Epcoritamab Shows Promise in Case of Richter Syndrome

A recent case report published in Cancer Reports highlights the potential of epcoritamab as a viable treatment option for elderly patients with diffuse large B-cell lymphoma-type Richter syndrome (DLBCL-RS) that has proven refractory to conventional therapies.¹ Richter syndrome (RS), the aggressive transformation of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) into diffuse large B-cell lymphoma (DLBCL), remains a major therapeutic challenge. Outcomes with conventional chemotherapy are poor, with complete response rates reported at only 20% and median overall survival (OS) ranging from 6 to 12 months. No consensus exists on the standard of care, making therapeutic advances particularly significant for this patient population.

“Epcoritamab is expected to have efficacy against DLBCL-­ RS, but there are few reports about this due to the rarity of RS,” the authors note.

The report describes an 80-year-old woman initially diagnosed with SLL in 2017. For nearly 6 years, her condition was managed with observation. In 2023, she presented with a bulky abdominal tumor, measuring 122 × 86 mm², accompanied by splenomegaly and mild axillary uptake. A biopsy confirmed progressive SLL with del17p positivity but no histological transformation.

First-line therapy with the BTK inhibitor acalabrutinib was discontinued within 2 weeks due to disease progression. Venetoclax plus rituximab produced a transient reduction in tumor size, but progression was documented at 10 months. Subsequent bendamustine plus rituximab also failed. The tumor continued to progress, with the abdominal tumor increasing to 143 × 112 mm², despite receiving first- and second-line cytotoxic regimens for DLBCL-RS.

Epcoritamab was initiated as third-line therapy in August 2024, given the refractory nature of her disease. Epcoritamab is a bispecific CD3xCD20 antibody that redirects T-cell cytotoxicity against malignant B cells. Its use in DLBCL, particularly in patients with refractory disease, is an emerging strategy. The patient experienced Grade 1 to 3 cytokine release syndrome (CRS), which was successfully managed with tocilizumab, dexamethasone, and noradrenaline. No signs of immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. Despite a slight temporary increase in tumor size and elevated LDH levels at week 4, treatment was continued based on an indeterminate response assessment. By week 12, a partial response (PR) was achieved, with a confirmed reduction in tumor volume of at least 50%. This response has been maintained for 10 months at the time of the last observation.

During the course of epcoritamab treatment, the management of infectious complications, including COVID-19 pneumonia and cytomegalovirus antigenemia, was successfully achieved with antivirals, corticosteroids, and a 2-week interruption of epcoritamab administration. Hypogammaglobulinemia required the initiation of immunoglobulin replacement therapy to maintain IgG levels above 400 mg/dL, successfully preventing subsequent infections.

This case contextualizes epcoritamab’s impact in DLBCL-RS relative to conventional and emerging therapies. Chemotherapy response rates for DLBCL-RS have been historically poor, with complete response rates only 20% to 36% and median OS often below 1 year. A retrospective analysis cited in the report found a median OS of 12 months with first-line regimens, though outcomes improved modestly with modern approaches, reaching 25.8 months in select cohorts. Patients previously treated with BTK or BCL2 inhibitors had worse survival, with a median OS of 12.3 months. Allogeneic transplantation remains the only strategy associated with long-term survival, with OS exceeding 54 months in some series, though often not feasible in elderly patients.

Chimeric antigen receptor (CAR) T-cell therapy has demonstrated responses in RS, with a 63% overall response rate and 46% complete response rate in a retrospective study of 69 patients. However, median progression-free survival was only 4.7 months, and OS was 8.5 months. Toxicity also remains a limitation, with grade ≥3 CRS in 15.9% and ICANS in 36.8%.

In comparison, early results from ongoing and recent clinical trials, including phase Ib/II EPCORE CLL-1 and phase III EPCORE NHL-1 trials, demonstrate high response rates with epcoritamab in large B-cell lymphoma populations, with grade 3 CRS in only 2.5% of patients over 75 years of age and a generally manageable safety profile.^2,3 In this case, the resolution of grade 3 CRS without long-term sequelae and the absence of neurotoxicity further support the feasibility of epcoritamab, even in elderly and frail patients.

Limitations acknowledged in this report include the relatively short observation period following epcoritamab initiation and the absence of some recommended molecular studies, such as IGHV sequencing, which might further inform prognosis.¹ However, the authors highlight the rapid and durable disease reduction observed, even in the context of bulky, aggressive, and chemoresistant disease, supporting “epcoritamab as a potentially valuable treatment option for patients with DLBCL-RS, particularly those with limited response to conventional chemotherapy.”

References

1. Nishikawa T, Saburi M, Urabe S, Ohtsuka E. Disease control and manageable toxicity with epcoritamab in refractory diffuse large B-cell lymphoma-type Richter syndrome: a case report in an elderly patient. Cancer Rep. 2025;8(9):e70349. doi:10.1002/cnr2.70349

2. Kater AP, Ye JC, Sandoval-Sus J, et al. Subcutaneous epcoritamab in patients with Richter's syndrome: early results from phase 1b/2 trial (EPCORE CLL-1). Blood. 2022;140(suppl 1):850-851

3. Kater AP, Janssens A, Eradat H, et al. CLL-280 epcoritamab induces deep responses in patients with Richter transformation (RT): primary results from the EPCORE CLL-1 trial. Clin Lymphoma Myeloma Leuk. 2024;24(suppl 1):S350-S351