Abstract
Introduction
Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are common toxicities associated with immunotherapies, including T cell redirecting bispecific antibodies. Although cooperative group guidelines recommend the use of tocilizumab or other IL-6/IL-6R inhibitors for the management of CRS and ICANS, reports on the use of siltuximab, an IL-6 inhibitor, for the treatment of CRS are limited.
Case report
We present the case of a 77-year-old male who received T cell redirecting bispecific antibody therapy with talquetamab for relapsed/refractory multiple myeloma (RRMM) and developed CRS with concurrent ICANS after receiving a second dose of talquetamab.
Management and Outcome
The patient received an infusion of siltuximab. The patient recovered from CRS within 1 h of siltuximab administration and ICANS within 7 h of siltuximab administration. Patient tolerated the subsequent dose of talquetamab with no evidence of CRS and continued on study.
Discussion
This case describes the successful use of siltuximab for the management of CRS in a patient treated with a T cell redirecting bispecific antibody for RRMM.
Introduction
Cytokine release syndrome (CRS) is a known side effect of immunotherapy, including chimeric antigen receptor (CAR)-T cell therapy, T cell redirecting bispecific antibodies, and bispecific T cell engagers.1,2 CRS can be mild to life-threatening and requires careful monitoring and management. 2 The anti-interleukin (IL)-6 receptor antibody tocilizumab is approved in the US and other regions to treat severe or life-threatening CRS induced by CAR-T cell therapy. Although recommended by cooperative group guidelines,3,4 tocilizumab is not approved for the treatment of CRS induced by bispecific antibodies. In June 2021, the US FDA issued an emergency authorization for the use of tocilizumab in patients with COVID-19 for the treatment of hospitalized adults and pediatric patients (aged ≥2 years) who are receiving systemic corticosteroids and require supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation. 5 Announcement of a shortage in the tocilizumab supply by Roche/Genentech has spurred the exploration of alternative agents to manage CRS in patients receiving immunotherapy treatment. 6 Here, we report the clinical outcomes for a patient treated for CRS with siltuximab as primary therapy.
Case report
The patient is a 77-year-old African American male who was diagnosed with multiple myeloma in October 2013 and subsequently received eight prior lines of therapy including proteasome inhibitors, immunomodulatory drugs, and an anti-CD38 antibody. Table 1 summarizes the patient's relevant medical history, prior lines of myeloma therapy, and disease characteristics at baseline. The patient was enrolled in a phase 2 study (NCT04634552) of talquetamab, a T cell redirecting bispecific antibody that targets G protein-coupled receptor, class C group 5 member D (GPRC5D) on multiple myeloma cells and CD3 on T cells. In the phase 1 part of the study (NCT03399799), 7 recommended phase 2 doses of talquetamab were identified (0.4 and 0.8 mg/kg). As of 17 January 2022, the most common adverse events were cytopenias and CRS. CRS occurred in 77% of patients in the 0.4 mg/kg group and 80% of patients in the 0.8 mg/kg group. Overall response rate was 70% in the 0.4 mg/kg group and 64% in the 0.8 mg/kg group.
Summary of medical history, prior treatments, and disease characteristics at baseline.
dFLC: difference between uninvolved and involved serum free light chains; SPEP: serum protein electrophoresis; UPEP: urine protein electrophoresis test.
The patient received a first dose of talquetamab (termed step-up dose 1 in study protocol) without incident; however, on the day after a second dose (termed step-up dose 2 in study protocol), the patient developed a fever of 39.6 °C, consistent with American Society for Transplantation and Cellular Therapy grade 1 CRS. Confusion was documented approximately 2 h after onset. Immune Effector Cell-associated Encephalopathy (ICE) score of 5 was documented and immune effector cell-associated neurotoxicity syndrome (ICANS) was assessed as grade 2. No hypotension or hypoxia was present. Investigations included blood cultures, urine culture, chest X-ray, and head CT scan.
The patient was treated with a single administration of siltuximab 11 mg/kg intravenously (IV) and began empiric piperacillin/tazobactam 4.5 g IV every 8 h (first dose 1 h prior to siltuximab). No additional steroids were given. CRS grade 1 resolved within 1 h of administration of siltuximab. At onset of ICANS grade 2, the patient was alert and oriented to name only, but within 7 h of siltuximab infusion, was alert and oriented to person, place, and date. The study protocol's guidelines for management of ICANS (ICE score 3–6) with concurrent CRS state “if no improvement … administer dexamethasone 10 mg IV every 6 hours if not already taking other corticosteroids. Continue dexamethasone use until the event is Grade 1 or less, then taper.” The patient's response to siltuximab abrogated the need for treatment with corticosteroids. Initial urinalysis showed no leukocyte esterase, white blood cells, or bacteria; urine cultures subsequently grew Enterobacter cloacae 10,000 to 50,000/mL, sensitive to piperacillin/tazobactam. Blood cultures remained negative. Prior to the febrile episode, the patient complained of his chronic back pain without new pain or dysuria. The patient continued treatment with piperacillin/tazobactam during his hospitalization for treatment of his urinary tract infection (UTI). While the altered mental status and fever were potentially related to the UTI, the rapid resolution of symptoms after siltuximab administration and lack of urinary symptoms argues for CRS and ICANS related to talquetamab. The patient received the scheduled subsequent dose of talquetamab one day after resolution of these events. The patient tolerated the subsequent dose of talquetamab with no evidence of CRS or ICANS and continued on study.
Discussion
Siltuximab is an IL-6 antagonist indicated for the treatment of patients with multicentric Castleman's disease who are negative for HIV and human herpesvirus-8. 8 The approved dose of siltuximab in this setting is 11 mg/kg given IV over 1 h every 3 weeks. Siltuximab binds to IL-6 to neutralize its activity. 2 The affinity (Kd) of siltuximab for IL-6 is approximately 1 pM, 9 whereas the Kd of IL-6 for the IL-6 receptor is 1.5 nM, 10 indicating that the IL-6 receptor is unlikely to compete with siltuximab for IL-6 binding. In contrast, tocilizumab binds to the IL-6 receptor with a Kd of 2.54 nM and thus may compete with IL-6 for IL-6 receptor binding. 11 The differential binding and affinity for its target suggest that siltuximab may have greater potency than tocilizumab.
Tocilizumab is approved for the treatment of CRS in patients who received CAR-T cell therapy; however, it has failed to demonstrate similar efficacy in the treatment of ICANS, in some cases even appearing to worsen ICANS.3,12–16 It is hypothesized by blocking IL-6R, tocilizumab results in an increase in the level of IL-6 present in the peripheral circulation. Upon permeating the blood-brain barrier (BBB), IL-6 triggers an inflammatory response in the central nervous system that cannot be neutralized by tocilizumab, which has poor penetration of the BBB.3,13–15 In contrast, siltuximab removes IL-6 from circulating serum, thereby reducing IL-6 entry into the CNS and preventing ICANS.3,13,15 Although further research is warranted, it appears that, in patients with concurrent CRS and ICANS, siltuximab may be a more effective treatment.
Recent reports indicate that siltuximab is being used to treat CRS in real-world settings of immunotherapies and in clinical trials (Table 2). Data are limited with respect to dose, timing of administration relative to CRS onset and other supportive measures, and outcomes of CRS.
Summary of recent literature reports of siltuximab as a primary treatment for CRS in the context of CAR-T cell therapy.
ALL: acute lymphoblastic leukemia; CAR: chimeric antigen receptor; CRS: cytokine release syndrome; ide-cel: idecabtagene vicleucel; LBCL: large B-cell lymphoma; MM: multiple myeloma; orva-cel: orvacabtagene autoleucel.
Of 37 patients in France with B-cell acute lymphoblastic leukemia who received tisagenlecleucel in sponsored clinical trials or as part of the French compassionate use program, 22/41 (54%) had CRS, of whom 4 (10%) were given siltuximab. 17 In a postmarketing study of axicabtagene ciloleucel in 295 patients with large B-cell lymphoma in the US, 83% experienced CRS, of whom 1% received siltuximab; CRS resolved in 94% of cases overall. 18 In a phase 1 study of an anti-CD19 CAR-T cell therapy in 12 patients with relapsed/refractory B-cell lymphoma, 2 of 5 patients with CRS were treated with siltuximab. 19
Siltuximab has been administered to patients with CRS following anti-BCMA CAR-T cell therapy. In the phase 2 KarMMa study (NCT03361748) of idecabtagene vicleucel, CRS was reported in 107 (84%) of 128 patients, one of whom was administered siltuximab for these symptoms. 20 In the phase 1/2 EVOLVE study (NCT03430011), 55 (89%) of 62 patients who were treated with orvacabtagene autoleucel developed CRS and 8 (13%) had neurological events; 2 patients received siltuximab as supportive care. 21
Conclusion
The patient described in this report adds to the limited literature of patients who received siltuximab as primary treatment for CRS. Siltuximab has been recommended by the Society for Immunotherapy of Cancer 3 and the European Society for Blood and Marrow Transplantation 4 as a potential treatment for patients whose CRS symptoms do not improve with tocilizumab, and by the CARTOX Working Group 22 for patients who are intolerant to tocilizumab. There are no FDA-approved alternatives for the treatment of CRS. A phase 2 study (NCT04975555) is planned to evaluate siltuximab 11 mg/kg administered IV over 1 h to decrease the severity of CRS and ICANS in patients treated with CAR-T cell therapy for hematologic malignancies.
Footnotes
Authors’ contributions
BL was responsible for acquisition, analysis, and interpretation of data; critically revised the case report for important intellectual content; approved the version to be published; and takes responsibility for the content. TR was responsible for analysis and interpretation of the data; critically revised the case report for important intellectual content; approved the version to be published; and takes responsibility for the content.
Ethics
Patient provided written informed consent.
Declaration of conflicting interests
Dr. Lipe receives compensation from Janssen for research and consulting fees. Thomas Renaud is an employee of Janssen.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Janssen Research and Development.