Single-center experience using anakinra for steroid-refractory immune effector cell-associated neurotoxicity syndrome (ICANS)

Abstract

In addition to remarkable antitumor activity, chimeric antigen receptor (CAR) T-cell therapy is associated with acute toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Current treatment guidelines for CRS and ICANS include use of tocilizumab, a monoclonal antibody that blocks the interleukin (IL)-6 receptor, and corticosteroids. In patients with refractory CRS, use of several other agents as third-line therapy (including siltuximab, ruxolitinib, anakinra, dasatinib, and cyclophosphamide) has been reported on an anecdotal basis. At our institution, anakinra has become the standard treatment for the management of steroid-refractory ICANS with or without CRS, based on recent animal data demonstrating the role of IL-1 in the pathogenesis of ICANS/CRS. Here, we retrospectively analyzed clinical and laboratory parameters, including serum cytokines, in 14 patients at our center treated with anakinra for steroid-refractory ICANS with or without CRS after standard treatment with tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) CD19-targeting CAR T. We observed statistically significant and rapid reductions in fever, inflammatory cytokines, and biomarkers associated with ICANS/CRS after anakinra treatment. With three daily subcutaneous doses, anakinra did not have a clear, clinically dramatic effect on neurotoxicity, and its use did not result in rapid tapering of corticosteroids; although neutropenia and thrombocytopenia were common at the time of anakinra dosing, there were no clear delays in hematopoietic recovery or infections that were directly attributable to anakinra. Anakinra may be useful adjunct to steroids and tocilizumab in the management of CRS and/or steroid-refractory ICANs resulting from CAR T-cell therapies, but prospective studies are needed to determine its efficacy in these settings.

Keywords: chimeric antigen receptors; combination; cytokines; drug therapy; inflammation.

Figure 1

Swimmer’s plot summarizing clinical course with CRS, peak ICANS, and corresponding treatment for each patient. CRS was graded according to autologous stem cell transplantation consensus grading 2020. ICANS was graded retrospectively based on clinical notes from the patient information system. Corticosteroid application is indicated in milligram in gray graduated boxes. Time period represents hospitalization days starting at CART infusion. The graph is subdivided into axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah). * indicates deceased; X indicates application of tocilizumab; star indicates application of anakinra. CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome.

Figure 2

Temperature and laboratory variables as parameters of toxicity in anakinra-treated patients. (A) Temperature: highest value 24 hours before/after the first/last anakinra dose. (B) Neutrophil and platelet count before and after anakinra. Each dot and square connected by a line indicate one patient, n=14. Temperature: paired t test. Neutrophil count: paired t test. Platelet count: paired t test, p value=0.4588 (ns). Pie charts of neutropenia and thrombopenia 3–4 weeks after anakinra application. Grading (G 0–4) in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) V.5 (C). Waterfall plots of percentage change of CRP (D) and ferritin (E). Each column represents a patient. Inflammatory markers were obtained within the 48 hours before the first dose and after the last anakinra dose. Dark red indicates patients alive at the time of data cut. Light red indicates patients deceased. Statistical analysis was performed using GraphPad Prism V.9.0 (GraphPad software, LLC). *P=0.0286, ***P=0.0002. CRP, C reactive protein; ns, not significant.

Figure 3

Analysis of inflammatory cytokines before and after anakinra application. Analysis of cytokines in patient’s serum before and after anakinra application. Samples were collected within 1–2 days (median 1 day) before and 2–8 days (median 4 days) after the last anakinra dose (corresponding to days 3, 7, 14, 21, and 28 after CART infusion). (A) The custom 27-plex Luminex assay panel was used. Each dot connected by a line indicates one patient. Peak ICANS grades 3–4 with subsequent neurotoxicity reduction (response) are indicated by red circles. Peak ICANS grades 3–4 without subsequent neurotoxicity reduction (no response) are indicated by black circles. Grade 1–2 ICANS are indicated by gray circles, n=9. Ratio paired t-test. Statistical analysis was performed using GraphPad Prism V.9.0 (GraphPad Software, LLC.). *P<0.05, **P<0.01. ICANS, immune effector cell-associated neurotoxicity syndrome; ns, not significant.