Management of the Critically Ill Adult Chimeric Antigen Receptor (CAR)-T Cell Treated Patient: A Critical Care Perspective

Abstract

Objective:

Chimeric antigen receptor (CAR)-T cell therapy, a type of immune effector therapy for cancer, has demonstrated encouraging results in clinical trials for the treatment of patients with refractory hematological malignancies. Nevertheless, there are toxicities specific to these treatments that, if not recognized and treated appropriately, can lead to multi-organ failure and death. This article is a comprehensive review of the available literature and provides, from a critical care perspective, recommendations by experienced intensivists in the care of critically ill adult CAR-T cell patients.

Data Sources:

Pubmed and Medline search of articles published from 2006 to date.

Study selection:

Clinical studies, reviews or guidelines were selected and reviewed by the authors.

Data extraction:

N/A.

Data synthesis:

N/A.

Conclusions:

Until modifications in CAR-T cell therapy decrease their toxicities, the intensivist will play a leading role in the management of critically ill CAR-T cell patients. As this novel immunotherapeutic approach becomes widely available, all critical care clinicians need to be familiar with the recognition and management of complications associated with this treatment.

Introduction

Chimeric antigen receptor (CAR)-T cell therapy, a type of Immune effector cell therapy, has demonstrated promising results in clinical trials of select hematological malignancies^1–4. In refractory B-cell precursor acute lymphoblastic leukemia(ALL) and large B-cell lymphomas(LBCL), complete remission rates as high as 50–90% are reported^4–8. As a consequence of these impressive responses, the number of CAR-T clinical trials has increased dramatically in the past 5 years and was recently approved by the US Food and Drug Administration(FDA) for the treatment of pediatric ALL and adult LBCL^9–12.

CAR-T cells are autologous or allogeneic T-cells modified to express a single chain antibody that recognizes a specific tumor antigen^9,10. Once the cells are ready, the patient receives fludarabine and/or cyclophosphamide, followed by CAR-T infusion. The most investigated cells are CD19-CARs, which recognize the CD19 antigen expressed in B-cell related hematological malignancies. New cell constructs and protocols are being created to target different malignancies, as well as to reduce treatment related toxicities¹⁰.

Although the results of clinical trials have been promising, CAR-T cell therapies have specific toxicities that if not recognized and treated, can lead to multi-organ failure and death. Understanding the spectrum and presentation of these toxicities can help clinicians recognize them and initiate timely and appropriate treatment. The purpose of this review article is to highlight, from a critical care perspective, the two most common toxicities associated with CAR-T cell therapy: cytokine release syndrome(CRS) and neurotoxicity. This review is based on a systematic search of currently available literature, and reflects the expert opinion of members of the Oncological Critical Care Research Network with extensive experience in the care of critically ill adult CAR-T cell patients. As CAR-T cell treatment becomes widely available, it will be of utmost importance for all intensivists, to be familiar with the recognition and management of complications associated to this treatment.

Clinical Presentation

Cytokine Release Syndrome

The prevalence of CRS varies depending on the malignancy and CAR T cell construct. Recent data suggest that CRS occurs in 60–93% of patients, with 13–14% exhibiting ≥Grade3^4,6–8. CRS occurs when antigen recognition by CAR-T cells leads to activation, proliferation, and cytokine release that further activates T-cells, B-cells, natural-killers and macrophages¹³. This exaggerated inflammatory response can be severe and cause multiple organ failure. Patients with CRS have elevated plasma levels of C-reactive protein(CRP), ferritin, interferon-gamma(IFN-γ), interleukin(IL)-6, IL-10, IL-2 and tumor necrosis factor-alpha(TNF-α)^3,13–16. Higher CRP and pro-inflammatory cytokines correlate with increased severity of CRS^15,17,18. Among patients post-CD19 CAR treatment, elevated IFN-γ and TNF-α levels were associated with higher Sequential Organ Failure Assessment(SOFA) scores³. IFN-γ, monocyte chemotactic protein-1(MCP-1) and soluble glycoprotein 130(sgp130), a mediator for IL-6 signaling, may predict severity of CRS prior to symptom onset^6,15. CRP has been recommended as a marker for CRS diagnosis since it is widely available^16,19. However, elevation of CRP levels is non-specific and its predictive value prior to symptom onset remains unclear.

CRS symptoms usually appear within 5–7 days of CAR-T cell infusion and as late as 10–14 days depending upon the CAR-T construct^6–8. The most common symptoms are tachycardia, fever, hypotension and hypoxemia^4,16,20. Mild CRS manifests with tachycardia, fever, chills, myalgia and headache^3,7,16,21,22. As the syndrome evolves, different organ systems are affected and can progress to multi-organ failure. Cardiovascular toxicity in CRS can present as tachycardia, arrhythmias, heart blocks, or hypertension which devolves to hypotension and vasodilatory and/or cardiogenic shock^3,21,23. A cardiomyopathy with decreased ejection fraction can also be present^16,21,23. Pulmonary capillary leak syndrome and non-cardiogenic pulmonary edema can lead to respiratory insufficiency and progress to acute respiratory distress syndrome(ARDS)^8,16,21. Acute kidney injury, hepatic failure, and disseminated intravascular coagulopathy(DIC) may also occur^6,8,22. Skin lesions, while rare, can be found⁸. Table. 1 summarizes the presentation and grading of CRS.

Table 1.

Cytokine Release Syndrome Grading and Treatment.^*

	Grade 1	Grade 2	Grade 3	Grade 4
Constitutional	Fever, malaise, fatigue, myalgia, arthralgia	Fever, malaise, fatigue, myalgia, arthralgia	Fever, malaise, fatigue, myalgia, arthralgia	Fever, malaise, fatigue, myalgia, arthralgia
Respiratory		Hypoxemia requiring <40% FiO2 to maintain O2 saturation >92%	Hypoxemia requiring >40% FiO2 (high-flow nasal cannula or non-invasive ventilation) to maintain O2 saturation >92%	Hypoxemia requiring mechanical ventilation
Cardiac	Tachycardia	• Stable dysrhythmias • Hypotension/shock: responsive to fluid resuscitation or requiring low dose vasopressors for <24 hours • Cardiomyopathy: EF>40% or 10% drop in EF from baseline	• Unstable dysrhythmias • Shock: requiring high dose vasopressors or multiple vasopressors, low dose vasopressors for >24 hours or showing signs of hypoperfusion independent of dose. • Cardiomyopathy: EF20–39% or >10% drop in EF from baseline	• Life threatening dysrhythmias • Shock: refractory requiring multiple vasopressors • Cardiomyopathy: EF<20%
Gastrointestinal °	Nausea, vomiting, diarrhea	Nausea, vomiting, diarrhea	Nausea, vomiting, diarrhea	Nausea, vomiting, diarrhea
Hepatic	AST/ALT<3normal limits (nl), T Bili <1.5 normal limits (nl)	AST/ALT 3–5 nl, T Bili 1.5–3 nl	AST/ALT 5–20 nl, T Bili 3–10 nl	AST/ALT >20 nl, T Bili >10 nl
Renal	Creatinine <2 x baseline with normal urine output	Creatinine 2–3 x baseline with normal urine output	Creatinine >3 x baseline with oliguria	Anuria and indications for dialysis
Hematologic		Coagulopathy without bleeding	Coagulopathy with bleeding	Coagulopathy with life-threatening bleeding
Electrolytes	Low PO4, Mg, Na, K	Low PO4, Mg, Na, K	Low PO4, Mg, Na, K	Low PO4, Mg, Na, K
Treatment	Monitoring and supportive care **	Tocilizumab or consider Siltuximab Ɨ	Tocilizumab or Siltuximab if not dosed yet. Corticosteroids: dexamethasone10 mg IV q 6hr or equivalent dosing #	Tocilizumab or Siltuximab if not dosed yet. Corticosteroids equivalent to pulse dosing (Methylprednisolone1 gm/day) #

^*Based on Common Terminology Criteria for Adverse Events (CTCAE) guidelines and experience at our institutions.

^°Severity as per CTCAE grading

^ƗTocilizumab dose is 8 mg/kg dosed every 6 hours until symptoms resolve, maximum of 3 doses. If no response after 2–3 doses, consider refractory to tocilizumab. Siltuximab dose is 11mg/kg, single dose.

^**Supportive care: Treatment with anti-pyretic, hydration, microbiologic cultures and imaging to rule out infectious cause of fevers, empiric antibiotics, monitor for any arrhythmias, replacement of electrolytes and continuous monitoring.

^#recommended dose of corticosteroids is as per our institutional practices and can vary within protocols. There is no data available to suggest one type of glucocorticoid is superior to another^4,5,21.

Neurotoxicity

CAR-T neurotoxicity presents in 40–64% of patients and 28% of these cases can be ≥Grade3^4,7,24. The presentation is biphasic, with the first phase occurring within 7 days of infusion, and the second 10 days after or once CRS symptoms have resolved. Mild neurotoxicity presents with confusion, lack of attention, “distant” gaze, lip-smacking, tremors, mild aphasia and dysgraphia^4,5,24. As the symptoms progress, aphasia becomes global, patients are agitated or obtunded, seizures and motor deficits can develop^5,7,24. Patients who develop convulsive and non-convulsive seizures can progress to status epilepticus. Irreversible cerebral edema, while not common, has been described^24–26. Neelapu et al. created an evaluation tool specific for CAR-T patients to recognize early signs of neurotoxicity⁵. Patients can have rapid progression and deterioration despite treatment, therefore close monitoring and early involvement of the critical care team is necessary. The clinical presentation and grading of neurotoxicity are described in Table. 2.

Table 2.

Neurotoxicity Grading and Treatment^*.

	Grade 1	Grade 2	Grade 3	Grade 4
Disorientation°	Mild	Moderate	Severe	Severe
Dysgraphia°	Present	Present	limited assessment	limited assessment
Aphasia°	Word finding difficulty	Moderate aphasia	Severe global aphasia	Severe global aphasia
Dyskinesia	Mild tremor	Intermittent facial twitching, tremors or myoclonus	Continuous facial twitching and myoclonus	Continuous facial twitching and myoclonus requiring airway protection.
Attention and consciousness°	Inattentive or mild delirium	Lethargic or moderate delirium	Obtundation/stupor or severe delirium	Coma or severe delirium requiring airway protection.
Seizure	_______	_______	Partial seizures, non-convulsive or convulsive seizures	Convulsive or non-convulsive status epilepticus.
Cerebral Edema	_______	_______	Grade 1–2 papilledema and associated headache, nausea and vomiting	Grade 3–5 cerebral edema, or clinical signs of herniation such as Cushing’s triad, posturing, cranial nerve VI palsy and diabetes insipidus.
Motor strength	5/5	5/5	3–4/5	0–2/5
Supportive care	• Imaging (CT or MRI brain) and EEG • Frequent neurologic exam • Consider seizure prophylaxis • Consider and treat other causes of encephalopathy as needed • Lumbar puncture if no contraindication	• Imaging (CT brain or MRI) and EEG • Frequent neurologic exam • Consider seizure prophylaxis • Consider and treat other causes of encephalopathy as needed • Lumbar puncture if no contraindication	• Imaging (CT or MRI brain) and EEG • Frequent neurologic exam • Treatment of seizures including benzodiazepines, levetiracetam or other anti-epileptic drugs • Consider and treat other causes of encephalopathy as needed • Lumbar puncture if no contraindication	• Imaging (CT or MRI brain) and continuous EEG • Frequent neurologic exam • Management of status epilepticus as per institutional guidelines • Consider and treat other causes of encephalopathy as needed
Treatment	• Supportive care and close monitoring for progression • Consider Tocilizumab if associated to CRS symptoms	• Supportive care and close monitoring for progression • Consider Tocilizumab if associated to CRS symptoms	• Corticosteroids: Dexamethasone 10 mg IV q 6hr or equivalent to methylprednisolone** • Consider Tocilizumab if associated to CRS symptoms	• Corticosteroids: Methylprednisolone IV 1gm/day** • Consider Tocilizumab if associated to CRS symptoms

^*Based on Common Terminology criteria for Adverse Events (CTCAE) guidelines and experience at our institutions.

^°Consider diagnostic tools to grade severity such as those recommended by Neelapu et. al⁵

^**Recommended dose of corticocorticosteroids is as per our institutional practices and it can vary within protocols. There is no data available to suggest one type of glucocorticoid is superior to another^4,5,8,21,24.

There is no consensus on the underlying pathophysiology that causes this neurotoxicity. Data suggest symptoms result from cytokine mediated central nervous system(CNS) injury as elevated IL-6, IFN-γ and TNF-α levels in serum and cerebrospinal fluid(CSF) are associated to worse symptoms^21,24,27,28. Another hypothesis is trafficking of CARs into the brain due to increased blood brain barrier permeability; CARs have been found in the CSF of patients with neurotoxicity, and data suggest an association between CAR expansion and neurotoxicity^{4,7,18,19,24,27}.

Differential Diagnoses

Given the broad range of conditions that can present in a similar fashion to CRS and neurotoxicity in this population, the intensivist must concurrently treat and rule out alternative diagnoses common in the oncological patient. Given that sepsis is a common cause of shock and respiratory failure in this population, it is prudent that the intensivist treat as such until an infectious etiology is ruled out. Table. 3 summarizes the differential diagnoses to be considered^29–33. However, it is important not to delay treatment of CRS and neurotoxicity when considering and treating other potential diagnoses.

Table 3.

Differential Diagnoses of CAR-T Related Toxicities.

Clinical Presentation	Diagnoses	Comments
Respiratory failure29,30,31	• Pneumonia • Diffuse alveolar hemorrhage • Cardiogenic pulmonary edema • “On-target, off-tumor” toxicity	• Empiric antimicrobial treatment and supportive care. • “On-target, off-tumor” has been described in CARs. Normal tissues express the tumor antigen that CARs are designed to recognize, causing direct tissue injury. Reports include gastrointestinal tract, liver, lung and cardiac toxicity.44
Shock29,32	• Neutropenic sepsis and septic shock • Cardiogenic shock (acute coronary syndrome, cardiac tamponade, “on-target, off-tumor”) • Hemorrhagic shock	• Empiric antibiotic treatment and supportive care of the neutropenic septic patient is recommended • Evaluate cardiac function and for signs of overt bleeding
Encephalopathy32	• Intracranial hemorrhage or ischemic stroke • Medication induced (eg: opiates,antibiotics, anxiolytics, anti-psychotics) • Septic encephalopathy • Multi-organ failure • Meningitis	• Neurotoxicity associated with CAR has specific symptoms such as dysgraphia, inattentiveness, aphasia and lip smacking. Therefore neurological assessment should always include these specific signs for CAR-T toxicity
Liver failure5	• Medication induced • Hypoperfusion • Infectious hepatitis • Hemophagocytic lymphohistiocytosis • “On-target off tumor” toxicity • Portal vein thrombosis or veno-occlusive disease	• Diagnosis of HLH should require referral or consultation with a specialist as diagnosis can be challenging and the experience in this patient population is limited.
Acute renal failure32,33	• Medication induced • Tumor Lysis syndrome • Obstructive uropathy	• Monitoring and management of tumor lysis syndrome should not differ from any other oncological patient

Both neurotoxicity and CRS have a broad clinical presentation and defining specific criterion to diagnose them can be challenging. In the future, a combination of clinical presentation and serum cytokine levels will play a role in diagnosis and prevention. Recent data suggest fever≥38.9°C and elevated serum MCP-1 are highly sensitive and specific for predicting CRS≥4⁶. Similarly, fever≥38.9C, elevated serum IL-6 and MCP-1 are highly sensitive and specific in predicting Grade≥4 neurotoxicity²⁴. Further studies are required to assess the applicability of this criteria prospectively, in different malignancies and CAR-T cell products. At our institutions, we collect daily serum cytokines from these patients; however the costs and slow turnaround of these results have been a constraining factor in their day-to-day applicability.

Treatment of Critically Ill Adult CAR-T Cell Patients

Early involvement of the intensivist in the care of CAR-T patients is of extreme importance as deterioration of these patients is rapid and severe. Rapid Response or Critical Care outreach teams can be useful to assist with monitoring, stabilization and rapid ICU admission. While the care of these patients is multidisciplinary, close attention and support of hemodynamic, respiratory, and multi-organ failure, is steered by the intensivist. Risk factors for early decompensation or severity of toxicity should be discussed between the oncologist and intensivist to assist triage and management(Table. 4).

Table 4.

Risk factors for severity of Cytokine Release Syndrome and Neurotoxicity.

Risk Factor	Comments
Tumor Burden	Higher activation and proliferation of CAR-T cells is observed with high tumor burden leading to an exaggerated inflammatory response and higher toxicity4,5,9,13,16.
Cell dosing	A higher dose of cells can lead to increased cytokine release, and therefore greater toxicities once these cells are activated18,24.
Comorbidities	Higher number of comorbidities has been associated with increased risk and severity of CRS17.
Age	Although there are no definitive studies, older patients may have a lower tolerance to CRS and neurotoxicity4,17.
Chemotherapy regimen	The chemotherapy regimen prior to cell infusion is important to ensure replication and survival of CAR T cells. A regimen that leads to severe immunosuppression and therefore an exaggerated proliferation of CAR T cells can result in increased toxicity 9,18,24,.
Timing of onset of symptoms	Early onset of symptoms is associated with worse toxicity and should lead to more aggressive monitoring and treatment5,24.
Cell product	Variabilities of the cell construct between protocols can potentially have an effect on cell proliferation and activity. Some factors include the costimulatory domain used, vector utilized, time in culture and type of culture9.

The two mainstays of treatment of CAR-T patients are: 1)anti-IL-6 monoclonal antibodies; 2)corticosteroids. Without initiation of these therapies, supportive ICU care will be insufficient. Tables 1 and 2 describe the indications and dosage of these treatments according to the grade of CRS and neurotoxicity based on published literature and experience at our institutions^4,5,16,22. A challenge in managing critically ill CAR-T patients originates from lack of data coming from randomized studies determining the choice, dose, length of corticosteroids, and the role of multiple doses of tocilizumab in severe toxicities. The approach at our institutions includes a careful and close evaluation of the patient’s clinical response to treatment to guide further interventions. Our algorithm(Figure. 1), which is based on our experience and available literature, is a guide for the assessment, monitoring, triaging and treatment of patients with CAR-T cell related toxicities.

Figure 1.

Assessment, Monitoring and Management of CRS and Neurotoxicity

Tocilizumab:

Tocilizumab binds to soluble and membrane bound IL-6 receptors, resolving mild CRS symptoms without affecting the replication of CARs²². Tocilizumab should be used in patients with grade ≥2CRS^4,5,16. In patients with neurotoxicity alone, its effectiveness is questionable and we do not recommend its use on neurotoxicity unless it’s associated to CRS^16,24. Toxicities include soft tissue infections, abnormal liver function tests and hypercholesterolemia³⁴.

Siltuximab

Siltuximab, another monoclonal antibody, binds to circulating IL-6. While there are no data to support the use of siltuximab in patients with toxicities post-CAR-T cells, we consider its use in patients with refractory CRS. The rationale for siltuximab is based on the following observations:1)patients can be refractory to tocilizumab after multiple doses, suggesting that despite blockade of IL-6 receptors there is a persistent inflammatory response; 2)data suggest that after administration of tocilizumab, IL-6 levels in serum can either increase or stay the same^35,36. Although we feel there is biochemical rationale for siltuximab, data supporting its efficacy are lacking. Toxicities reported with siltuximab include rash, hyperuricemia and increased liver function tests³⁷.

Corticosteroids

Corticosteroids play a role in the treatment of grade≥3 CRS, grade 2 CRS refractory to anti-IL-6 treatment and neurotoxicity. In addition to blunting the inflammatory cascade, corticosteroids suppress the replication of CAR-T cells^13,22. In severe cases(Grade3–4) corticosteroids should be used immediately^4–6,16,24. It is important that the initiation, dose and duration of therapy be reevaluated depending on the patients’ response to treatment as there is no standardized protocol for their use. While corticosteroids are reserved for more severe presentations of CRS, we have anecdotally observed that patients with neurotoxicity respond better to corticosteroids, even single doses, than tocilizumab alone. Despite initial concerns of corticosteroids suppressing CAR-T cell replication, short courses do not appear to affect tumor response rates or long term clinical remission^5,7,28. Regardless, corticosteroid use should be discussed carefully with the oncologist.

Specific ICU Considerations

Cardiovascular toxicity in CRS

CRS with vasodilatory shock is a common reason for ICU admission of CAR-T patients. While guidelines describe a dose of vasopressor agents to determine grading, clinical judgement plays an important role in treatment decisions in conjunction with vasopressor dosing^5,16. Signs of end-organ hypo-perfusion, increasing lactate, poor lactate clearance, or rapid increase in vasopressor requirement, should lead to consideration of early use of corticosteroids. While shock usually responds to tocilizumab and corticosteroids, some patients develop refractory shock³⁸.

Early recognition and adequate management of patients with CRS related cardiomyopathy is important given the high associated mortality rate^3,21. Electrocardiographic changes and elevation of cardiac troponins should be monitored as they suggest higher severity of CRS and not necessarily an acute coronary syndrome^3,4,21. The most common arrhythmias associated with CRS are sinus tachycardia and atrial fibrillation^8,16,21. QTc prolongation and fatal arrhythmias have been described^17,18.

Ruling out infectious causes of fever and following guidelines for septic shock is recommended^39,40. Diligent physical examination, obtaining blood, sputum and urine cultures, and commencing empiric broad spectrum antibiotics should be initiated in these patients even if CRS is suspected. An immediate echocardiogram to assess ejection fraction and rule out other causes of shock is of extreme importance. Interventions to assess and optimize fluid status and cardiac output should be considered.

Neurotoxicity with seizures and status epilepticus

Non-convulsive seizures are associated with CAR-related neurotoxicity and can progress to non-convulsive status epilepticus(NCSE) in up to 10% of treated patients⁵. Early recognition and treatment of seizures and NCSE is essential, therefore an EEG should be performed in all patients with signs of neurotoxicity. While preference of antiepileptic drug(AED) varies, it is imperative to have clear institutional guidelines for management of these patients. Due to the high prevalence of seizures, two of our institutions have initiated seizure prophylaxis with levetiracetam in all patients being treated with CAR-T cells. The use of levetiracetam is preferred due to its favorable drug-drug interaction and low toxicity⁵. In our experience, patients with partial seizures usually respond to benzodiazepines, a second line AED and corticosteroids. A quick steroid taper can be considered if the seizures are easily controlled and mental status improves. However, in patients who develop NCSE or are not improving after an initial trial of corticosteroids, higher doses should be initiated(Table. 2). All patients with seizures post CAR-T treatment should be admitted to the ICU as these patients have the potential to deteriorate rapidly and progress to status epilepticus, and in some rare cases cerebral edema^23,25,26. Continuous video EEG is recommended to help in the management of patients with NCSE. Burst suppression with midazolam, propofol or phenobarbital might be necessary and the choice requires consideration of hemodynamics and concomitant organ failure.

Neurotoxicity with cerebral edema

Five cases of cerebral edema were first documented in ALL patients treated with CD19-CARs²⁵. Their presentation was acute, with fulminant cerebral edema within 24 hours which was attributed to the fludarabine used for conditioning^13,14. However, two other patients treated without fludarabine and a patient with refractory non-Hodgkin lymphoma, treated with a different CAR-T construct, also developed cerebral edema^24,25. While no other cases are reported since, it is important for the intensivist to consider this fatal complication. The pathophysiology of the cerebral edema is still unclear, but with our current knowledge of toxicities related to CARs, it would be difficult to ignore the possibility of an uncontrolled inflammatory response in the brain and breakdown of the blood brain barrier²⁴.

Monitoring for signs of elevated intracranial pressure should be performed on patients with Grade≥2 encephalopathy. Non-invasive methods such as fundoscopy, transcranial Doppler and ocular ultrasound to measure optic nerve sheath diameter can be considered. If there is evidence of significant neurotoxicity associated with elevated ICP, corticosteroids should be initiated; if the patient does not improve or deteriorates, a pulse dose should be considered(Table. 2)⁵. The role of brain imaging with CT scan is limited as parenchymal changes were only evident after clinical signs of herniation and brain death presented. However, CT scan is still recommended to rule out other neurological emergencies such as an ischemic stroke or intracerebral hemorrhage. Specific flair changes in brain MRI have been observed in neurotoxicity, and these findings may be useful in the future to monitor and guide treatment, however data is still scarce^5,24. If patients need to be intubated for airway protection, it is important to avoid induction agents that can cause hypotension or elevated ICP. Other basic considerations include head elevation, aggressive treatment of fevers and seizures, and avoiding aggressive stimulation. Blood pressure management to maintain adequate cerebral perfusion pressure and treatment with hypertonic saline, especially in patients with hyponatremia, should be a priority. Due to the prevalence of coagulopathy and severe thrombocytopenia in these patients, our experience with invasive ICP monitoring is limited. However, if a patient is a candidate for an external ventricular device, it can be considered. Tapping of Ommaya reservoirs could be used for reading of intracranial pressure, however underestimation of ICP can occur due to the technique used for their access.

Additional Toxicities

Respiratory insufficiency due to non-cardiogenic pulmonary edema in these patients is acute, presenting in a majority after fluid resuscitation and progressing rapidly to ARDS and respiratory failure⁴¹. We recommend that any patient with rapid progression of FiO2 requirements or pulmonary infiltrates on chest x-ray, those requiring FiO2>40% (via high flow nasal cannula) or those on bilevel positive airway pressure be admitted to the ICU for careful monitoring. Early antibiotics, intubation, mechanical ventilation, and bronchoalveolar lavage to evaluate for infection or alveolar hemorrhage should be considered. Lung-protective ventilator strategies with low tidal volume ventilation should be used⁴².

Electrolyte disturbances such as hyponatremia, hypokalemia, hypophosphatemia and hypomagnesemia are present in patients post CARs and should be treated aggressively in the setting of neurotoxicity and cardiotoxicity^3,8,18,23. Renal failure usually occurs in the presence of multi-organ failure and not as a symptom of CRS alone. Diffuse cutaneous manifestations such as macules and papules may occur and are reversed quickly with corticosteroids⁸. If the presentation is extreme, patients may be managed in line with burn care protocols.

Coagulopathy, independent of liver dysfunction, may be present and has been associated with bleeding, therefore careful monitoring of fibrinogen and coagulation profile should be performed^6,43. Recent data suggest that severe neurotoxicity is associated with DIC²⁴.

Hemophagocytic Lymphohistiocytosis (HLH), was described in one patient treated with CD19 CARs²⁸. The exaggerated immune response is similar in both CRS and HLH, making an already challenging diagnosis, to be more so in patients who have underlying CRS. HLH, regardless of concomitant CRS, portends a poor prognosis and expert consultation is suggested. HLH in CAR-T patients can be considered in patients with CRS>Grade3 with liver, renal and pulmonary toxicity, ferritin levels>10.000ng/ml and hemophagocytosis on organ biopsy ⁵.

B-cell aplasia is usually a delayed complication post CAR-T therapy and has been described from 10 weeks to 3 years post-infusion⁹. This complication can be monitored with immunoglobulin-G levels and managed with monthly immunoglobulin infusions to decrease risk of opportunistic infections.

Future Research

Areas of future research should include: 1)use of serum cytokines and other inflammatory markers as tools to assist with diagnosis, treatment or recognize high risk patients; 2)further understanding of the pathophysiology of neurotoxicity to optimize management of this toxicity and understand how CSF studies and imaging could be used for its identification; 3)use of other strategies to suppress CARs in the setting of severe toxicities such as suicide genes that trigger CAR-T cell apoptosis and resolve the immune mediated toxicity^{9,15,41,44,45}. This important safety switch is in the early stages of clinical trials and their efficacy is still being investigated^41,45.

Conclusions

CAR-T cell therapy is a promising treatment for an increasing number of refractory malignancies^{1–4,7,8,14,19,43}. However, the morbidity associated with this novel therapy is significant, with many patients requiring ICU admission. Early recognition, grading and treatment is the cornerstone of management of CRS and neurotoxicity. Until modifications in CAR-T cell therapy can decrease these toxicities, the intensivist will play a leading role in the management and support of CAR-T cell patients. As with many of the oncological patients, frequent communication between the ICU team, oncologists and other consultants is essential to providing high quality care to this complex population. All institutions participating in CAR-T cell therapy should be familiar with their complications, have protocols in place and a streamlined process of ICU admission for patients who are deteriorating. Our practice recommendations should serve as a tool for all clinicians caring for a critically ill adult CAR-T patient.