Median time to the first event was 6 days from infusion (range: 1-359), and the median duration was 6 days for patients with r/r ALL and 14 days for patients with r/r DLBCL. Resolution occurred within 3 weeks in 79% of patients with r/r ALL and 61% of patients with r/r DLBCL. Encephalopathy lasting up to 50 days was noted. 

The onset of neurological toxicity can be concurrent with CRS, following resolution of CRS or in the absence of CRS. 

The most common neurological toxicities observed with KYMRIAH include headache (37% in r/r ALL; 21% in r/r DLBCL), encephalopathy (34% in r/r ALL; 16% in r/r DLBCL), delirium (21% in r/r ALL; 6% in r/r DLBCL), anxiety (13% in r/r ALL; 9% in r/r DLBCL), sleep disorders (10% in r/r ALL; 9% in r/r DLBCL), dizziness (6% in r/r ALL; 11% in r/r DLBCL), tremor (9% in r/r ALL; 7% r/r DLBCL) and peripheral neuropathy (4% in r/r ALL; 8% in r/r DLBCL). Other manifestations included seizures, mutism and aphasia. 

Monitor patients for neurological events and exclude other causes for neurological symptoms. Provide supportive care as needed for KYMRIAH-associated neurological events.

5.3     KYMRIAH REMS to Mitigate Cytokine Release Syndrome and Neurological Toxicities

Because of the risk of CRS and neurological toxicities, KYMRIAH is available only through a restricted program under a Risk eva luation and Mitigation Strategy (REMS) called the KYMRIAH REMS [see Boxed Warning, Warnings and Precautions (5.1, 5.2)]. The required components of the KYMRIAH REMS are:

Healthcare facilities that dispense and administer KYMRIAH must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of two doses of tocilizumab are available for each patient for administration within 2 hours after KYMRIAH infusion, if needed for treatment of CRS.

Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer KYMRIAH are trained about the management of CRS and neurological toxicities.

Further information is available at www.kymriah-rems.com or 1-844-4KYMRIAH.

5.4     Hypersensitivity Reactions

Allergic reactions may occur with infusion of KYMRIAH. Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) or dextran 40 in KYMRIAH. 

5.5     Serious Infections

Infections, including life-threatening or fatal infections, occurred in 95 (55%) of 174 patients with r/r ALL or r/r DLBCL after KYMRIAH infusion. Fifty eight patients (33%) experienced Grade ≥ 3 infections, including fatal infections in 2 patients (3%) with r/r ALL and 1 patient (1%) with r/r DLBCL. Prior to KYMRIAH infusion, infection prophylaxis should follow local guidelines. Patients with active uncontrolled infection should not start KYMRIAH treatment until the infection is resolved. Monitor patients for signs and symptoms of infection after treatment with KYMRIAH and treat appropriately [see Dosage and Administration (2.3)].