: CYTOKINE RELEASE SYNDROME AND NEUROLOGICAL TOXICITIES
Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving KYMRIAH. Do not administer KYMRIAH to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab, or tocilizumab and corticosteroids
Neurological toxicities, which may be severe or life-threatening, can occur following treatment with KYMRIAH, including concurrently with CRS. Monitor for neurological events after treatment with KYMRIAH. Provide supportive care as needed
KYMRIAH is available only through a restricted program under a Risk eva luation and Mitigation Strategy (REMS) called the KYMRIAH REMS
Warnings and Precautions
Cytokine Release Syndrome: CRS, including fatal or life-threatening reactions, occurred following treatment with KYMRIAH. CRS occurred in 54 (79%) of the 68 patients with relapsed or refractory (r/r) ALL receiving KYMRIAH, including ≥ grade 3 (Penn Grading System) in 33 (49%) of patients. The median time to onset of CRS in KYMRIAH trials was 3 days (range: 1-51), and in only 2 patients was onset after Day 10. The median time to resolution was 8 days (range: 1-36).
Of the 54 patients with r/r ALL who had CRS, 27 (50%) received tocilizumab; 7 (13%) patients received 2 doses of tocilizumab, 3 (6%) patients received 3 doses of tocilizumab and 14 (26%) patients received addition of corticosteroids (eg, methylprednisolone).
Five deaths occurred within 30 days of KYMRIAH infusion. One patient with r/r ALL died with CRS and progressive leukemia, 1 patient had resolving CRS with abdominal compartment syndrome, coagulopathy, and renal failure when an intracranial hemorrhage occurred. Among patients with r/r ALL who had CRS, key manifestations included fever (96%), hypotension (67%), hypoxia (20%), and tachycardia (30%). CRS may be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy.
Delay KYMRIAH infusion after lymphodepleting chemotherapy if patient has unresolved serious adverse reactions from preceding chemotherapies including pulmonary toxicity, cardiac toxicity, or hypotension, active uncontrolled infection, active graft vs host disease, or worsening of leukemia burden.
Ensure that 2 doses of tocilizumab are available on-site prior to KYMRIAH infusion. Monitor patients for signs or symptoms of CRS 2 to 3 times during the first week, then for at least 4 weeks after treatment. Counsel patients to remain within proximity of the health care facility for at least 4 weeks following infusion and seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, immediately eva luate the patient for hospitalization and institute treatment with supportive care, tocilizumab, and/or corticosteroids as indicated.
Risk factors for severe CRS are high pre-infusion tumor burden (≥50% blasts in bone marrow), uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy, active infections, and/or inflammatory processes.
Neurological Toxicities: Neurological toxicities, including severe or life-threatening reactions, occurred in 49 (72%) of the 68 patients with r/r ALL following treatment with KYMRIAH including ≥ grade 3 in 21% of patients. Among patients who had a neurological toxicity, 88% occurred within 8 weeks after KYMRIAH infusion. Median time to the first event was 6 days (range: 1-359) from infusion, and t |
