outcomes following relapse or progression have historically been poor.¹ Relapse less than 12 months after treatment and in older patients are often deemed ineligible criteria for curative-intent ASCT. 

Anti-CD19 CAR T-Cell Therapy

Three CAR T-cell products are currently FDA-approved for patients with relapsed/refractory (R/R) DLBCL: axi-cel, tisagenlecleucel, and lisocabtagene maraleucel. 

Axi-cel is considered in the second-line setting for patients who relapse within 12 months of initial therapy or have primary refractory disease, based on data from the phase 3 ZUMA-7 trial.² Data presented at the 2023 American Society of Hematology Annual Meeting demonstrated median overall survival (OS) for patients receiving axi-cel and standard of care was 43.5 months (95% CI: 20.9 to not estimable [NE]) and 19.6 months (95% CI: 12.3-NE), respectively, among those age ≥65, and 24.7 months (95% CI: 12.8-NE) and 11.2 months (95% CI: 6.1-NE), respectively, among those age ≥70. The median progression-free survival (PFS) was 28.7 months (95% CI: 5.1-NE) and 5.0 months (95% CI: 2.8-7.2), respectively, for those age ≥65, and 11.4 months (95% CI: 4.1-NE) and 2.7 months (95% CI: 1.7-5.0), for those age ≥70.³ 

Bridging Therapy

Based on the extent of this patient’s relapse, bridging therapy is needed to maintain disease control while she waits for the manufacturing and infusion of axi-cel. When a pola-based combination is selected as bridging therapy, BR should only be considered and added after completion of leukapheresis because it can lead to significant lymphopenia and an inability to obtain sufficient T cells.⁴    

Pola +/- BR

The antibody-drug conjugate pola, which targets CD79b, demonstrated significant efficacy combined with BR compared with BR alone in patients with transplantation-ineligible R/R DLBCL. The addition of pola significantly improved CR rate (40.0% vs 17.5%; P = .026), median PFS (9.5 vs 3.7 months, HR 0.36; P < .001), and median OS (12.4 vs 4.7 months, HR 0.42; P = .002). The combination was associated with a higher rate of grade 3/4 neutropenia, anemia, and thrombocytopenia vs the BR-alone group. Peripheral neuropathy was reported in 43.6% of patients.⁵

Safety and Management of CAR T-Cell Therapy

The most common adverse events (AEs) occurring early after CAR T-cell therapy include CRS, fever, infections, fatigue, musculoskeletal pain, nausea, and diarrhea. As with this patient, CRS is primarily low grade and typically occurs within a few days of CAR T-cell infusion (median onset ranging from 2 to 5 days). With supportive measures, CRS often resolves within a few days (median duration of CRS ranging from 4 to 8 days). Patients should also be monitored for the development of ICANS, which can include encephalopathy, headaches, tremors, and dizziness. Due to these potential AEs, the FDA requires patients treated with CAR T-cell therapy to remain near the designated cellular therapy institution for 1 month with a dedicated caregiver.⁶ 

Third-Line Treatment Options for R/R DLBCL

Bispecific therapies, unlike CAR-T, are off-the-shelf options to allow immediate treatment. There are currently two FDA-approved bispecific antibodies—epcoritamab and glofitamab—that direct cytotoxic T cells to produce an immune response toward target cells that express CD20 and are indicated for the treatment of adult patients with R/R DLBCL, not otherwise specified, including DLBCL rising from indolent lymphoma, and high-grade B-cell lymphoma, after two or more lines of systemic therapy failure.⁷ 

Epcoritamab—which this patient received—binds CD3 on T cells and CD20 on B cells, leading to the elimination of CD20-positive B cells. In EPCORE NHL-1—a pivotal trial leading to FDA approval of epcoritamab for patients with R/R DLBCL who have received ≥2 lines of therapy—of 157 patients, 61.1% had primary refractory disease, and 75.8% had a disease that was refractory to two or more consecutive lines of therapy. Many of the patients in this study were heavily pretreated and refractory to multiple lines of therapy. The overall response rate (ORR) was 63.1%, with a 38.9% CR rate.⁸  

Epcoritamab is administered subcutaneously over a 28-day treatment cycle, with step-up dosing during cycle 1 to a fixed dosing of 48 mg to minimize the risk of 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.⁹ 

Adverse Effects and Management of Epcoritamab

Like other CD3 x CD20 T-cell–engaging bispecific antibodies, epcoritamab is administered with step-up dosing and premedication with corticosteroids, antipyretics, and antihistamines with cycle 1 to minimize the risk of CRS. Corticosteroids are given before administration of epcoritamab and once daily for 3 days following each dose with cycle 1 for a 28-day cycle. Antipyretics and antihistamines are administered pre-dose. Premedications beyond cycle 1 are not required unless the patient experiences grade 2 or higher CRS with their prior dose. Antiviral and Pneumocystis jirovecii pneumonia prophylaxis is also recommended to reduce the risk of infection while on treatment. This patient received prophylaxis with acyclovir and sulfamethoxazole/trimethoprim. Additional antibacterial and antifungal prophylaxis should be considered, applicable in the setting of neutropenia.⁸  

Epcoritamab carries a black box warning given the risk of CRS and ICANS; however, data from EPCORE NHL-1 demonstrated that these toxicities are manageable, and the majority were low-grade (grade 1/2).^8-10 CRS occurs most commonly following the administration of full-dose epcoritamab (48 mg) on cycle 1, day 15. Therefore, patients are required to be inpatient for a 24-hour observation.^9,10 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.⁸ The majority of ICANS events occurred during cycle 1, with a median time to onset of 3 days. The median duration of ICANS was 4 days (range: 0 to 8 days) with resolution in 90% of patients with supportive care.^8,9 Further administration of epcoritamab should be held if ongoing CRS or ICANS occurs.^9,10  

An important consideration is that patients receiving bispecific therapies are often heavily pretreated, and cytopenia at baseline is not uncommon. Epcoritamab can be administered as long as the patient’s absolute neutrophil count is >500 and platelet count is >50,000.^8,10 

Discontinuation of epcoritamab due to AEs in the EPCORE NHL-1 trial occurred in 7.6% of patients.^8,10 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 the risk for steroid-induced hyperglycemia. Patients should also be educated on the importance of close glucose monitoring. This patient had well-controlled diabetes mellitus and did not require any adjustments. She experienced no further CRS or ICANS beyond cycle 1; therefore, premedication was no longer required.^9,10   

References

1. Vodicka P, Klener P, Trneny M. Diffuse large B-cell lymphoma (DLBCL): Early Patient Management and Emerging Treatment Options. Onco Targets Ther. 2022;15:1481-1501.  
2. Westin JR, Oluwole OO, Kersten MJ, et al; ZUMA-7 Investigators; Kite Members. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. 2023;389:148-157. 
3. Kersten MJ, Farooq U, Rapoport AP, et al. Improved overall survival with axicabtagene ciloleucel vs standard of care in second-line large B-cell lymphoma among the elderly: A subgroup analysis of ZUMA-7. Blood. 2023;142(suppl 1):1761. 
4. Morita Y, Yagi Y, Kanemasa Y, et al. [Polatuzumab vedotin, bendamustine, and rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma, including the outcome as a bridging treatment to CAR-T cell therapy or allogeneic hematopoietic stem cell transplant]. Rinsho Ketsueki. 2023;64:586-595. 
5. Abdur Raqib M, Haseeb A, Shafique MA, et al. Advances in polatuzumab vedotin-piiq therapy: A review of treatment efficacy in diffuse large B cell lymphoma and high-grade B cell lymphoma. Pediatric Health Med Ther. 2023;14:323-331. 
6. YESCARTA^® (axicabtagene ciloleucel) prescribing information. Kite Pharma, Inc; 2022. https://www.gilead.com/-/media/files/pdfs/medicines/oncology/yescarta/yescarta-pi.pdf 
7. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas V.6.2023. October 10, 2023. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf 
8. 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;41:16s (suppl; :abstr 7525). 
9. EPKINLY (epcoritamab) prescribing information. AbbVie; 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761324s000lbl.pdf 
10. Thieblemont C, Phillips T, Ghesquieres H, et al. Epcoritamab, a novel, subcutaneous CD3xCD20 bispecific T-cell-engaging antibody, in relapsed or refractory large B-cell lymphoma: Dose expansion in a phase I/II Trial. J Clin Oncol. 2023;41:2238-2247.