A 2022 letter to the editor highlighted the use of anakinra as an alternative treatment option for toxicities associated with chimeric antigen receptor (CAR) T-cell therapy in pediatric patients. While not United States Food and Drug Administration (FDA) approved for use, anakinra has often been utilized off-label for the treatment of multiple adult and pediatric autoinflammatory disorders and has been explored as a potential treatment option for toxicities, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), that are associated with inflammatory pathways affected by CAR T-cell therapies. Anakinra has been evaluated as an adjunctive and/or refractory treatment for CRS, ICANS, and/or CAR T-cell-associated hemophagocytic lymphohistiocytosis (carHLH). Experience with anakinra in multiple pediatric care centers for the treatment of ICANS and CRS unresponsive to tocilizumab and/or steroids, as well as carHLH, was often similar across institutional protocols, with minor variations in anakinra initiation based upon toxicity as well as diagnostic criteria for carHLH. While limited, published clinical evidence for anakinra use for the treatment of CAR T-cell therapy-associated toxicities in pediatric patients were provided, as summarized in Table 1. Overall, limited data on anakinra for the treatment of ICANS in pediatric patients secondary to CAR T-cell therapy is available to adequately assure safety and efficacy of anakinra treatment, but may potentially be considered as a potential alternative treatment regimen for ICANS refractory to first and second-line treatment options. [1]
The 2022 guidelines from the American Society of Clinical Oncology (ASCO) regarding the management of immune-related adverse events in CAR T-cell therapy, including CRS and ICANS, suggest the use of tocilizumab, with or without corticosteroids, for the treatment of severe or prolonged CRS associated with CAR T-cell therapy. The guidelines note there is limited experience regarding additional therapies. Anakinra has demonstrated preliminary data for mitigating CRS in some CAR-T patients with high-grade CRS, but it is not yet part of their recommendations. ICANS, in the absence of concurrent CRS, is recommended to be managed only with supportive care and corticosteroids, as tocilizumab does not resolve ICANS and may even worsen the condition. There is no recommendation for the use of anakinra within the guidelines; however, it is noted that anakinra is under investigation for the management of ICANS. [2]
The 2020 Society for Immunotherapy of Cancer (SITC) clinical practice guidelines for management of CRS and ICANS provide similar recommendations to the ASCO, except that anakinra may be considered as a third-line agent if 2 doses of tocilizumab plus steroids does not improve CRS. Pharmacologic management of ICANS is limited to the use of steroids, as multiple studies have demonstrated the failure of tocilizumab to resolve symptoms of ICANS despite alleviating severe CRS symptoms. The reason for the lack of efficacy may be related to the inability of tocilizumab to cross the blood-brain barrier, and the transient rise in serum interleukin-6 (IL-6) can worsen neurotoxicity. [3]
According to a consensus report of the European Myeloma Network on the prevention and management of adverse events during treatment with bispecific antibodies and CAR T-cells in multiple myeloma, tocilizumab is far less effective in ICANS than in CRS and should be administered to patients with concurrent CRS. Anakinra could be considered; however, to date, it has only been shown to decrease ICANS in mice models. [4]
A 2020 letter to the editor described the efficacy of anakinra for CRS and ICANS in patients with relapsed or refractory large B-cell lymphoma (LBCL) treated with standard axicabtagene ciloleucel therapy. The authors reported preliminary findings from a study conducted at The University of Texas MD Anderson Cancer Center. Of 100 total patients with relapsed or refractory LBCL treated with standard-of-care axicabtagene ciloleucel, 8 were treated with anakinra (n= 2 with high-grade ICANS and n= 6 with secondary hemophagocytic lymphohistiocytosis [HLH]). Anakinra was initiated at a median of 12 days after axicabtagene ciloleucel infusion, with a median daily dose of 100 mg subcutaneously for 7 days, amounting to a median cumulative dose of 700 mg. After initiation of anakinra, patients continued therapy with corticosteroids, but not tocilizumab. Clinical response was observed in 4 patients after starting anakinra, as reflected by ferritin, lactate dehydrogenase (LDH), and C-reactive protein (CRP) levels, while 4 were refractory. Overall, 4 of 6 patients who received anakinra for high-grade ICANS experienced clinical benefit, although the benefit was only transient for one of these 4. Results reported in this letter are merely preliminary and are limited by the single-center, retrospective study design, as well as small sample size and lack of serial IL-1 serum measurements. [5]
Interim results of a single-arm, phase 2 trial on the use of anakinra in patients with relapsed/refractory large B-cell lymphoma and mantle cell lymphoma were summarized in a recent article. Patients who were treated with commercial anti-CD19 CAR T-cell therapy are enrolled into two independent cohorts, with sequential enrollment in cohort 1 followed by enrollment in cohort 2 (currently ongoing enrollment). In cohort 1 (n= 31), patients were subcutaneously administered anakinra 100 mg every 12 hours, commencing either on day 2 post-infusion or after two documented fevers ≥ 38.5°C, whichever occurred first, for a 10-day duration. Three patients (9.7%) experienced severe (grade ≥ 3) ICANS and six patients (19%) experienced any grade ICANS, with a median onset approximately 4.5 days after CAR T-cell infusion. Although five patients required dexamethasone treatment for ICANS management, no patient required high-dose methylprednisolone. All-grade CRS occurred in 23 patients (74%), mostly grade 1 or 2 events. Although prophylactic anakinra shows promise in reducing rates of high-grade ICANS without affecting CAR T-cell efficacy, the study is still ongoing to determine the most optimal timing for CRS and ICANS rate reduction, and the use of a single arm and a small sample size limits how compelling these preliminary results are. [6]
Siltuximab has been used in cases of severe neurotoxicity in CAR-T patients; however, siltuximab is not approved for cytokine release syndrome. While siltuximab binds IL-6 similar to tocilizumab, the evidence for its use in ICANS remains primarily anecdotal. As such, siltuximab is typically reserved for tocilizumab-refractory cytokine release syndrome off-label use. Some authors suggest siltuximab may be a better choice than tocilizumab (which has an established role in cytokine release syndrome) because it is not clear if tocilizumab crosses the blood-brain barrier to a sufficient degree to ameliorate neurotoxicity or brain exposure to IL-6. Siltuximab, in contrast to tocilizumab, binds soluble directly to the IL-6 molecule with a Kd of 1 pM, eliminating the potential for increasing serum IL-6 levels and subsequent diffusion of IL-6 into the central nervous system (CNS). [7], [8], [9], [10], [11]
According to the ClinicalTrials.gov database, a phase 2 pilot study (NCT04975555) is currently underway to evaluate the role of siltuximab in the treatment of CRS and ICANS in patients receiving CAR T-cell therapy for FDA-approved hematologic malignancies. Eligible patients are enrolled at the time of CAR-T infusion and are prospectively monitored for the development of grade ≥1 CRS and/or ICANS, at which point siltuximab is administered with close clinical follow-up. Additional doses of siltuximab may be administered for worsening symptoms, with rescue tocilizumab permitted if CRS fails to resolve. The primary endpoint is the response rate of siltuximab in achieving CRS resolution within 14 days, while secondary endpoints include response rates for ICANS resolution, safety of siltuximab, and overall response to CAR-T therapy. The study initiated enrollment on November 15, 2021, and has an estimated primary completion date of December 31, 2026, with no results reported to date. [12]