In patients with relapsed/refractory non-Hodgkin lymphoma (NHL), administration of prophylactic tocilizumab prior to anti-CD19 chimeric antigen receptor (CAR)-T cell therapy appears to be feasible and associated with a low incidence of high-grade cytokine release syndrome (CRS), without an increase in immune effector cell-associated neurotoxicity syndrome (ICANS) rates or a deleterious impact on cell product efficacy. The findings were published in Frontiers in Immunology.
Tocilizumab is a monoclonal antibody targeting the interleukin-6 (IL-6) receptor. Following an update to include tocilizumab infusion prior to CAR T-cell administration in the institutional CAR-T premedication procedures at a single center, the investigators evaluated the outcomes of patients with relapsed/refractory NHL who underwent this procedure.
All patients received tocilizumab (8mg/kg, intravenous infusion) 1 hour prior to infusion of anti-CD19 CAR-T cell products with CD3ζ/4-1BB costimulatory signals. The researchers measured cytokine plasma levels before lymphodepleting chemotherapy, prior to infusion, and following treatment (days 2, 4, 6, and 14).
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Overall, 20 patients (75% male), with a median age of 56 years (range, 33-76), were treated. Of those, 18 received a locally manufactured, investigational anti-CD19 CAR-T cell product (as part of a phase 1 clinical trial; ClinicalTrials.gov Identifier: NCT03434769) and 2 received tisagenlecleucel. Most patients had a diagnosis of diffuse large B cell lymphoma (40%), mantle cell lymphoma (30%), or follicular lymphoma (20%).
No adverse events were attributed to prophylactic infusion of tocilizumab. Half of patients experienced grade 1 (n=7) or 2 (n=3) CRS, with a median time from CAR-T cell
infusion of 4 days (range, 3-7). No grade ≥3 CRS occurred. ICANS was reported in 25% of patients (grade 1, n=4; grade 4, n=1).
Findings from laboratory studies revealed significant higher IL-15 plasma concentrations in patients with than those without CRS, across all time points (all P <.05). Following treatment, patients with CRS also had higher peak ferritin (P =.0057) and C reactive protein (P=.043) and showed more significant increases in IL-6, IL-15, IFN- γ, fractalkine, and MCP-1 (all P <.01) levels than patients without CRS.
Most patients achieved complete (75%) or partial (10%) response. The 1-year overall survival was 83%, and the 1-year progression free survival was 73%.
Limitations of the study included heterogeneity of the cell products used and the absence of a matched control group that did not receive prophylactic tocilizumab.
“Our results indicate that prophylactic tocilizumab is feasible in NHL patients receiving anti-CD19 CAR-T cells with CD3ζ/4-1BB costimulatory signaling, without increased risk of [immune effector cell-associated neurotoxicity syndrome] and with preserved disease control,” the authors concluded in their report. “Additional studies evaluating pre-infusion [cytokine release syndrome] prevention strategies, including risk-adapted pharmacologic interventions, should be undertaken.”
Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Reference
Caimi PF, Pacheco Sanchez G, Sharma A, et al. Prophylactic tocilizumab prior to anti-CD19 CAR-T cell therapy for non-Hodgkin lymphoma. Front Immunol. 2021;12:745320. doi:10.3389/fimmu.2021.745320
