What drug therapy is recommended for management of immune-related adverse events in patients treated with chimeric antigen receptor T-cell therapy?

Introduction

In the past decade, chimeric antigen receptor (CAR) T-cell technology has advanced the treatment of various hematologic cancers.¹ In 2014, the FDA granted breakthrough therapy designation to tisagenlecleucel, a CD19-targeted CAR T-cell therapy, acknowledging its potential for significant improvement in treatment of hematologic cancers.^2,3 In 2017, the first CAR T-cell therapy was approved, and currently 6 CAR T-cell products are available for treatment of B-cell malignancies, lymphomas, and multiple myeloma.^3-5

Chimeric antigen receptor T-cell therapy involves the removal, genetic modification, and reinfusion of a patient’s naïve T-cells.⁶ These T-cells are modified to express a CAR which directs the T-cells to attack malignant T-cells that express the corresponding antigen. Most CAR T-cell therapies target CD19, which is abundantly expressed in B-cell lineages. CAR T-cell therapy has a variety of advantages compared to other treatments.¹ It produces a robust response against malignant cells, which is expected to last long-term because CAR T-cells persist in the body potentially for decades.

While CAR T-cell therapy represents a significant advancement, these therapies present unique challenges.^1,6 Potentially life-threatening immune-related adverse events (irAEs) can occur, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hemophagocytic lymphohistiocytosis (HLH), B-cell aplasia, cytopenias, and disseminated intravascular coagulation (DIC). Because pharmacists in various settings may have questions regarding these serious adverse events and their appropriate management, this document reviews recommended pharmacologic strategies for managing irAEs of CAR T-cell therapy.

Current Guidelines

Because of their frequency and severity of irAEs of CAR T-cell therapy, professional oncology societies recently issued guidelines on management of these events.^1,7 In 2021, the most recent guidelines were published from both the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN). These guidelines serve as the cornerstone of recommendations for current management of common irAEs of CAR T-cell therapy, which are summarized in this review.

American Society of Transplantation and Cellular Therapy (ASTCT) Grading of CRS

Guidelines from both ASCO and NCCN offer recommendations for management of CRS and ICANS based on the severity of the event, defined using the American Society of Transplantation and Cellular Therapy (ASTCT) consensus criteria.^1,7 In this grading system, a fever of 38⁰ C or greater is required, and the severity is based on the degree of hypotension and hypoxia (Table 1). Recommendations for management depend on ASTCT grading, which are summarized in Table 1; further detail on pharmacotherapy recommendations is presented in the following sections.

Cytokine Release Syndrome (CRS)

Cytokine release syndrome is potentially life-threatening and is the most common irAE following CAR T-cell therapy, with reported incidence ranging from 57% to 93%.¹ Cytokine release syndrome is caused by an excessive release from T-cells and other immune cells of cytokines, including interleukin-6 (IL-6), interferon-gamma (IFN-g), and tumor necrosis factor alpha (TNF-α).⁸ This irAE is usually observed within 2 to 7 days of administration of CAR T-cell therapy, but has been observed up to 3 weeks later.¹ Symptoms include fever, rash, headache, hypoxia, hypotension, coagulopathy such as disseminated intravascular coagulopathy (DIC), and multiorgan system failure.

Supportive Care of CRS

Because CRS complications include fever, hypotension, hypoxia, and multisystem organ toxicity, an important component of management is supportive care, including antipyretics and symptomatic management of organ toxicities.^1,7,8 Patients with severe CRS (grades 3 to 4) should be transferred to an intensive care unit.^1,7 For hypotension, IV hydration (including fluid boluses as needed for patients with hypotension) and vasopressors are recommended as necessary. For hypoxia, supplemental oxygen may be administered as need; mechanical ventilation may be required in severe hypoxia (grade 4). Patients should be assessed for infection with blood and urine cultures and a chest radiograph, and empiric broad-spectrum antibiotics and granulocyte colony stimulating factor (G-CSF) should be given if the patient is neutropenic.

Anti-interleukin-6 Therapy

Although CRS involves the excessive release of various cytokines, interleukin-6 (IL-6) is considered central to its pathophysiology.^6,8 Interleukin-6 is associated with many of the complications of CRS, including vascular leakage, activation of the complement and coagulation cascades, DIC, and cardiomyopathy. The importance of IL-6 is demonstrated by the efficacy of IL-6 blockade in this toxicity.^1,6-8

Tocilizumab, a monoclonal antibody targeting the IL-6 receptor, is indicated for the treatment of severe or life-threatening CAR T-cell-related CRS in patients 2 years and older.⁹ Tocilizumab received FDA approved for this use in August 2017 after analyses of CAR T-cell clinical trials demonstrated that 69% of cases of severe or life-threatening CRS resolved within 2 weeks after 1 to 2 doses of tocilizumab.^10,11 Tocilizumab remains the only anti-IL-6 therapy to carry this indication.

In patients with grade 2 or higher CRS, both ASCO and NCCN recommend tocilizumab 8 mg/kg as a 1-hour IV infusion (Table 1).^1,7 Based on a reassessment of the patient’s response, repeat doses may be given every 8 hours, with a maximum of 3 doses in a 24-hour period. No more than 4 doses should be given during a CRS episode. Patients with grade 1 CRS with persistent (longer than 3 days) or refractory fever may be considered for management as per grade 2 disease, including tocilizumab administration.

In August 2021, a shortage of tocilizumab occurred because of its use for hospitalized COVID-19 patients.¹² This shortage has complicated treatment with CAR T-cell products because they currently have risk evaluation and mitigation strategies (REMS) requirements that there be 2 doses of tocilizumab available on-site ready for administration within 2 hours.¹³ In December 2021, the FDA issued guidance that relaxed this requirement for the duration of the tocilizumab shortage.¹² Under this guidance, only 1 tocilizumab dose need be readily available within 2 hours, with the second dose obtainable within 8 hours of the first. Also, additional therapies targeting IL-6 or other cytokines that have limited data may be considered. Similarly, NCCN has recommended conservation strategies, including limiting use to a maximum of 2 doses instead of 4, considering more aggressive use of steroids, or replacing the second dose of tocilizumab with siltuximab or anakinra.⁷

Corticosteroids

In addition to tocilizumab, ASCO and NCCN recommend corticosteroids in patients with grade 3 or higher CRS (Table 1).^1,7 Corticosteroids may also be considered in grade 2 CRS for patients with refractory hypotension after 1 to 2 doses of tocilizumab and 2 fluid boluses. Earlier use of corticosteroids appears to be beneficial and is recommended for certain CAR T-cell therapies, such as axicabtagene ciloleucel or brexucabtagene autoleucel. For example, corticosteroids are recommended after initial tocilizumab dosing regardless of the response to tocilizumab.

The recommended corticosteroid and dosage depend on the severity of CRS. For patients with grade 2 CRS who are receiving corticosteroids, the recommended dosage is dexamethasone 10 mg IV (or equivalent) every 12 hours.^1,7 In grade 3 CRS, the dosage is increased to dexamethasone 10 mg IV every 6 hours. Once the patient has improved to grade 1, rapid tapering as clinically appropriate is recommended. For more severe cases (grade 4), high-dose IV methylprednisolone is recommended with a regimen of 500 mg every 12 hours for 3 days, followed by 250 mg every 12 hours for 2 days, 125 mg every 12 hours for 2 days, and 60 mg every 12 hours until CRS improves to grade 1. For any patient receiving corticosteroids, both ASCO and NCCN strongly recommend antifungal prophylaxis.

Alternative Agents

While there are limited data on alternative agents to tocilizumab, both ASCO and NCCN recommend trying additional therapies if the patient is refractory to tocilizumab plus high-dose corticosteroids.^1,7 These alternative agents may also be considered earlier if shortages are present. Alternative agents may include other anti-IL-6 therapies, although compared with tocilizumab, there is limited data on their use in CRS.¹  Both ASCO and NCCN recommend that siltuximab be considered as an off-label alternative anti-IL-6 therapy.^1,6 Anakinra is an interleukin-1 (IL-1) receptor antagonist that has demonstrated efficacy in CAR T-cell-related CRS. Additionally, NCCN recommends that ruxolitinib (a Janus kinase inhibitor), cyclophosphamide (an alkylating agent), or extracorporeal cytokine adsorption with continuous renal replacement therapy be considered.

Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS)

The disorder characterized by neurotoxicity after CAR T-cell treatment is referred to as ICANS.^1,6 While the mechanism of this toxicity is not entirely understood, it is thought that systemic inflammation and cytokine release lead to disruption of the blood-brain barrier and subsequent inflammatory cascade within the central nervous system (CNS). Although ICANS can occur in the absence of CRS, it typically occurs 2 to 4 days after CRS occurs.

The incidence of ICANS is estimated to range between 20% and 70% of patients treated with CAR T-cell therapy.^1,6 While some patients may have mild cases and the condition is generally self-limiting, ICANS can be fatal. Symptoms include disruption of speech, altered level of consciousness, impairment of cognition, and motor weakness. In more severe cases, patients can develop seizures and elevated intracranial pressure (ICP).

ASTCT Grading of ICANS

Similar to CRS, ICANS is graded according to the ASTCT consensus grading system.^1,7 This system consists of 5 domains, including an Immune Effector Cell-Associated Encephalopathy (ICE) score, level of consciousness, seizures, motor findings, and elevated ICP/cerebral edema (Table 2).

Supportive Care of ICANS

Patients with ICANS are recommended by ASCO and NCCN to be monitored closely for signs of improvement or deterioration.^1,7 Supportive care should include IV hydration and aspiration precautions for all patients. Those with grade 3 or higher neurotoxicity should be treated in an intensive care unit, and mechanical ventilation should be considered for airway protection in grade 4 ICANS.

Seizure prophylaxis should be considered in patients with ICANS and elevated risk for seizures, such as those with a history of seizures or who received CAR T-cell products associated with a higher risk of ICANS (axicabtagene ciloleucel and brexucabtagene autoleucel).^1,7 Status epilepticus should be treated following institutional guidelines.

Corticosteroid therapy

Corticosteroids are the primary treatment for ICANS and are recommended for patients with grade 3 or higher neurotoxicity.^1,7 For grade 3 ICANS, ASCO and NCCN recommend dexamethasone 10 mg IV every 6 to 12 hours or methylprednisolone 1 mg/kg IV every 12 hours. In patients with grade 4 neurotoxicity or patients with grade 3 neurotoxicity who received axicabtagene ciloleucel or brexucabtagene autoleucel, high-dose methylprednisolone is recommended at a dosage of 1000 mg IV 1 to 2 times daily for 3 days. If the patient does not improve, the frequency may be increased to 2 to 3 times daily. Steroid treatment should be continued until improvement to grade 1, at which point methylprednisolone should be tapered. While rapid tapering is recommended, it has been associated with ICANS flares and should be performed carefully if deemed clinically appropriate.

Anti-IL-6 Therapy

Tocilizumab has not demonstrated efficacy in the treatment of ICANS, and may in fact worsen ICANS.¹ For this reason, tocilizumab is not recommended for isolated ICANS, and care should be taken when using this agent in patients experiencing ICANS.^1,7 While both ASCO and NCCN recommend tocilizumab in patients with CRS and concurrent ICANS, ASCO states that the relative severity of the two adverse events should be considered. For patients with severe ICANS and mild CRS, clinicians may need to prioritize the treatment of ICANS.

Hemophagocytic Lymphohistiocytosis (HLH)

Hemophagocytic lymphohistiocytosis involves abnormal activation of immune cells, leading to excessive inflammation and tissue damage.¹⁴ Histiocytes and lymphocytes accumulate in organs, which can cause organ damage. Additionally, macrophages attack other blood cells. Patients with HLH may present with fever, rash, signs of organ toxicities, and constitutional symptoms such as weakness. The presentation of HLH overlaps with CRS, making their differentiation difficult. However, HLH is much rarer than CRS, occurring in approximately 3.5% of CAR T-cell patients.¹ Unlike CRS and ICANS, there is no widely accepted diagnostic or grading criteria of HLH. However, an elevated serum ferritin greater than 10,000 ng/dL and the presence of 2 organ toxicities have been proposed as diagnostic criteria.

Corticosteroids and anti-IL-6 therapy have the best evidence for treatment of HLH and are recommended for patients with grade 3 or higher organ toxicity.¹ Several agents, including anakinra and etoposide, may be considered in patients with severe disease who are refractory to treatment, but data are limited on these agents. However, there is a concern that etoposide will be harmful to lymphocytes in patients treated with CAR T-cell therapy. For patients with HLH-associated neurotoxicity, intrathecal cytarabine with or without hydrocortisone may be considered. For patients with low fibrinogen concentrations (<150 mg/dL), fibrinogen replacement may be considered.

B-Cell Aplasia and Infection

CD19-directed CAR T-cell therapies target B-cell malignancies that express CD19.¹ In addition to providing a robust antitumor effect, this mechanism also leads to B-cell aplasia. This adverse effect may persist for up to 1 year after CAR T-cell infusion. Signs of B-cell aplasia include low B-cell counts, hypogammaglobulinemia, and frequent infections.

In order to prevent infections, ASCO recommends influenza and COVID-19 vaccination for all patients receiving CAR T-cell treatment and their family members, including those with B-cell aplasia.¹ Also, patients should receive antiviral and Pneumocystis jiroveci pneumonia (PJP) prophylaxis following institutional guidelines for at least 6 to 12 months following CAR T-cell infusion and/or until the CD4 count is above 200 cells/µL. If the patient experiences recurrent infections, IV immunoglobulin (IVIG) replacement should be considered if immunoglobulin G (IgG) concentrations are below 400 mg/dL. Antifungal prophylaxis should also be considered for patients at high risk of infection.

Disseminated Intravascular Coagulation

Disseminated intravascular coagulation is a coagulopathy that can occur after CAR T-cell infusions with or without concurrent CRS.¹ This coagulopathy involves systemic activation of coagulation mechanisms, leading to extensive clot formation and depletion of endogenous clotting factors.¹⁵ This depletion can result in potentially life-threatening bleeding and/or thrombosis. Generally, patients with DIC should receive supportive care and factor replacement based on fibrinogen levels, partial thromboplastin time, and bleeding.¹ Anti-IL-6 therapy and corticosteroids may be used for patients with concurrent CRS or for patients with severe bleeding complications. If the patient has bleeding complications, high-dose methylprednisolone should be used.

Cytopenias

Cytopenias, including anemia, thrombocytopenia, leukopenia, and neutropenia, can occur with CAR T-cell therapy.¹ These irAEs are more common within 3 months of CAR T-cell infusion, but some patients may experience prolonged cytopenias. Treatment of cytopenias consists mostly of supportive care, and other recommendations for other treatments depend on the grade of cytopenia (Table 3). Use of G-CSF and corticosteroids can be considered for cases that are more severe and not related to myelodysplastic syndrome. Corticosteroids can be used for grade 2 cytopenias until the patient returns to grade 1, at which point steroids should be tapered over 4 to 6 weeks. For grade 3 to 4 cytopenias, high-dose methylprednisolone should be used, and G-CSF can be considered per institutional guidelines.

Conclusion

The unique mechanism and considerable efficacy of CAR T-cell therapy signify its important role in the treatment of hematologic cancers. However, CAR T-cell therapy is associated with frequent and potentially severe irAEs that are challenging to manage. Current treatments for irAEs include anti-IL-6 therapy for CRS, corticosteroids for ICANS, and infection prophylaxis. Tocilizumab is currently the anti-IL-6 therapy with the best supporting evidence and FDA approval for use in CRS related to CAR T-cell therapy. Other drugs targeting cytokines currently have less supporting data but may be considered in specific situations. The information in this summary will aid pharmacists in providing optimal care for patients experiencing irAEs of CAR T-cell therapy.

References

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3. Memorial Sloan Kettering Cancer Center. CAR T Cells: Timeline of Progress. Memorial Sloan Kettering Cancer Center. Accessed March 10, 2022. https://www.mskcc.org/timeline/car-t-timeline-progress#:~:text=2002%20%E2%80%94First%20effective%20CAR%20T%20cells%20developed
4. DynaMed. EBSCO Health; 2022. Accessed March 10, 2022. www.dynamed.com
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7. National Comprehensive Cancer Network. Management of immunotherapy-related toxicities Version 1.2022. National Comprehensive Cancer Network. Published February 28, 2022. Accessed March 10, 2022. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf
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9. Actemra. Package insert. Genentech Inc; 2021.
10. US Food and Drug Administration. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. US Food and Drug Administration. Updated September 7, 2017. Accessed March 10, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-b-cell-all-and-tocilizumab-cytokine-release-syndrome
11. Roche. FDA approves Roche’s Actemtra/RoActemra (tocilizumab) for the treatment of CAR T-cell-induced cytokine release syndrome. Roche. Updated August 30, 2017. Accessed March 10, 2022. https://www.roche.com/media/releases/med-cor-2017-08-30.htm
12. US Food and Drug Administration. Policy for Certain REMS Requirements During the Tocilizumab Shortage Related to the COVID-19 Public Health Emergency. US Food and Drug Administration. Updated February 1, 2022. Accessed March 10, 2022. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/policy-certain-rems-requirements-during-tocilizumab-shortage-related-covid-19-public-health
13. US Food and Drug Administration. Approved Risk Evaluation and Mitigation Strategies (REMS). US Food and Drug Administration. Accessed March 10, 2022. https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm
14. McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic lymphohistiocytosis. In: Post TW, ed. UpToDate. UpToDate; 2022. Accessed March 10, 2022. UpToDate
15. Arruda VR, High KA. Coagulation disorders. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 20th ed. McGraw-Hill Education; 2018.

Prepared by:
Matthew Smith, PharmD Candidate
University of Illinois at Chicago College of Pharmacy

Ryan Rodriguez, Clinical Associate Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

April 2022

The information presented is current as January 31, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.