CAR T-cell therapy and critical care

The CRS is the most common acute toxicity following CAR‑T cell therapy with a reported incidence between 37% and 93% across different studies. [3, 4, 6, 20, 21]. The onset of CRS typically occurs within hours up to 4–7 days after CAR‑T cell infusion, but late occurrence up to 14 days has also been reported [3, 4, 6, 20, 22].

The CRS is characterized by excessive immune reaction triggered by various factors, such as infections and immune-modulating drugs, in particular T‑cell engaging treatment strategies [17, 23].

Increased IL‑6 levels correlate with the onset of severe CRS symptoms [24] and seem to play a key role in CRS pathophysiology, as they are higher in patients with CRS than in patients without [25‐28]. To date, there is no evidence that T‑cells or CAR‑T cells are a significant source of IL‑6 production [29, 30].

The leading symptom is fever, defined as ≥ 38.0 °C, and is required for a diagnosis of CRS [10]. Other nonspecific symptoms, including malaise, myalgia, fatigue, gastrointestinal complaints (nausea, vomiting, diarrhea), tachycardia, and rash, may also be present [9, 16, 17, 31]. The CRS may be self-limiting and can resolve with supportive care alone or may become life-threatening with capillary leak leading to pulmonary edema, hypotension, multiorgan failure, and circulatory collapse [9, 20], see also Table 1.

The ICANS was reported to become manifest in around 40% of CAR‑T cell recipients [32]. The onset of neurotoxicity typically occurs after the start of CRS, and sometimes even after CRS has completely resolved [18]. Typically, ICANS becomes clinically manifest within 4–10 days following CAR‑T cell infusion [3, 4, 20].

The mechanisms underlying CAR‑T cell-related neurotoxicity are not yet fully understood but disruption of the brain-blood barrier and cerebral edema via cytokine release by CAR‑T seem to be key features of ICANS [3, 18]. In up to 95% of patients, CAR‑T cells could be detected in the cerebrospinal fluid (CSF); however, the numbers did not correlate with the severity of ICANS as they could also be found in patients without neurological pathology [18, 33].

Patients with ICANS often develop a characteristic sequence of neurologic symptoms [10, 31], with tremor, dysgraphia, mild expressive aphasia, apraxia and impaired attention in the initial phase. Particularly, expressive aphasia evolving over a period of hours to global aphasia has been reported as a specific symptom [18]. This characteristic finding of an awake patient who is mute and unable to follow commands distinguishes ICANS from other causes of encephalopathy [31]. Furthermore, neurotoxicity can proceed to diffuse cerebral edema with subclinical or clinical seizures [10].

For the assessment and grading of CAR-related encephalopathy, the so-called immune effector cell-associated encephalopathy (ICE) score has been developed [10]. The latter score has recently replaced the CARTOX-10, both scores incorporate key elements of the mini-mental state examination and evaluate alterations in speech, orientation, handwriting, and concentration (Table 1; [10]).

Due to the similarity of symptoms and the immunosuppressed state of the patient it is crucial to exclude sepsis and treat infections appropriately. In a recent study on outcomes in critically ill CAR T recipients, sepsis was one of the main reasons for ICU admission [34]. Sepsis-related encephalopathy and meningitis/encephalitis can mimic ICANS. Moreover, severe CRS has been associated with a higher infection risk [35]. The reason for this association is unclear: high cytokine levels, immunosuppressive therapies, aggressive supportive care, and intensive care unit (ICU) management might play a role. Tumor lysis syndrome can usually be distinguished by typical laboratory findings, such as hyperuricemia, hyperkalemia, hypocalcemia, and hyperphosphatemia [36]; however, tumor lysis syndrome and CRS may occur coincidentally [37]. Furthermore, the progression of the underlying malignancy may cause tumor-associated fever and other clinical, metabolic, and imaging abnormalities that resemble those of CRS. CRS is reminiscent of macrophage activation syndrome (MAS) as well as hemophagocytic lymphohistiocytosis (HLH). Both represent syndromes with dysregulated immune response resulting in a severe cytokine storm, hence laboratory findings and the cytokine profile are closely related between MAS/HLH and severe CRS [38]. Thus, MAS/HLH might be regarded as consequence of CRS and CAR‑T cells acting as a trigger for subsequent development of HLH/MAS [39]. In addition, fungal infections as well as fulminant relapses of the underlying disease might be triggers for HLH/MAS [40], which is why consistent and repeated investigation are important once a diagnosis of HLH following CAR‑T therapy has been established.

Hypersensitivity reactions may appear after CAR T infusions and typically present with rash and urticaria, fever, dyspnea, hypotension, and gastrointestinal symptoms and eventually cardiorespiratory failure. Considering ICANS, important differential diagnoses are intracranial bleeding (especially when thrombocytopenia is present) or stroke. ICANS can result in epileptic seizures, which have to be identified in an electroencephalogram (EEG), especially when nonconvulsive.

In general, patients with higher (≥ 3) grade of toxicity (see also Table 1) should be managed on the ICU [9, 10, 15, 16, 43]. Thus, patients requiring one or more organ support or have a reduced level of consciousness fulfil the criteria for ICU admission [10, 16]; however, a recently published survey evaluating ICU management of CAR‑T cell-associated toxicities revealed that a majority of ICU admitted patients presented with CRS grade 1–2 (73%) and ICANS grade 2 (81%) [44]. In this survey, reasons for admitting lower grade toxicities were concerns for later deterioration, need for further interventions, concerns for evolving noncardiogenic pulmonary edema, or risk for rapid deterioration due to large tumor burden [10]. The CARTTAS trial investigating outcomes in patients treated with CAR‑T cells revealed that about 30% of the patients required admission to ICU, all for CRS, ICANS, or sepsis [34].

Supportive management of organ dysfunction or failure follows respective standard intensive care guidelines [11, 31]. The CAR-ICU survey has shown that management practices are very similar amongst participating units [44]. For the fluid management, most units use repetitive fluid bolus of 4 ml/kg BW, and fluid responsiveness was assessed with noninvasive modes (stroke volume variation, cardiac output, ultrasound guided). Early experience has shown that treating persistent hypotension in CRS with overt fluid management was inferior to early vasopressors use [10]. First line vasopressor in most units is noradrenaline, followed by vasopressin and epinephrine [44]. For patients with respiratory failure, most units perform a noninvasive ventilation trial before intubation [44]. In patients with prolonged severe CRS (persisting for > 72 h without response to intervention), a cardiac assessment, including cardiac biomarkers (e.g. troponin, NT-proBNP/BNP) or the performance of a echocardiography, is recommended [21]. For patients with neurotoxicity, along with neuroprotective measurements, more invasive intracranial pressure monitoring and enhanced neuroprotective treatment (hypertonic saline, mannitol, pharmacological coma) might be necessary [9, 15, 45, 46]. Nonconvulsive and convulsive status epilepticus should be managed with benzodiazepines and additional antiepileptic drugs, preferably levetiracetam, followed by phenobarbital [9]. As sepsis at ICU admission might be an important determinant of mortality in this patient population, particularly when they are neutropenic, screening for infections and commencing broad-band antibiotics has to be considered [34].

Corticosteroids are immunosuppressive and are effective in the management of CRS and ICANS [11, 16, 47]. Intravenous corticosteroids are the first-line therapy for patients with ICANS ≥ grade 2 [18], while in CRS they are used for second-line in case of refractory symptoms. Recent recommendations even suggested to add steroid in cases of severe CRS not responding to first dose of tocilizumab [21]; however, the evidence for this is not sound and therefore needs to be considered individually In both CRS and ICANS, methylprednisolone (2 mg/kg and day) or dexamethasone (0.5 mg/kg, maximum 10 mg) are commonly used steroids. To avoid jeopardizing CAR‑T cell function, the initial recommendation of steroid use was limited to patients with CRS refractory to anti-IL‑6 therapy or patients with grade 3–4 CRS toxicities [9]. Today, however, this concern turns out to be unjustified [46, 48‐50]. Once CRS symptoms are improving, steroids should be gradually tapered off [21].

Tocilizumab, an IL-6R antagonist, represents the first-line immunosuppressive therapy of CRS [16]. It binds both the soluble and the cell-associated IL‑6 receptor. In several studies, tocilizumab has proven to be effective for severe or life-threatening CRS, and usually patients with CRS rapidly respond to tocilizumab—fever and hypotension often resolve within a few hours [51, 52]; however, considerations have been given to use tocilizumab pre-emptively or even as prophylaxis, as blocking IL‑6 with tocilizumab neither significantly compromised therapeutic efficacy of CAR‑T cells, nor did it negatively affect prognosis of the CAR‑T cell recipients [3, 9, 48, 53]. For patients with isolated ICANS, tocilizumab was shown to be ineffective and should only be administered in patients with concurrent CRS [18, 30, 32]. This might be due to the fact that tocilizumab does not cross the blood-brain barrier [16]; however, IL‑6 is likely involved in the pathogenesis of CAR T-related neurotoxicity and levels of IL‑6 have shown to rise transiently following tocilizumab administration, which might lead to an aggravation of neurologic symptoms [16].

Siltuximab is a direct IL‑6 antagonist and has similar effects as tocilizumab. Siltuximab might have a favorable outcome in the case of passive diffusion of IL‑6 into the CNS [9]; however, a randomized prospective comparison between siltuximab and tocilizumab is still missing [9] and siltuximab has not yet been approved for this indication by US and European drug agencies (FDA and EMA).

For therapy refractory CRS, the addition of third line therapies has been suggested [21]; however, these therapies are currently considered investigational. Whereas IL‑6 blockade prevents mainly CRS, the additional IL‑1 blockade achieved with the use of anakinra could potentially prevent both CRS and ICANS [30]. A recent report suggested that anakinra could be a potential steroid-sparing strategy for the treatment of CAR T‑cell therapy-associated toxicities, mainly ICANS. Several clinical trials investigating its early and/or prophylactic use are ongoing [54].