Anakinra shows promise as steroid-sparing agent for CAR T-cell therapy-related toxicities
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Steroids are commonly used to mitigate severe treatment-related adverse events associated with chimeric antigen receptor T-cell therapy.
Because the potential effects of steroids on CAR T-cell proliferation are not fully known, several groups of researchers have initiated studies of anakinra (Kineret, Swedish Orphan Biovitrum) — an interleukin (IL)-1 receptor antagonist — for its ability to act as a steroid-sparing agent and reduce the incidence and severity of toxicities related to CAR T-cell therapy.
A study presented at this year’s TCT Meetings Digital Experience focused on the first three pediatric patients — aged 12, 16 and 21 years — with B-cell malignancies treated with IV anakinra plus dexamethasone to manage the effects of CAR T-cell therapy-related toxicities.
Healio spoke with researcher Anant Vatsayan, MBBS, attending physician in the division of blood and marrow transplantation at Children's National Hospital and assistant professor of pediatrics at George Washington University School of Medicine and Health Sciences, about the findings and the potential role anakinra may have in treatment.
Healio: Can you describe your rationale for the use of IV anakinra for the management of CAR-T-related toxicities?
Vatsayan: Both IL-1 and IL-6 are involved in the pathophysiology of CAR T-cell-related toxicity, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and hemophagocytic lymphohistiocytosis (HLH)-like syndrome. Preclinical and clinical case studies of anakinra, an IL-1 receptor antagonist, have shown promising results in the management of these toxicities.
Use of tocilizumab (Actemra, Genentech), an IL-6 receptor blocker, with or without steroids for CRS and steroids for ICANS are considered standard of care. Tocilizumab cannot cross the blood-brain barrier; hence, it is not indicated for management of ICANS. However, use of high cumulative doses of steroids to treat CAR-T-related toxicities can potentially compromise the activity and efficacy of CAR T cells. We wanted to use anakinra early in the course of toxicities as a steroid-sparing agent to decrease the cumulative dose and duration of therapy with steroids. Anakinra has been used before for HLH in children — including HLH-like syndrome secondary to CD22-directed CAR T cells — and for the treatment of CRS in patients with COVID-19. In our study, we used anakinra to treat ICANS and HLH-like toxicities after tisagenlecleucel (Kymriah, Novartis) — a CD19-directed CAR T-cell therapy — among younger patients with relapsed or refractory acute lymphoblastic leukemia.
We chose IV instead of subcutaneous anakinra because IV administration can rapidly achieve steady-state concentrations, both in blood and cerebrospinal fluid, especially in patients with poor skin perfusion secondary to CRS or shock. This is crucial to managing life-threatening complications of CRS and ICANS in patients receiving CAR T cells.
Healio: What have the results thus far shown?
Vatsayan: We combined the use of anakinra with steroids after the patient first developed symptoms of neurotoxicity. We started both agents at the same time or initiated anakinra soon after steroids — within 24 hours — with the intent of decreasing the cumulative dose of steroids. Every patient responded to the combination therapy within 48 hours in our small cohort. The use of anakinra did not have an impact on CAR T-cell activity because all three patients eventually achieved disease remission and were minimal residual disease-negative at a 30-day post-infusion disease evaluation.
Healio: What are the key takeaways from this research?
Vatsayan: First, adjuvant use of anakinra with a steroid may be a safe and effective strategy for treating ICANS or HLH-like toxicity to shorten the duration and cumulative dose of steroids. Early initiation of anakinra appears to be crucial in preventing worsening of toxicities and potentially reducing the adverse effects of high cumulative doses of steroids on the efficacy of CAR T cells. Second, overall and complete response rates may improve using the combination of anakinra plus steroids when compared with steroid monotherapy. Third, anakinra also may be effective for CRS because we saw rapid responses for both CRS and ICANS, which is in sync with preclinical studies describing the role of IL-1 in the pathophysiology of these CAR T-cell-related toxicities. Finally, IV rather than subcutaneous administration of anakinra may be more effective for the treatment of CAR T cell-related toxicities. This is especially important for patients who develop CRS because IV anakinra has shown very promising results in CRS secondary to COVID-19 infection.
Healio: Do the results of this study have any potential impact on clinical practice?
Vatsayan: Anakinra should be strongly considered for patients with steroid-refractory ICANS, HLH-like syndrome and possibly CRS. Earlier initiation of anakinra may shorten the duration of CAR T-cell therapy-related toxicities and reduce the cumulative steroid dose needed to control them.
Healio: Do you have any plans for further study?
Vatsayan: Anakinra may be effective both for prophylaxis and/or treatment of CRS and ICANS among patients receiving CAR-T. Studies are underway in adults to validate preclinical and preliminary clinical findings. HLH-like syndrome related to various CAR T-cell constructs has been reported recently, with patients responding well to anakinra. Further studies should examine existing questions around optimal dosing regimen, timing, duration of therapy and mode of administration. Data in pediatric populations are lacking, and there is an urgent need for similar studies in these patients.
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Vatsayan A, et al. Abstract 227. Presented at: 2021 TCT Meetings Digital Experience (virtual meeting); Feb. 8-12, 2021.
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