Current concepts in the diagnosis and management of cytokine release syndrome

Case 1: grade 1 CRS after CAR T-cell therapy for leukemia

An 11-year-old girl with primary refractory pre-B-cell ALL failed to obtain remission after 3 cycles of intensive chemotherapy and was referred for CD19–chimeric antigen receptor (CAR) therapy. At the time of enrollment, 58% of her marrow mononuclear cells were lymphoblasts. She received fludarabine and cyclophosphamide for lymphodepletion on days −4 through −2, and then 1 × 10⁶ CD19 CAR T cells/kg on day 0. She developed fever on day 1 that peaked at 40.7°C associated with rigors, which persisted for 5 days. No source of infection was identified, and she remained hemodynamically stable with no evidence of neurologic dysfunction. Plasma interleukin (IL)-6 levels peaked at 222 pg/mL (∼30-fold over baseline). Assessment on day 28 revealed minimal residual disease-negative complete remission. She subsequently underwent matched sibling HSCT and remains disease free 16 months later.

Case 2: grade 3 CRS after genetically unmodified cytotoxic T cells (CTL) therapy for EBV-associated lymphoma

A 19-year-old woman with relapsed Epstein-Barr virus (EBV)-negative Hodgkin’s lymphoma received a 9/10 HLA DRB1 mismatched unrelated HSCT following conditioning with 600 cGy total body irradiation, fludarabine, and alemtuzumab. Rapidly progressive EBV-positive post-transplant lymphoproliferative disease (EBV-PTLD) developed 3 months after transplant with elevated EBV DNA (>100 000 copies/10⁶ cells) and extensive nodal involvement on positron emission tomography. Biopsy confirmed EBV-PTLD. She experienced only a transient response following 2 doses of rituximab. A donor-derived, peptide rapidly generated multispecific (EBV, adenovirus, BK virus, and HHV6) CTL line was generated, and 5 × 10⁶ cells/m² were infused on a patient-specific investigational new drug application. EBV DNA levels fell to normal levels with clinical and radiological improvement within 2 weeks after infusion. Shortly afterward, she developed fever, rash, tachycardia, and hypotension with elevated IL-5, IL-13, IL-10, IL-6, and interferon (IFN)γ levels (range, 5- to 69-fold over baseline), associated with ≥10 000-fold expansion of EBV (EBNA1, LMP2, and BZLF1)-specific CTLs in the peripheral blood. She had no evidence of tumor lysis. She was treated with dopamine and norepinephrine, etanercept, and methylprednisolone (1 mg/kg/day × 2). Symptoms resolved within hours, and vasopressor support was discontinued. Cytokine levels returned to baseline within 3 weeks. Nine months after this CRS, her EBV lymphoma remains in remission.

Case 3: grade 3 CRS after CAR T-cell therapy for leukemia

An 11-year-old girl relapsed 6 months after HSCT for B-ALL and enrolled on a clinical trial of CD19-CAR therapy. She received cyclophosphamide and fludarabine for lymphodepletion: on day –1, her marrow showed 51% blasts, and on day 0, 2 × 10⁷ CD19-CAR cells were administered. On day 1, she was admitted to the hospital with fever. Blood cultures grew Streptococcus mitis, and she became afebrile on vancomycin. On day 4, she developed a new fever with headache and nausea. On day 5, she developed tachycardia, hypotension (70/40 mm Hg), and a new oxygen requirement. She received 2 fluid boluses and was transferred to the pediatric intensive care unit, where she received dopamine and norepinephrine. She was treated with 8 mg/kg tocilizumab and within hours became afebrile and no longer required supplemental oxygen, and pressors were weaned to minimal levels. On day 7, she became febrile again and experienced intermittent hypotension requiring continued pressor support. Ferritin (130 000 ng/mL) and C-reactive protein (CRP; 21.5 mg/L) peaked on day 7. On day 9, she developed encephalopathy, with near aphasia, disorientation, and lethargy, which improved rapidly over the next 2 days without further immunosuppressive therapy. Pressors were discontinued on day 10, and encephalopathy resolved completely by day 13. She was discharged home on day 15, and her marrow demonstrated complete remission on day 28.

Grading system and treatment algorithm

The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v4.0) contains a grading system that was designed for CRS associated with antibody therapeutics (supplemental Table 1, available on the Blood Web site). We modified this grading system to define mild, moderate, severe, and life-threatening CRS regardless of the inciting agent and to guide treatment recommendations (Table 2). Because many patients with CRS have overlapping symptomatology due to fever and neutropenia, infection, tumor lysis syndrome, or other medical complications, it is essential that attribution be carefully considered. This is particularly important given that the treatment algorithm relies heavily on the grading schema and incorporates immunosuppression. One could imagine, for example, a patient with hypotension related to sepsis wherein intervention with tocilizumab or corticosteroids (see below) would not be indicated. Hence, accurate application of this grading system requires clinical judgment to confirm that the symptoms are most likely due to CRS rather than another medical condition.

The clinical symptomatology comprising CRS is an indicator of response in the setting of immune-based therapies. It remains unclear to what extent the cytokines mediating the symptomology are required for antitumor effects. Hence, the goal of management is not to extinguish all evidence of CRS but to prevent life-threatening toxicity while maximizing the potential for antitumor effects. For this reason, we recommend symptomatic treatment of grade 1 CRS (Figure 2, case 1). We defined CRS as grade 2 when the patient develops hypotension responsive to fluids or 1 low-dose vasopressor or mild respiratory symptoms responsive to low flow oxygen (<40% FiO₂) or grade 2 organ toxicity. Because hypotension is a major driver of severity grading, it is imperative that a clear baseline blood pressure be established prior to initiation of therapy that could induce CRS. As shown in Figure 2, the decision to intervene with immunosuppressive agents for patients with grade 2 CRS is influenced by the degree to which the patient is judged to be able to tolerate the altered hemodynamics and organ stresses associated with the syndrome. In older patients and patients with significant comorbidities, depending on clinical judgment, it may be appropriate to intervene with immunosuppression in patients with grade 2 CRS.

Patients in whom fluid therapy and 1 low-dose vasopressor are not sufficient to reverse hypotension are classified as severe or grade 3 CRS. Similarly, patients who require more than low flow oxygen or show evidence for grade 3 organ toxicity, including but not limited to coagulopathy, renal, or cardiac dysfunction, should be considered grade 3. Patients with grade 3 CRS need to be monitored very closely, likely in an intensive care unit with 1:1 nursing care. Importantly, in patients with grade 2 or grade 3 CRS, careful attention should be paid to cardiac function, as cardiac decompensation may occur and may not be readily evident without careful monitoring. Frequent echocardiographic monitoring may be indicated in patients in whom there is a concern of cardiac dysfunction. All patients with grade 3 CRS should be treated with immunosuppressive agents because of the risk for progression and the potential for irreversible organ dysfunction, with the goal of preventing progression to grade 4. Grade 4 CRS occurs when patients experience toxicity that is immediately life threatening, including a need for mechanical ventilation or grade 4 organ toxicity. We recommend that all patients with grade 4 CRS be treated with immunosuppressive agents in an attempt to suppress the inflammatory cascade and to prevent irreversible organ dysfunction.

Tocilizumab

Tocilizumab is a humanized, immunoglobulin G1κ (IgG1κ) anti-human IL-6R mAb approved for treatment of rheumatoid arthritis,⁴¹ juvenile idiopathic arthritis,⁴² and polyarticular juvenile rheumatoid arthritis. It has also been reported to have activity in Castleman disease,⁴³ Crohn’s disease,⁴⁴ and steroid refractory chronic graft-versus-host disease.⁴⁵ Tocilizumab prevents IL-6 binding to both cell-associated and soluble IL-6Rs and therefore inhibits both classical and trans-IL-6 signaling (Figure 1). Emerging clinical experience at several institutions has concluded that tocilizumab is an effective treatment for severe or life-threatening CRS.^8,22,24 The dose of tocilizumab approved for adults with rheumatoid arthritis is 4 to 8 mg/kg every 4 weeks, and the pediatric recommended dose is 8 to 12 mg/kg every 2 to 4 weeks. Using these recommendations as a guide, we typically administer tocilizumab over 1 hour at a dose of 4 mg/kg in adults and 8 mg/kg in children, with an option to repeat the dose if clinical improvement does not occur within 24 to 48 hours.

Side effects attributed to tocilizumab in rheumatologic disease, where the drug is given chronically, include transaminitis, thrombocytopenia, elevated cholesterol, and low-density lipoproteins.⁴¹ Neutropenia has also been uncommonly attributed to tocilizumab therapy, and this appears to resolve with discontinuation of the agent. The incidence of viral, bacterial, fungal, and mycobacterial infection is modestly increased in patients receiving chronic therapy for rheumatologic disease, thus providing the basis for a black box warning associated with the agent.⁴¹ We have not observed acute infusional toxicities secondary to tocilizumab in patients treated on our studies.

In patients with CRS who respond to tocilizumab, fever and hypotension often resolve within a few hours, and pressors and other supportive care measures can be weaned quickly thereafter. In some cases, however, symptoms may not completely resolve, and continued aggressive support may be necessary for several days (case 3). If the patient’s condition does not improve or stabilize within 24 hours of the tocilizumab dose, administration of a second dose of tocilizumab and/or a second immunosuppressive agent, such as corticosteroids, should be considered. Whether lack of response is related to ongoing production of IL-6, inadequate dosing of tocilizumab, or other factors is not yet known.

As discussed above, neurologic symptoms associated with CRS sometimes follow a different time course of onset and resolution (case 3). We have occasionally witnessed patients whose hemodynamic instability resolves rapidly following administration of tocilizumab, but who subsequently develop signs and symptoms of neurotoxicity. Based on the following evidence, we hypothesize that this relates to IL-6-directed neurotoxicity. First, IL-6 has been reported to mediate substantial neurologic effects and has been implicated in several neurologic conditions spanning Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, schizophrenia, depression, and MERS.^34-36 Second, elevated central nervous system IL-6 levels are likely to occur in CRS due to direct transit of IL-6 via production in the periphery and/or production of IL-6 via trafficking of activated immune cells to the CNS. Indeed, we have observed elevated IL-6 levels in the cerebrospinal fluid associated with neurotoxicity. Third, IL-6 levels rise transiently following administration of tocilizumab due to blockade of the receptor,⁴⁶ which inhibits receptor-mediated clearance, and tocilizumab is not expected to cross the blood:brain barrier. Hence, elevations in IL-6 within the CNS are not likely to be directly ameliorated in the short term and may even be transiently aggravated by tocilizumab therapy. For these reasons, for patients with grade 3 or 4 CRS associated with neurologic dysfunction without significant hemodynamic instability or other life-threatening symptomatology, consideration may be given to the use of corticosteroids as a preferred first-line immunosuppressive.

Figure 3 depicts a hypothetical patient with grade 3 CRS who develops fever on day 3, then hypotension on day 5 that is initially managed with a low-dose vasopressor, and then tocilizumab on day 6 after cardiovascular decompensation. IL-6 and IFNγ peak coincident with decompensation. IFNγ rapidly returns to baseline after tocilizumab, but owing to its mechanism of action, whereby receptor-mediated endocytosis of IL-6 is blocked by tocilizumab, IL-6 levels typically rise transiently immediately following tocilizumab before returning to baseline. Numerous other cytokines are also elevated and follow a similar time course. As depicted, neurologic symptoms can manifest either before or after tocilizumab administration and not infrequently persist for some time after tocilizumab, presumably due to its inability to cross the blood:brain barrier.

Corticosteroids and other agents

Clinical experience also demonstrates that corticosteroids are effective treatment of CRS, and a rapid steroid taper can generally be accomplished within several days without recurrence of the CRS. Despite this, we currently consider corticosteroids as second-line therapy for CRS. This is based on our clinical observation that response to tocilizumab may be more rapid than response to corticosteroids. In addition, corticosteroids appear to have more widespread effects on the immune system, and emerging evidence suggests that they may mediate a greater adverse effect on the antitumor activity of adoptively transferred T cells.²⁶ We acknowledge, however, that the recommendation to use tocilizumab over corticosteroids is based on limited clinical experience and that in some settings wherein immune toxicity is associated with antitumor therapies, such as graft-versus-host disease and checkpoint inhibitor therapy, corticosteroids do not prevent therapeutic benefit.^1,47 Thus, some physicians may choose to use corticosteroids as a frontline agent or to use both agents in cases of severe or life-threatening CRS. Although dosing and choice of corticosteroid should be tailored to the individual patient, commonly used initial doses include methylprednisolone (2 mg/kg/day), which can generally be weaned over several days. For patients with severe neurologic symptoms, consideration may be given to using dexamethasone (0.5 mg/kg; maximum, 10 mg/dose) due to more efficient penetration of the blood:brain barrier,⁴⁸ although evidence for differential efficacy of methylprednisolone vs dexamethasone in this setting has not been established. It is also important to note that, especially in the case of B-ALL, many patients have chronically received corticosteroids as part of their treatment regimen, and therefore some patients who experience CRS may have a relative corticosteroid deficiency due to chronic suppression of their hypothalamic-pituitary axis wherein stress doses of hydrocortisone may be indicated.

Targeted immunosuppressive agents are also available to inhibit TNFα and IL-1, both of which may contribute to CRS. Hence, anti-TNFα mAbs (infliximab) and soluble TNFα receptor (etanercept) and IL-1R-based inhibitors (anakinra) could also provide benefit and have been used successfully (case 2). These agents have also demonstrated efficacy in the setting of macrophage activation syndrome and other syndromes^49-51 that likely overlap with CRS in terms of pathophysiology. However, because supportive care with tocilizumab ± corticosteroids has been efficacious in our experience, we are not currently routinely using these agents.