Management of Cytokine Release Syndrome (CRS) Following CAR T-Cell Therapy

Initial Assessment and Monitoring

The American Society of Clinical Oncology recommends establishing baseline laboratory values, including CBC, comprehensive metabolic panel, magnesium, phosphorus, CRP, ferritin, LDH, uric acid, fibrinogen, and PT/PTT, before initiating any treatment for patients with suspected CRS following CAR T-cell therapy 3.
The National Comprehensive Cancer Network suggests performing CRS grading at least twice daily and with any clinical status change, typically within the first 3 weeks post-infusion, to monitor for signs of CRS 4.
Blood and urine cultures, plus chest radiograph, should be obtained to rule out infectious etiologies, as fever alone cannot distinguish CRS from sepsis, according to the Infectious Diseases Society of America 4, 3.
Daily monitoring of CRP and ferritin is essential for CRS surveillance, as recommended by the American Society of Clinical Oncology 3.

For grade 1 CRS, the American Society of Clinical Oncology recommends providing supportive care with acetaminophen for fever, IV hydration, and symptomatic management, without routine administration of tocilizumab or corticosteroids 1, 3, 5.
For grade 2 CRS, the National Comprehensive Cancer Network suggests administering tocilizumab 8 mg/kg IV immediately, with repeat doses every 8 hours if no improvement, up to 3-4 total doses 1, 2, 3.
For grade 3 CRS, the American Society of Clinical Oncology recommends transferring the patient to the ICU immediately, continuing tocilizumab 8 mg/kg IV every 8 hours as needed, and adding dexamethasone 10 mg IV every 6-12 hours 1, 2, 5.
For grade 4 CRS, the National Comprehensive Cancer Network suggests administering high-dose methylprednisolone 500 mg IV every 12 hours for 3 days, with a tapering schedule, and continuing tocilizumab 8 mg/kg IV as in lower grades 2, 3, 5.

The American Society of Clinical Oncology recommends considering alternative agents with limited evidence, such as anakinra (IL-1 receptor antagonist) or siltuximab (alternative IL-6 antagonist), if CRS persists despite tocilizumab and corticosteroids 1, 5.
The National Comprehensive Cancer Network suggests considering ruxolitinib, cyclophosphamide, or antithymocyte globulin in refractory cases 1, 2.

The American Society of Clinical Oncology recommends suspecting CAR T-cell-related HLH-MAS when ferritin exceeds 10,000 ng/ml plus any two of: grade ≥3 organ toxicities (liver, kidney, lung) or hemophagocytosis in bone marrow, and administering simultaneous tocilizumab and corticosteroids from the outset 4, 3.
The National Comprehensive Cancer Network suggests prioritizing corticosteroids over tocilizumab when grade 2+ ICANS occurs with low-grade CRS, as tocilizumab may worsen neurotoxicity 1, 2.

The Infectious Diseases Society of America recommends strongly considering antifungal prophylaxis in all patients receiving corticosteroids for CRS or ICANS 1, 2, 3.
The American Society of Clinical Oncology suggests not using GM-CSF (though G-CSF is permissible), leukapheresis filters for CAR T-cell infusion, or routine administration of corticosteroids as pre-medication before CAR T-cell infusion 3.

The American Society of Clinical Oncology recommends continuing daily laboratory monitoring, including CBC, CMP, CRP, ferritin, fibrinogen, and coagulation studies, to watch for tocilizumab-associated adverse effects 3, 5.

The National Comprehensive Cancer Network suggests defining hypotension as SBP <(70 + 2×age in years) mmHg for ages 1-10 years, or SBP <90 mmHg for ages >10 years, and using age-specific heart rate ranges to define tachycardia in pediatric patients 4.
The American Society of Clinical Oncology recommends using oliguria (<0.5 mL/kg/hour for 8 hours) and anuria (<0.3 mL/kg/hour for 24 hours) as indicators of renal dysfunction in pediatric patients 4.