Anakinra utilization in refractory pediatric CAR T-cell associated toxicities

TO THE EDITOR:

Toxicity mitigation is central to maximizing the therapeutic potential of chimeric antigen receptor (CAR) T-cell therapy. The off-label use of tocilizumab (based on its efficacy in targeting interleukin-6 [IL-6] receptor in rheumatoid arthritis) to treat cytokine release syndrome (CRS) in the first child receiving CAR T cells¹  led to its widespread use for years before approval by US Food and Drug Administration (FDA) in 2017 for treatment of CRS. Tocilizumab remains the only approved agent for CRS, with utilization primarily guided by expert opinion^2,3  and preemptive use under investigation.^4-6  In severe CRS suboptimally responsive to tocilizumab or for treatment of immune effector cell–associated neurotoxicity syndrome (ICANS), which may inadvertently worsen with tocilizumab (possibly from shift of excess unbound IL-6 into the cerebrospinal fluid [CSF] compartment), corticosteroids are adjunctively employed to target alternative inflammatory pathways^2,3  but are associated with substantial short- and long-term toxicities. In circumstances where CAR T-cell toxicities are refractory to standard management and in an evolving pandemic where tocilizumab shortages are a reality,⁷  alternative adjunctive agents to treat ongoing inflammatory toxicities are needed.

Anakinra, a recombinant IL-1 receptor antagonist, is FDA approved for treatment of refractory rheumatoid arthritis in adults and both neonatal-onset multisystem inflammatory disease and deficiency of the IL-1 receptor antagonist in children.⁸  Routine off-label use of anakinra in numerous adult and pediatric autoinflammatory disorders provides additional experience with safety and efficacy in toxicities resembling CRS.^9,10  Clinical trials of anakinra for refractory Kawasaki disease, hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), sepsis with MAS, and severe acute respiratory syndrome coronavirus 2–associated cytokine storm have also shown benefit.^10,11 

In the context of CAR T cells, preclinical data suggest that IL-1 contributes to CRS and ICANS^12,13  and that IL-1 blockade may be effective in prevention and treatment of CRS/ICANS by suppressing additional inflammatory pathways¹⁰  without impacting CAR T-cell efficacy.¹⁴  Although prospective trials are limited, clinical use of anakinra for adjunctive treatment of CRS, ICANS, and/or CAR T-cell–associated HLH (carHLH) has been increasing, especially when standard therapies are insufficient.^3,15 ,,,, -²²  Several prospective studies evaluating anakinra in adults for prevention and/or management of CRS and ICANS are underway (clinicaltrials.gov #NCT04148430, #NCT04359784, and #NCT04432506), and early experiences are promising.^23,24 

While we await definitive results from prospective adult studies, given the clinical equipoise of optimizing care when standard toxicity mitigation has failed and ongoing inflammatory toxicities compromise outcomes, understanding current approaches and experiences with anakinra for its real-world application is imperative, especially in children where reports are limited and for whom prospective studies are not yet available but urgently needed. This letter aims to share our collective multi-institutional experiences and summarize available reports using anakinra as an adjuvant to standard therapies for immune-related toxicities in pediatric CAR T-cell recipients.

Six pediatric centers were represented by providers treating children and young adults on CAR T-cell clinical trials and/or with commercial constructs, collectively infusing more than 700 children to date. Treatment was primarily for B-cell acute lymphoblastic leukemia (B-ALL) with CD19 and CD22 single or combinatorial antigen targeting and occasionally alternate solid or brain tumor–targeted constructs.

Indications for anakinra varied by center and most frequently included refractory ICANS and CRS not responsive to tocilizumab and steroids, followed by carHLH. Given the lack of consensus definitions, carHLH was defined by local centers. Anakinra was typically initiated with clinical worsening of CRS, despite front-line therapy with tocilizumab and steroids, severe and/or refractory ICANS, or with carHLH, particularly when manifestations were delayed (Table 1).^18,20,25  Steroids were often started concurrently or before adding anakinra. Patient parameters, not IL-1β levels, were generally used to guide anakinra initiation or subsequent dosing given both limitations of monitoring IL-1β, particularly because peripheral elevations may be transient and not accurately reflect localized elevations of IL-1 (eg, in the bone marrow or liver²⁶ ) and because anakinra impacts inflammatory pathways beyond just IL-1.¹⁰ 

A wide range of dosing strategies incorporating higher subcutaneous (SC) and intravenous (IV) administration, IV bolus/intermittent dosing, and/or continuous infusion strategies (given the very short half-life of 4-6 hours) have been incorporated in children for the treatment of inflammatory conditions (supplemental Table 1).^8,27  Based on dosing used in autoimmune/rheumatologic conditions and sepsis, a starting dose of 2 mg/kg SC/IV every 6 hours (max daily dose, 400 mg) for CAR T-cell toxicities was generally used, with escalation based on tolerability and response. In a single-center experience with CD22 CAR T cells and carHLH, high-dose anakinra (8-10 mg/kg per day SC) was the typical starting dose in patients more severely impacted, whereas a lower dose (5-8 mg/kg per day SC) was used in those less ill.¹⁸  In circumstances of late-onset carHLH, single-agent anakinra has been used to treat underlying inflammation.²⁸ 

Although SC administration provides more continued blockade, the IV route may be especially appealing in severe CRS with edema and poor skin perfusion or severe ICANS where higher CSF levels with IV anakinra are purportedly more effective compared with the SC route.^19,29  Use of an IV loading bolus or continuous IV infusion could enable steady-state plasma concentrations to be rapidly attained and maintained, avoiding potentially subtherapeutic troughs.^11,27  Recent experience with IV anakinra for CRS on a CAR T-cell trial targeting GD2 additionally confirmed CSF penetration.³⁰  Optimal weaning schedule is unknown, and duration varied from days to weeks following clinical stability and/or improvement in clinical status.

Published reports of anakinra utilization in children receiving CAR T cells are limited.^19,20,28,31  Thus, we provide both a summary of our anecdotal experiences and a summary of available publications on anakinra use for CAR T-cell toxicity management (Tables 1 and 2). Given concurrent utilization of tocilizumab and/or corticosteroids, elucidating the specific benefit of anakinra or its role in facilitating weaning of steroids and/or serving as a steroid-sparing agent is limited.

General anakinra toxicities include injection site reaction, infection (upper respiratory tract infection), headaches, vomiting, arthralgia, and pyrexia.⁸  Infusion reactions are rare, and primary contraindications are established hypersensitivity to Escherichia coli–derived proteins or other components of anakinra.⁸  In our experience, anakinra was generally well tolerated, with administration site bruising and pain the most frequent side effects in those receiving SC administration. In patients with coagulopathy and/or thrombocytopenia, however, bruising could be significant. Thus, IV administration should be considered, particularly in children where pain from SC injections may be substantial.

The potentially additive impact of multiple immunosuppressants on risk of serious infection remains of concern, particularly in severe CRS where cytopenias may increase infection predisposition.³²  Use of anakinra with etanercept (tumor necrosis factor blockade) is specifically discouraged because of a higher infection risk.⁸  Studies of infection risk with concurrent tocilizumab and anakinra are limited and primarily derived from experiences with COVID-19.³³  Given concern for worse outcomes with concurrent infection and CRS^34,35  and masking of fevers with immunosuppression, monitoring closely for infection is essential. Although anakinra’s short half-life permits easy discontinuation in cases of toxicity, potentially modifying antimicrobial prophylaxis³⁶  in patients receiving multiple immunosuppression may be needed.

A host of alternative immunomodulatory and/or anti-cytokine–directed therapies are emerging for use in treatment of refractory CRS and/or HLH-like CAR T-cell toxicities and include ruxolitinib and emapalumab, among others. Ruxolitinib, a Janus kinase inhibitor, is approved for myelofibrosis, polycythemia vera, and steroid-refractory acute and chronic graft-versus-host disease, has approval in children who are ≥12 years, and has also been used for secondary or refractory HLH.^37,38  Limited reports in treatment of steroid-refractory CRS^39,40  support further study of this agent in treatment of CAR T-cell toxicities. However, thrombocytopenia associated with ruxolitinib can be especially challenging to manage with concurrent cytopenias or disseminated intravascular coagulation during severe CRS/carHLH. Furthermore, the impact of ruxolitinib on CAR T-cell expansion needs to be evaluated, given potential concern for impact on CAR T-cell efficacy.³⁹ 

Alternatively, emapalumab, an interferon-γ (IFN-γ) blocking antibody, approved for treatment of refractory/progressive/recurrent primary HLH, is also approved in children.⁴¹  Given the role of IFN-γ in CRS severity and HLH, blockade may effectively treat CAR T-cell toxicities by mitigating macrophage activation signals while preserving the antileukemic effect of CAR T cells. Recent reports supporting both preclinical⁴²  and initial clinical experience in children⁴³  are encouraging, but further study is needed.

Based on our collective experiences, anakinra is increasingly being used as an adjunctive agent for CAR T cell–associated toxicities, in part because of its FDA approval in other pediatric inflammatory settings where efficacy and tolerability are well established. Thus, identifying clear indications, optimal dosing, route of administration, and timing after infusion are needed to optimize the role of this agent in CAR T-cell therapy and facilitate improved utilization of this therapeutic agent. Collectively, emergence of these novel immunomodulatory and/or cytokine targeting agents opens multiple avenues for exploring treatment of CAR T-cell toxicities. Prospective studies in children are urgently needed, particularly to understand the role of anakinra in toxicity mitigation and its potential as a steroid-sparing agent and to evaluate for the impact of anakinra on CAR T-cell cytotoxicity and/or persistence.

Acknowledgments: The authors gratefully acknowledge the contributions of all respective medical teams who provided their expertise in the management of the study participants, CAR T-cell recipients and families, the data managers and research nurses, and patient care coordinators involved with this work.

This work was supported in part by the Intramural Research Program, National Cancer Institute and National Institutes of Health Clinical Center, National Institutes of Health (Grant ZIA BC 011823 to N.N.S.). A.C.T. is supported by a grant from the American Society of Hematology. S.L.M. is supported by grants from the St. Baldrick’s Foundation-Stand up to Cancer (Grant SU2C-AACR-DT-27-17), the V Foundation, and the Children’s Oncology Group. Stand Up To Cancer is a division of the Entertainment Industry Foundation. The indicated SU2C grant is administered by the American Association for Cancer Research, the scientific partner of SU2C. C.D. was supported by an American Society of Clinical Oncology Young Investigator Grant and by the Canadian Institute for Health Research.

The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Contribution: All authors provided patient care and reviewed the manuscript and agreed to the contents of the manuscript prior to submission.

Conflict-of-interest disclosure: S.L.M. reports clinical trial support from Novartis and consulting fees, placement on advisory boards, and placement on a study steering committee from Novartis and Wugen.

Correspondence: Caroline Diorio, Children’s Hospital of Philadelphia 3401 Civic Center Blvd Philadelphia, PA 19104; e-mail: DIORIOC@chop.edu; Anant Vatsayan, Department of Blood and Marrow Transplantation Children’s National Hospital Washington, DC 20010; e-mail: avatsayan@childrensnational.org; Aimee C. Talleur, Department of Bone Marrow Transplantation and Cellular Therapy St. Jude Children’s Research Hospital Memphis, TN 38105; e-mail: Aimee.Talleur@stjude.org; Rebecca A. Gardner, Division of Hematology and Oncology Seattle Children’s Hospital Seattle, WA 98105; e-mail: Rebecca.gardner@seattlechildrens.org; and Nirali N. Shah, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; e-mail: nirali.shah@nih.gov.