CAR T-cell Therapy
Guidelines on CAR T-cell therapy by researchers at the University of Texas MD Anderson Cancer Center in Houston[7,8]
Researchers at MD Anderson have developed a framework to help recognize and manage unique acute toxicities associated with CAR T-cell therapy.
CRS (cytokine-release syndrome), the most common adverse event observed after CAR T-cell therapy, is an escalated immune response and on rare occasions can evolve into fulminant hemophagocytic lymphohistiocytosis (HLH), also known as macrophage activation syndrome (MAS).
CRES (CAR T-cell–related encephalopathy syndrome) is the second most common adverse event and can occur concurrently with or after CRS. It may sometimes lead to fatal cerebral edema.
Overall, the authors recommend a basic 3-step approach to assessing and managing acute toxicities:
The first step is to monitor both clinical and biological symptoms to determine the nature of the CAR T-cell–related toxicity and to diagnose CRS, CRES, and HLH/MAS.
In the second step, the severity of CRS, CRES, and HLH/MAS should be graded by using the criteria provided in the recommendations and also according to the Common Terminology Criteria for Adverse Events (CTCAE).
The third step is to manage the toxicities by using the algorithms provided in the framework for CRS, CRES, and HLH/MAS.
For CRS, the interventions include treatment with the interleukin-6–blockers tocilizumab or siltuximab and corticosteroids, and in severe cases mechanical ventilation may be needed.
CRES appears to develop in a biphasic pattern; the interileukin-6 inhibitors appear to be effective in the first phase but not in the second, when corticosteroids are the preferred treatment; in severe cases, patients should be monitored in an intensive care unit because mechanical ventilation may be necessary.
A new grading system for CRES and a 10 point neurologic assessment (CARTOX 10) tool were created. The CARTOX 10 was developed to simplify evaluation of the acute neurotoxic events that have been observed in patients treated with CAR T cells. Incorporating some of the key components from the 30 point Mini Mental Status Examination, it emphasizes alterations in concentration, speech, and writing ability that are associated with CRES.
Before and during CAR T-cell infusion
Baseline brain MRI to rule out any central nervous system (CNS) disease.
Central venous access, preferably with double or triple lumen catheter, for intravenous fluid and other infusions in case of toxicities.
Cardiac monitoring by telemetry starting on the day of CAR-T-cell infusion and continued until cytokine-release syndrome (CRS) resolves, in order to detect arrhythmias.
Tumor lysis precautions for patients with bulky tumors, as per standard institutional guidelines.
Seizure prophylaxis with levetiracetam at 750 mg orally every 12 hours for 30 days, starting on the day of infusion for CAR-T-cell therapies known to cause CAR-T-cell-related encephalopathy syndrome (CRES).
Hospitalization recommended for at least 7 days after CAR-T-cell therapy.
Patient monitoring after CAR T cell infusion.
Assess vital signs every 4 hours, close monitoring of oral and intravenous fluid input and urine output, and daily measurement of body weight.
Daily review of patient history and physical examination.
Daily blood counts, complete metabolic profiling, and coagulation profiling.
C-reactive protein and ferritin levels measured daily, starting on the day of infusion.
Assessment and grading of CRS should be done at least twice daily, and whenever the patient's status changes.
Assessment and grading of CRES using the CAR-T-cell-therapy-associated toxicity 10-point neurological assessment (CARTOX-10) should be done at least every 8 hours.
Maintenance of intravenous fluids with normal saline to ensure adequate hydration.
Notifications and contingency orders
The physician should be notified on detection of any of the following: systolic blood pressure (SBP) >140 mm Hg or <90 mm Hg; heart rate >120 bpm or <60 bpm, or arrhythmia; respiratory rate >25 breaths/min or <12 breaths/min; arterial oxygen saturation <92% on room air; urine output <1,500 ml/day; upward trend in blood creatinine levels or the results of liver function tests; tremors or jerky movements in extremities; change in mental status (alertness, orientation, speech, ability to write a sentence, or CARTOX-10 score).
For patients with a temperature ≥38.3°C, order blood cultures (central and peripheral), urinalysis and urine cultures, and portable chest radiography, and notify physician.
For patients with neutropenia and fever, start empiric broad-spectrum antibiotics.
Corticosteroids should not be administered unless approved by physician.
If patient develops CRES, withhold oral intake of food, fluids, and medicine, and notify physician.
Pro re nata (as needed) medications, acetaminophen (first choice) or ibuprofen (second choice, if not contraindicated), and cooling blanket for fever ≥38.3°C; normal saline 500–1,000 ml bolus for SBP <90 mm Hg, with one repeat if SBP remains <90 mm Hg after first bolus.
Anti-IL-6 therapy with tocilizumab or siltuximab to be initiated only on physician order.
Medscape © 2017 WebMD, LLC
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: John Anello, Brian Feinberg, John Heinegg, et. al. New Clinical Practice Guidelines, October 2017 - Medscape - Oct 06, 2017.
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