Practical Implications of Multi-Institution Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity (ICANS) Rates in Lymphoma Targeted Bispecific Antibodies (BsAb)

Introduction

Bispecific antibodies (BsAb) including epcoritamab, glofitamab, and mosunetuzumab are crucial options for the treatment of relapsed/refractory lymphoma. Known complications of BsAb therapy include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Currently hospitalization is required or should be considered for the initiation of BsAb therapy due to these associated risks. As these therapies continue to gain traction, practitioners seek to assess the safety and feasibility of outpatient administration and toxicity management. This study aims to offer real-world incidence of CRS/ICANS for lymphoma-directed BsAb therapy.

Methods

A multicenter review of adult patients who received commercial or investigational epcoritamab, glofitamab, or mosunetuzumab for non-Hodgkin’s lymphoma from November 7^th, 2022, to May 21^st, 2024, was performed. The primary outcome was incidence of CRS/ICANS. Key secondary outcomes were surrogates for resource utilization including CRS/ICANS management strategies, level of care required, and hospitalization.

Results

Eighty-seven patients were included in the final analysis, of whom the median age was 69 (Interquartile Range [IQR], 61-79) with 57 (66%) patients being male. The most common diagnosis was that of diffuse large B cell lymphoma (56%), followed by follicular lymphoma (17%), marginal zone lymphoma (8%), Richter’s transformation (7%), and mantle cell lymphoma (1%). Seventy-six (87%) patients had advanced stage disease and 6 (7%) of patients were identified to have central nervous system (CNS) involvement. Patients had a median of 4 prior lines (IQR, 3-5) of therapy, with 13 (15%) patients having received prior hematopoietic stem cell transplant and 35 (40%) having received prior chimeric receptor antigen T cell therapy. Sixty-three (72%) patients received commercial products and of the 3 available products, 28 (32%) received epcoritamab, 23 (27%) glofitamab, and 36 (41%) mosunetuzumab. All patients received standard steroid prophylaxis, with 37 (43%) of those patients receiving additional pre-medications. CRS occurred in 24 (28%) patients. Of these, 10 (28%) patients received mosunetuzumab, 9 (32%) epcoritamab, and 5 (23%) glofitamab. Grade 1 CRS was most common (18%) with grade 2 and 3 being 8% and 1%, respectively. For management of CRS, patients required steroids (14%), tocilizumab (10%), and vasopressors (1%). ICANS occurred in 6 (7%) patients, with 5 (83%) having received epcoritamab and 1 (17%) having received mosunetuzumab. Two (2%) patients experienced grade 1 ICANS, 3 (3%) grade 2 ICANS, and 1 (1%) grade 3 ICANS. For management of ICANS, 5 (83%) patients required steroids. There were no patients that experienced grade 4 CRS or ICANS. Of note, the grade 3 CRS and ICANS events that occurred were both in patients that received mosunetuzumab. Seventy-four (85%) patients received their first BsAb dose outpatient; of the 13 (15%) patients that received their first dose inpatient, 3 (3%) required transfer to the intensive care unit. Eighteen (24%) and 3 (4%) patients that received dosing outpatient experienced CRS and ICANS, respectively. Only 4 patients that experienced CRS/ICANS outpatient required a hospitalization within 4 weeks of their dose for management of symptoms. Out of all patients receiving BsAb therapy, 7 (8%) required admission for future doses.

Conclusion

This large multicenter report of CRS/ICANS incidence with the use of lymphoma-directed BsAb showed low overall CRS/ICANS rates. Overall incidence of CRS, as well as incidence by grade appeared to be similar or lower than pivotal trials for all 3 BsAbs. Overall incidence of ICANS, as well as incidence by grade appeared to be similar or lower than pivotal trials for glofitamab and mosunetuzumab. This pattern was not seen for epcoritamab, where the overall incidence of ICANS seen was tripled in this review (6% versus 18%) and incidence of both grade 1 and grade 2 ICANS was higher (Dickinson, 2022; Thieblemont, 2022; Bude, 2022). The need for CRS/ICANS management, escalation of level of care, and hospitalization in our patients was minimal. Comparisons of this data to pivotal trials are limited by lack of homogeneity between study populations. Overall, this review offers a real-world view of CRS/ICANS incidence, as well as resource utilization that supports the safety and feasibility of outpatient administration.