ATLANTA (FRONTLINE MEDICAL NEWS) – Closely monitoring for cytokine release syndrome (CRS) and starting anticytokine therapy early can prevent life-threatening organ toxicities in recipients of chimeric antigen receptor (CAR) T-cell therapy, according to Daniel W. Lee III, MD.

There’s no evidence that early anticytokine therapy impairs antitumor response, he noted. “If you wait to give anticytokine therapy until a patient is intubated, it’s too late,” Dr. Lee said at the annual meeting of the American Society of Hematology. “If you wait until a patient has been hypotensive for days, it’s probably too late. If you intervene earlier, you can avoid intubation.”

Cytokine release syndrome affects multiple organs, explaining its diverse symptomatology, said Dr. Lee of the University of Virginia, Charlottesville. Fever and flu-like illness mark its onset, while potentially life-threatening CRS includes wide pulse pressures, hypotension, ventricular strain, and capillary leak leading to pulmonary edema and hypoxia. Excessive cytokine release also can cause coagulopathy, azotemia, hyperbilirubinemia, transaminitis, flushing, and rash, Dr. Lee noted. Neurotoxicity, presenting as headache, altered mental status, delirium, aphasia, hallucinations, or seizures, is now often considered an event separate from CRS, he said.

Treating CRS is a clinical decision that shouldn’t hinge on cytokine levels, according to Dr. Lee. He and his colleagues base treatment on their revised severity grading assessment, which spans mild, moderate, severe, and life-threatening syndromes ( Blood. 2014;124:188-95 ).

Using a consistent CRS severity grading system enables physicians to treat rationally across trials and CAR T-cell therapies, he said. His system defines grade 1 CRS as flu-like symptoms and fever up to 41.5 degrees Celsius. Patients with grade 1 CRS should receive antipyretics and analgesia as needed and should be monitored closely for infections and fluid imbalances, Dr. Lee said.

Hypotension signifies progression beyond grade 1 CRS. Affected patients should receive no more than two to three IV fluid boluses and then should “quickly move on to vasopressors,” such as norepinephrine, he emphasized.

His and his team implemented this important change after one of their patients, a 14-year-old boy with severe hypotensive grade 4 CRS, died of a cardiovascular event after receiving multiple IV fluid boluses. “We had not appreciated the extent of this patient’s ventricular strain,” Dr. Lee said. The patient was heavily pretreated and had an “extremely high disease burden” (more than 99% marrow involvement, hepatosplenomegaly, and pronounced blastic leukocytosis), which increased his risk of severe CRS, he noted. “Admittedly, we pushed the envelope a little bit, and we learned you should start anticytokine therapies much earlier. Earlier seems to be better, although we do not yet know if prophylactic tocilizumab or corticosteroids can prevent CRS symptoms before they start.”

For hypotensive patients on pressors, Dr. Lee recommends vigilant supportive care and daily echocardiograms to monitor ejection fraction and ventricular wall mobility. His system defines grade 2 CRS as hypotension responsive to one low-dose pressor or to fluid therapy and hypoxia responsive to less than 40% oxygen therapy. Patients with grade 2 CRS who also have comorbidities should receive tocilizumab – with or without corticosteroids – both of which “remain the standard of care for managing CRS,” he said. Severe CRS often stems from supraphysiologic release of interleukin 6, which induces not only classic IL-6 signaling but also proinflammatory trans-signaling across many cell types. Tocilizumab reverses this process by binding and blocking the IL-6 receptor, Dr. Lee noted.

Patients with grade 3 CRS have hypotension requiring multiple or high-dose pressors and hypoxia requiring at least 40% oxygen therapy. These patients have grade 3 organ toxicity and grade 4 transaminitis, Dr. Lee said. Even if they lack comorbidities, they need vigilant supportive care, tocilizumab, and possibly corticosteroids, he added. The ultimate goal is to avoid grade 4 CRS, he said, which involves grade 4 organ toxicity, requires mechanical ventilation, and yields a poor prognosis despite vigilant supportive care, tocilizumab, and corticosteroids.

Dr. Lee reported having no relevant conflicts of interest.


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