Assessment of Early Intervention Strategies for Management of Cytokine Release Syndrome and Neurologic Events after Brexucabtagene Autoleucel (Brexu-Cel) Treatment in Patients with Relapsed or Refractory Mantle Cell Lymphoma (R/R MCL) in ZUMA-2
Authors: Oluwole Olalekan O. , Reagan Patrick M. , Miklos David B. , Locke Frederick L. , Goy Andre , Jacobson Caron A. , Munoz Javier L. , Forcade Edouard , Topp Max S. , Zheng Dan , Nunes Ana , Zhang Wangshu , Shen Rhine R. , Kloos Ioana , Kersten Marie José , Wang Michael L. 
Published: December 2023

Introduction: Brexu-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the United States for the treatment of adults with R/R MCL and in the European Union for adults with R/R MCL after ≥2 prior therapies, including a Bruton tyrosine kinase inhibitor (BTKi). In the Phase 2 ZUMA-2 study, with a median follow-up of 35.6 months, brexu-cel showed an objective response rate of 91%, a median duration of response of 28.2 months, and a median overall survival of 46.6 months with a manageable safety profile in treated patients (pts) with R/R MCL (N=68). Grade (Gr) ≥3 infections, cytokine release syndrome (CRS), and neurologic events (NEs) occurred in 37%, 15%, and 31% of pts, respectively (Wang et al. J Clin Oncol. 2023). In August 2018, CRS and NE management strategies for ZUMA-2 were updated to initiate treatment of these adverse events earlier at the onset of Gr 1 events to improve safety outcomes. Here, we report 4-yr safety outcomes for pts in ZUMA-2 by initial and updated CRS and NE management strategies.

Methods: Pts with R/R MCL and ≤5 prior treatments, including a BTKi, underwent leukapheresis and conditioning chemotherapy followed by a single infusion of brexu-cel (2×10 6 CAR T cells/kg). For CRS, the initial toxicity management strategy was to consider tocilizumab ± corticosteroids (methylprednisolone 1 mg/kg bid or dexamethasone 10 mg q6h) for Gr 2 CRS with extensive comorbidities or older age and Gr 3 CRS, and to increase the dose of corticosteroids (methylprednisolone 1 g/day x3, followed by a rapid taper consisting of 250 mg bid x2 days, 125 mg bid x2 days and then 60 mg bid x2 days) for Gr 4 CRS. The updated guidance was to administer tocilizumab for Gr 1/2 CRS that does not improve after 24 hours, and tocilizumab + corticosteroids (only if no resolution after 24 hours) and vasopressors for Gr 2 and 3 CRS.

For NEs, the initial guidance was to consider use of tocilizumab for Gr 2 NEs only if other comorbid conditions exist (8 mg/kg IV over 1 hour, not to exceed 800 mg) and to add corticosteroids (dexamethasone 10 mg IV q6h, methylprednisolone 1 mg/kg bid) for Gr ≥3 NEs. In the updated guidance, steroid treatment without concurrent CRS remained the same, but both tocilizumab + dexamethasone 10 mg IV were to be administered for Gr ≥2 NEs concurrent with CRS. Both guidance protocols recommended treatment with antibiotics for management of infections. This exploratory post hoc analysis examined safety outcomes related to CRS, NEs, and infections for pts in each management group, with descriptive statistics reported.

Results: As of July 23 2022, the median follow-up in the 68 treated pts was 47.5 months (range, 37.9-68.3). Of these pts, 40 received updated guidance (early intervention group [EIG]) and 28 received initial guidance (later intervention group [LIG]). Gr ≥3 CRS events were experienced at similar rates in both groups while Gr ≥3 NEs and Gr ≥3 infections occurred less often in the EIG vs the LIG (Table). Gr 5 infections occurred in 2 pts in the EIG and 0 pts in the LIG. No Gr 5 CRS or NEs occurred in either group. The median durations of Gr ≥3 CRS and infections were shorter for the EIG than the LIG while the median duration of Gr ≥3 NEs was longer for the EIG. Any Gr CRS and NEs were resolved at similar rates in both groups, but fewer any Gr infections were resolved for the EIG (all unresolved events in both groups were due to pt death before event resolution). Concomitant medications of interest were used in 80% (n=32) and 82% (n=23) of pts in the EIG and LIG, respectively. Tocilizumab was used at similar rates in the EIG and LIG (73% vs 68%), but steroids (55% vs 68%), vasopressors (18% vs 29%), and immunoglobulins (28% vs 50%) were used at lower rates in the EIG. Median CAR T-cell peak levels and area under the curve were lower for the EIG than the LIG while median CAR T-cell levels peaked at similar times in both groups.

Conclusions: With an updated safety management protocol emphasizing early intervention with tocilizumab and corticosteroids for CRS and NEs, only 20% of pts had Gr ≥3 NEs and 30% had Gr ≥3 infections. Additionally, a lower percentage of EIG pts required steroid, vasopressor, and immunoglobulin use than pts in the LIG. CAR T-cell expansion levels were numerically lower in the EIG. Although limited by small pt numbers, these findings support the current clinical guidance for safety management during brexu-cel treatment, which is close to the ZUMA-2 updated toxicity management guidance that was examined in this study.