Kathleen Cunningham RN, BSN, ... Elizabeth Weber RN, BSN, in Seminars in Oncology Nursing, 2021
Postinfusion
Immediate Care
After the tisagenlecleucel infusion, the patient receives another 1-hour infusion with normal saline for hydration. The patient may be discharged from the apheresis unit once vital signs are stable but should be reminded to remain within a 1-hour transportation distance from Penn for at least 28 days postinfusion.
Follow-Up Care and Toxicity Management
Two to three follow-up patient appointments occur during the first week postinfusion, and set visits occur weekly thereafter for the next month. Appointments beyond the first month are at the provider's discretion. Triaging patient phone calls and judging AE severity for subsequent patient admission is a challenge for outpatient therapy. From the nurse's perspective, these decisions require exceptional communication across the multidisciplinary team, the patients, and their families. Factors that may inform a provider's decision for admission may include changes in vital signs, severity of symptoms, tumor burden, potential for toxicity, and/or signs of neurotoxicity. For outpatient postinfusion monitoring, patients and caregivers are educated about signs and symptoms of potential serious AEs, given a wallet card that directs them when to seek emergency care, and are instructed to have an oral thermometer [plus a backup] and taught how to use it to monitor for fever. Patients are also instructed to call the oncology call center during business hours and are triaged to the appropriate team, and the treating oncologist or nurse practitioner will contact the patient for additional information. After hours, the general hospital operator pages the treating oncologist, who then instructs the patient to report to the most appropriate location for evaluation based on symptoms.
Fever is an expected AE of tisagenlecleucel therapy and an early indicator of CRS, a potentially life-threatening inflammatory response. Patients are instructed to have two oral thermometers available for postinfusion monitoring and to monitor their temperature at the same time in the morning, afternoon, and evening each day and if they are feeling unwell. Patients with a temperature of 38°C [100.4°F] or higher are evaluated by a physician or APP to exclude infection as the source. Patients with fever will be evaluated in the oncology evaluation center or the hematology-oncology clinic and, depending on severity of symptoms, may be admitted to the hospital.
Cytokine Release Syndrome
CRS is a systemic inflammatory response associated with CAR T-cell therapy and other immunotherapies.11 The severity of CRS can range from mild to life-threatening depending on the magnitude of the immune cell activation. Preparation for the early identification and clear management of CRS is crucial for patient safety. CRS severity is assessed by grade according to easily accessible clinical features. A consensus grading scale for CRS has been published by the American Society for Transplantation and Cellular Therapy [ASTCT], and Penn has adopted the ASTCT CRS grading scale [Table 2].12 CRS is managed according to guidance provided in the Kymriah prescribing information.2 The presentation, onset, and management of other common AEs are shown in Table 3.2,11,13,14
Table 2. ASTCT CRS Grading Scale12
1 | ≥38°C | None | None | ||
2 | ≥38°C | With | Not requiring vasopressors | And/or† | Requiring low-flow nasal cannula‡ or blow-by |
3 | ≥38°C | With | Requiring a vasopressor with or without vasopressin | And/or† | Requiring high-flow nasal cannula,‡ facemask, nonrebreather mask, or Venturi mask |
4 | ≥38°C | With | Requiring multiple vasopressors [excluding vasopressin] | And/or† | Requiring positive pressure [eg, CPAP, BiPAP, intubation and mechanical ventilation] |
ASTCT, American Society for Transplantation and Cellular Therapy; BiPAP, bilevel positive airway pressure; CPAP, continuous positive airway pressure; CRS, cytokine release syndrome.
⁎Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia.†Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/min. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/min.‡CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with temperature of 39.5°C, hypotension requiring one vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS. Note: Reprinted from Biology of Blood and Marrow Transplantation, Vol. 25, Lee DW, et al, ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells, pages 625-638, Copyright 2019, with permission from Elsevier.Table 3. Anticipated Sequelae and Management After Tisagenlecleucel Infusion2,11,13,14
CRS | Fever, hypotension, hypoxia, and tachycardia May be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy | Median time to onset, 3 days | Managed according to grade [ASTCT scale] |
Neurotoxicity | Headache, encephalopathy, delirium, anxiety, sleep disorders, dizziness, tremor, and peripheral neuropathy. Other manifestations include seizures, mutism, and aphasia | Median time to the first event, 6 days | Managed according to grade. Low grade may be managed with supportive care; higher grades treated with steroids. Seizure prophylaxis [such as levetiracetam] may be considered. Neurologic workup [such as CT and/or brain MRI, lumbar puncture, EEG] should be considered to rule out other causes |
Hypersensitivity | Allergic reactions | Immediately* | |
Infections and febrile neutropenia | Fevers may be associated with infection or CRS. ANC <1,000/mm3 with a single temperature of >38.3°C [101°F] or sustained temperature of ≥38°C [100.4°F] for more than 1 hour | Neutropenia often occurs after LD chemotherapy | Patients are evaluated for infection and managed with broad-spectrum antibiotics, fluids, and other supportive care |
Prolonged cytopenias | Delayed anemia, neutropenia, and thrombocytopenia increasingly reported | Several weeks after LD chemotherapy and infusion | Growth factor and transfusion support and antibiotic/antiviral prophylaxis as appropriate; consider bone marrow biopsy to rule out other causes of cytopenia [such as myelodysplasia] |
Hypogammaglobulinemia | Often a laboratory finding; some patients will have recurrent infection | Can occur in responding patients after infusion† | Immunoglobulin levels are monitored and managed using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement standard guidelines |
ASTCT, American Society for Transplantation and Cellular Therapy; ANC, absolute neutrophil count; CRS, cytokine release syndrome; CT, computed tomography; EEG, electroencephalography; LD, lymphodepleting; MRI, magnetic resonance imaging.
⁎Cruz CR, et al. Cytotherapy. 2010;12[6]:743-749.†Porter DL, et al. Sci Transl Med. 2015;7[303]:303ra139.Note: Unless otherwise noted, based on information from the Kymriah [tisagenlecleucel] package insert, 2020, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey. Retrieved from //www.fda.gov/media/107296/download.Neurological Events
After receiving CAR-T cell therapy, patients may also experience neurological events that may occur concurrent with CRS, after resolution of CRS, or in the absence of CRS. Before infusing tisagenlecleucel in the outpatient setting, patients and caregivers are educated by the APP, a nurse clinical trials coordinator, and a physician about the potential for developing immune effector cell-associated neurotoxicity syndrome [ICANS], which may manifest as altered or decreased consciousness, delirium, confusion, agitation, seizures, difficulty speaking and understanding, and loss of balance. Patients are also given a wallet card that lists the key symptoms of immune effector cell-associated neurotoxicity syndrome and advises them to contact their oncologist or seek emergency care. As indicated, it is often the APP who advises patients when to seek emergency care based on their symptoms. Overall, neurological events are managed based on the underlying pathophysiology. At Penn, neurological symptoms are assessed using the ASTCT consensus grading scale for neurologic toxicity, which uses the immune effector cell-associated encephalopathy [ICE] score to grade neurotoxicity.12 For patients who experience neurological events, such as cognitive changes, encephalopathy, aphasia, or motor disturbances, seizure prophylaxis [such as levetiracetam] may be administered [Table 3]. Patients experiencing mild events are observed and monitored closely. In patients with more pronounced neurological symptoms, the treating oncologist may administer steroids [eg, dexamethasone 10-20 mg, every 8-12 hours] until symptoms return to baseline. In the event of concurrent CRS and neurotoxicity, tocilizumab may be appropriate; however, tocilizumab is not approved by the US Food and Drug Administration [FDA] for the treatment of neurological symptoms alone.