Special Considerations for ICU Management of Patients Receiving CAR Therapy

Outreach, Monitoring, and ICU Admission Criteria

A successful CAR T-cell program requires multidisciplinary and interprofessional collaboration. At inception of a program, ICU collaboration is imperative to develop ICU admission criteria, assist with monitoring of high-risk patients, and create guidelines for the management and care of severe toxicities. ICU admission criteria may vary among institutions and even within institutions based upon staffing and bed availability. In general, patients with > grade 3 CRS or neurological toxicity (ICANS) should be admitted to the ICU. Other considerations for ICU admission include patients with rapid progression of pulmonary infiltrates on imaging and/or rapid progression of hypoxemia, hypotension especially when associated with elevated lactate levels, and signs of hypoperfusion (such as organ dysfunction and poor mental status) or rapidly progressing neurotoxicity. Risk factors for severe CRS and ICANS such as high tumor burden, higher CAR T-cell dose administration, high number of comorbidities, and early onset of symptoms have been described. The presence of one or more risk factors may prompt consideration of either close monitoring by the ICU team on the floors or early ICU admission. Variability in the frequency and severity of toxicity seen based on product used and patient characteristics make close and regular communication between the cell therapy and ICU teams imperative to mitigate the impact to ICU staffing and bed availability.

For CAR T-cell patients admitted to the ICU, close and frequent communication is needed between the ICU team, consultants, and the cell therapy team. Evaluation and treatment of patients with CRS and ICANS should not be static, especially among those with grade 3 and grade 4 toxicities. Frequent reevaluation of response to treatment should occur, with a timely response and escalation of care if no response is observed. Management algorithms and call escalation trees should be clearly delineated for staff. Different products may be associated with specific toxicity management protocols. For example, while agents directed at interleukin-6 (IL-6), such as tocilizumab, and corticosteroids are commonly used for severe toxicities associated with CAR T-cells, other products may use first-line administration of drugs that trigger specific off-switch receptors. In recent clinical trials, an inducible caspase 9 (iCasp9) “safety switch” allows for the removal of inappropriately activated CAR T-cells by administration of the small molecule drug AP1903, which causes dimerization and activation of iCasp9, leading to rapid induction of apoptosis in transduced cells. Coexpression on the CAR T-cell of a truncated protein recognized by clinically approved mAbs may also allow transduced T-cells to be eliminated by antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity after the administration of the relevant mAb, such as rituximab.

Aggressive support in this patient population is important. Despite the advanced stage of malignancy, severe toxicities are usually reversible, and patients achieve long-term survival and durable cancer remission. Considerations for ICU admission of CAR T-cell patients are summarized in Table 6.1 .

Shock and Other Cardiovascular Manifestations

Vasodilation and secondary hypotension may occur as a consequence of the exaggerated inflammatory process observed in CRS. Hypotension and shock are pillars of CRS, varying from grade 2 (hypotension that responds to fluid resuscitation) and grade 3–4 that is shock (hypotension requiring one to multiple vasopressors). Reports suggest that as many as 42% of patients with CRS will require vasopressors and ICU admission. Hypotension might not initially present with overt shock; more subtle clinical signs such as a need to decrease the dose of antihypertensives could serve as an early indicator. Knowing the patient's baseline blood pressure is important. A drop in a patient's blood pressure from baseline may be a better indicator, rather than choosing a specific value for a systolic blood pressure to define hypotension (e.g.,: <90 mmHg).

Guidelines recommend 20–30 mL/kg of fluid resuscitation for patients in vasodilatory shock secondary to sepsis. Shock due to CRS occurs as a vasodilatory response to cytokines and is associated with significant endothelial dysfunction and capillary leak. In this setting, careful resuscitation is paramount, as fluid overload can worsen the inflammatory response and lead to secondary organ damage and increased mortality (in particular, among younger children and infants). Assessment of intravascular fluid status using minimally invasive monitoring or targeted ultrasound should be considered to help guide fluid therapy in these patients.

If a patient continues to be hypotensive after two fluid boluses, use of vasopressors should not be delayed. While no specific vasopressors are recommended for this patient population, considerations such as ongoing arrhythmias and evidence of a cardiomyopathy with low cardiac output can help with the specific agents used. Data from other causes of vasodilatory shock, such as sepsis, could be extrapolated to this patient population. Norepinephrine can be considered as the vasopressor of choice, as it has shown to reduce the incidence of arrhythmias and mortality when compared with dopamine. Epinephrine could be useful in patients with low cardiac output from new onset cardiomyopathy, as it has inotropic effects; however, it is important to note that supraventricular tachycardia can be increased with its use. Adding noncatecholamine vasopressors such as vasopressin or angiotensin-2 agonists, especially in patients with refractory shock, can be considered. Signs of end-organ hypoperfusion, increasing lactate, poor lactate clearance, or rapid increase in vasopressor requirement should lead to consideration of early use of both tocilizumab and corticosteroids as the latter has been shown to be beneficial in patients with vasodilatory shock.

Cardiomyopathy with a depressed ejection fraction can be observed in patients with CRS, and up to 5% of them can develop cardiogenic shock. For patients with new onset cardiomyopathy, electrocardiographic changes and elevated troponins have been associated with increased mortality; therefore, early monitoring is recommended. Moreover, an electrocardiogram, echocardiogram and serum troponins can help rule out other causes of shock and decreased cardiac output such as cardiac tamponade, acute coronary syndrome, and myocarditis or pericarditis. Treatment with inotropes such as dobutamine and milrinone can be considered in patients with low cardiac output. In these cases, minimally invasive monitoring devices can be beneficial to evaluate response to inotropes and guide treatment. Arrhythmias have also been described during CRS, most commonly sinus tachycardia and atrial fibrillation, but QT prolongation and fatal arrhythmias have also been observed. Treatment for these arrhythmias should be supportive and no different than for any other critically ill patient. It is important to note that patients with significant cardiac risk could benefit from closer monitoring and telemetry postinfusion. Patients with Down syndrome, for example, should have an appropriate baseline cardiac evaluation to stratify their risk prior to CAR therapy, given their predisposition to cardiac abnormalities.

Lastly, CAR T-cell patients are at high risk of sepsis; therefore, following guidelines for neutropenic sepsis and septic shock is recommended while treating concomitantly for CRS. A careful physical examination, cultures, imaging, and initiation of broad-spectrum antibiotics should not be delayed in this patient population.

Besides the supportive care described above, specific treatment for CRS with therapies such as anti-IL-6 and anti-IL-1 agents and steroids should be initiated without delay in patients with hypotension and shock. In this patient population, the ICU clinician should monitor closely the patient's response to therapy, so treatment decisions and interventions are made in a timely manner.

Respiratory Failure

In some series, as much as 45% of patients with CAR T-cell–related complications will require mechanical ventilation, although the data are unclear if this is all related to pulmonary complications versus a need for endotracheal intubation in patients with severe neurotoxicity and altered mentation. Careful attribution of the need for intubation is important for delineating between true respiratory failure and the need for airway protection due to ICANS, with the latter not contributing to the grading of CRS as put forth by the recent ASTCT consensus manuscript.

In regard to respiratory complications, the ASTCT consensus grading has defined grade 2 CRS as requiring low-flow nasal canula or blow by oxygen supplementation; grade 3 CRS as hypoxemia that requires oxygen supplementation with high flow devices; and grade 4 as the need for noninvasive ventilation (such as bilevel positive airway pressure [BiPAP]) or invasive mechanical ventilation. When concurrent hypotension is present, thoughtful balance of fluid resuscitation with initiation of vasopressor support may avoid respiratory failure. We caution that for small infants, increasing oxygen supplementation even below a 2L threshold may signal worsening acuity. The overall trend in the need for oxygen supplementation should be considered carefully. The need for noninvasive ventilation (e.g., high-flow nasal cannula, bilevel positive airway pressure, continuous positive airway pressure) and invasive mechanical ventilation suggests very severe disease.

Respiratory failure in the patient post-CAR T-cell therapy may present with pleural effusions, noncardiogenic pulmonary edema, and cardiogenic pulmonary edema. When evaluating patients with hypoxemia, it is of great importance to consider if the hypoxemia is acute and related to CRS or if there are underlying chronic processes (e.g., malignant pleural effusions, progression of disease, pulmonary embolism, underlying chronic obstructive pulmonary disease) that require the patient to use oxygen supplementation. Therefore, as with hypotension, knowing the patients and their underlying comorbidities is of extreme importance. In patients requiring invasive mechanical ventilation, careful assessment of their airway prior to endotracheal intubation is important ( Table 6.2 ). For example, patients with Down syndrome have a 20-fold increased likelihood of developing childhood leukemia.

Respiratory illness is a significant cause of hospitalization for children with Down syndrome. The upper airway in these patients is narrow, with smaller midface and lower face skeleton, macroglossia, narrow nasopharynx, relatively larger tonsils and adenoids, and short palate; laryngomalacia is a common cause of airway obstruction in Down syndrome patients. These patients also have smaller trachea, with subglottic stenosis and dysfunctional cilia. Hypotonia and obesity are also often present in these patients. Altogether, these patients may have difficult airways for intubation. Furthermore, they have a smaller functional residual capacity and may be prone to hypoxia during intubation so preoxygenation may be helpful. Reverse Trendelenburg position (feet lower than head) may help displace the obese abdomen off the chest and may improve alignment of the external auditory meatus with the sternal notch. Techniques to minimize cervical manipulation are recommended given the potential for cervical spine instability. Using an endotracheal tube that is two times smaller than expected for age may account for the smaller trachea in these patients and facilitate successful intubation.

Patients that present with noncardiogenic pulmonary edema due to CRS can progress quickly to ARDS or P-ARDS (definitions vary). The overall inflammatory state underlying CRS leads to endothelial dysfunction, capillary leak, and acute lung injury and ARDS. High-flow nasal cannula and BiPAP can be considered in these patients; however, intubation should not be delayed when indicated. Patients requiring high-flow nasal cannula or noninvasive ventilatory support should be managed in the ICU.

Once on mechanical ventilation due to ARDS, a lung-protective strategy with low tidal volumes (4–6 mL/kg) to avoid further lung injury is important. Daily awakenings and minimizing sedation or oversedation to avoid delirium can have a positive impact on mortality in the critically ill. Sedation choice can be complex in the CAR T-cell population and should be carefully considered. Sedatives such as dexmedetomidine and propofol can decrease the incidence of delirium when compared with benzodiazepines. Moreover, their shorter time from discontinuation to light sedation or arousability could help with daily evaluation of ICANS. Despite these obvious benefits, concurrent cardiovascular toxicities from CRS (e.g., shock, baseline bradycardia, or high-grade heart blocks) may limit their use as both drugs are known to cause decreased systemic vascular resistance, hypotension, and bradycardia.

Careful fluid resuscitation and early diuresis should be paramount in patients with CRS-related respiratory failure. Available data in the critically ill show that patients with respiratory failure have increased mortality when there is evidence of fluid overload and overall positive fluid balance during their ICU stay. Increased fluid balance has not been studied in the CAR T-cell patients with CRS; however, one may extrapolate data from the general ICU population in this setting; fluid overload leads to worsening inflammatory response, secondary organ damage, and increased mortality. Therefore, close monitoring of intake and output, diuresis when possible, and early consideration of renal replacement therapy (RRT) to avoid further complications are recommended.

Treatment for grade 3 and 4 CRS with hypoxemia includes not only ICU support but also specific treatment such as steroids and anti-IL-6 or other anticytokine therapy if not already initiated. Moreover, ruling out additional causes of respiratory failure while treating concomitantly for CRS is imperative. Other causes of respiratory failure to consider include viral, fungal, and bacterial pneumonia and disease progression involving the lungs. Diffuse alveolar hemorrhage can also occur as these patients may have disseminated intravascular coagulation (DIC) and thrombocytopenia. Studies such as computerized tomography (CT) of the chest, bronchoscopy with bronchioalveolar lavage, and microscopic studies are helpful to rule out other concomitant causes of respiratory failure.

Neurological Complications and Neurotoxicity (ICANS)

The precise pathophysiology of ICANS remains unclear but may be related to a combination of endothelial activation in the central nervous system (CNS), elevated cytokine levels in the cerebrospinal fluid (CSF), and cerebral T-cell infiltration. Risk factors, diagnosis, grading, and specific management of ICANS are discussed elsewhere in this book. Here, we focus on critical care management considerations of patients receiving CAR therapy who experience neurotoxicity.

ICANS may manifest as delirium, encephalopathy, aphasia, lethargy, impaired concentration, agitation, tremor, seizures, and, rarely, cerebral edema. The onset can be biphasic, occurring concurrently with CRS and/or after CRS has resolved. When corticosteroids and/or other definitive therapies are used, patients should be monitored closely for recurrence of neurotoxicity symptoms posttreatment or during tapering. Patients with an ICANS grade of 3 or 4 require ICU monitoring for airway protection, management of possible seizures, status epilepticus, and signs of elevated intracranial pressure (ICP). We will discuss in detail some specific considerations of patients with neurotoxicity while in the ICU.