Nursing Considerations for Adverse Events From CAR T-Cell Therapy

In their article in the April 2017 issue of the Clinical Journal of Oncology Nursing (https://cjon.ons.org/), Smith and Venella discussed the oncology nursing interventions for inpatient management of moderate to severe toxicities from CAR T-cell therapy.

Primary Complications With CAR T-Cell Therapy

The more critical adverse events associated with CAR T-cell treatment are cytokine release syndrome (CRS), neurologic symptoms, tumor lysis syndrome, and graft-versus-host disease. See Table 1 for an overview of the side effects and their treatment.

Cytokine release syndrome (CRS): Smith and Venella explained (https://cjon.ons.org/cjon/21/2-0/supplement/cytokine-release-syndrome-inpatient-care-side-effects-car-t-cell-therapy) that CRS is the primary complication requiring hospitalization after CAR T-cell therapy; it occurs when T cells proliferate throughout the body and cause a general inflammatory response. It is clinically marked by a dramatic increase in interleukin 6 (IL-6) and elevations in other cytokines (e.g., IL-10), lactate dehydrongenase, C-reactive protein, and ferritin. CRS symptoms can appear as early as one day after infusion and can resolve quickly or last for weeks. Its severity appears to be related to the disease burden prior to CAR T-cell therapy.

Fevers are a hallmark of CRS and can range from low to high grade and persist for days or weeks. Acetaminophen is used for comfort but does not usually relieve the fever. Associated symptoms are tachycardia, chills, anorexia, nausea, and vomiting, which can be managed with supportive care. If patients develop myalgia or headaches, intermittent IV opioids can be used.

More severe symptoms are capillary leak syndrome and hypotension, which can lead to pulmonary edema and the need for oxygen support. Hypotension treatment should start with IV fluid boluses but should move quickly to vasopressor support to minimize the risk of massive pulmonary edema. Smith and Venella said that in their institution (https://cjon.ons.org/cjon/21/2-0/supplement/cytokine-release-syndrome-inpatient-care-side-effects-car-t-cell-therapy), once a second IV fluid bolus is needed, the critical care team steps in and patients are proactively transferred to the intensive care unit.

CRS can also lead to severe coagulo­pathy with prolonged prothrombin time or partial thromboplastin time and low fibrinogen levels. Treatment includes transfusions with cryoprecipitate and fresh frozen plasma, if indicated. Inflammation from CRS and increased cytokine production can change hemodynamics, decreasing renal blood flow and glomerular filtration rate and potentially causing acute kidney injury and renal dysfunction. Some patients have also developed macrophage-activation syndrome or hemophagocytic lymphohistiocytosis.

Because CRS inflammation is reversible, the treatment goal is to control symptoms without interfering with the T cells’ ability to destroy cancer cells. First-line treatment is always supportive, such as antipyretics, pain medications, antiemetics, vasopressor support, and oxygen supplementation. As patients appear to develop multisystem organ failure, Smith and Venella said (https://cjon.ons.org/cjon/21/2-0/supplement/cytokine-release-syndrome-inpatient-care-side-effects-car-t-cell-therapy) to consider other medications that decrease inflammation.

• Tocilizumab: This monoclonal antibody binds to the IL-6 receptor, preventing inflammation. But it does not directly affect T cells and may not have long-term effects on T cell efficacy. It tends to quickly resolve symptoms and is clinically indicated for hypotension or worsening respiratory status that could lead to intubation.
• Methylprednisolone: This medication directly blocks T-cell activation and may stop the benefit of CAR T-cell therapy, so it is only indicated if other interventions, including tocilizumab, are unsuccessful.

Neurologic symptoms: CAR T cells have been found in the cerebral spinal fluid and may cause some patients to develop encephalopathy. Symptoms include confusion, hallucination, and delirium, and patients with a history of seizure activity may have seizures. Encephalopathy cannot be reversed with treatment, but it usually resolves on its own with no long-term effects. Patients at risk for seizures should receive prophylactic levetiracetam at the start of CRS until all symptoms are resolved.

B-cell aplasia: With CART-19 therapy, the T cells are engineered to kill CD19-positive cells, including healthy B cells, so patients who receive and respond to CART-19 will develop B-cell aplasia, leading to hypogammaglobulinemia. To prevent risk of infection, Smith and Venella said (https://cjon.ons.org/cjon/21/2-0/supplement/cytokine-release-syndrome-inpatient-care-side-effects-car-t-cell-therapy) that patients receive monthly IV immunoglobulin infusions to maintain an IgG level greater than 500 mg/dl for as long as B-cell aplasia persists.

Tumor lysis syndrome: As leukemia cells die quickly from treatment, it can cause hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia, which can lead to acute renal failure. Patients with a high tumor burden are at greater risk. Smith and Venella said that patients are treated with allopurinol and their uric acid and electrolytes are monitored daily so treatment can begin as needed.

Graft-versus-host disease (GVHD): Activated donor T cells used in CAR T-cell therapy can cause GVHD in patients who have undergone previous stem cell transplantation. It most commonly affects the skin (e.g., rash), gastrointestinal tract (e.g., diarrhea), and liver (e.g., hyperbilirubinemia). Although Smith and Venella said that no patients at their institution have developed GVHD after CAR T-cell therapy, usual treatment with prednisolone is contraindicated because of the effect on T-cell proliferation.

Hospital Discharge Criteria

Patients who are afebrile for at least 24 hours, have required twice weekly or fewer transfusions, and are able to maintain adequate hydration are eligible for discharge after admission for CAR T-cell therapy toxicity. Patients with severe CRS should be screened by physical therapists; if deconditioning is severe, they may require inpatient rehabilitation. If patients are neutropenic at discharge, prophylactic oral levofloxacin is given. In Smith and Venella’s (2017) experience, the outpatient team collaborates with referring providers to ensure patients have a six-week supply of homecare equipment and medications, and family caregivers are educated on the importance of infection prevention and when to call about new signs and symptoms.

For more information about CAR T-cell therapy toxicities, including psychosocial care considerations, refer to the full article by Smith and Venella (https://cjon.ons.org/cjon/21/2-0/supplement/cytokine-release-syndrome-inpatient-care-side-effects-car-t-cell-therapy).

This monthly feature offers readers a concise recap of full-length articles published in the Clinical Journal of Oncology Nursing (CJON) or Oncology Nursing Forum. This edition summarizes the immunotherapy supplement to the April 2017 issue of CJON (https://cjon.ons.org/cjon/21/2-0/supplement). Questions regarding the information presented in this article should be directed to the CJON editor (mailto:CJONEditor@ons.org). Photocopying of this article for educational purposes and group discussion is permitted.