e 106 adult patients with r/r DLBCL receiving KYMRIAH, including ≥ Grade 3 (Penn grading system1) in 49% of patients with r/r ALL and in 23% of patients with r/r DLBCL. The median time to onset was 3 days (range: 1-51), and in only two patients was onset after Day 10. The median time to resolution of CRS was 8 days (range: 1-36).
Of the 54 patients with r/r ALL who had CRS, 27 (50%) received tocilizumab. Seven (13%) patients received two doses of tocilizumab, 3 (6%) patients received three doses of tocilizumab, and 14 (26%) patients received addition of corticosteroids (e.g., methylprednisolone). Of the 78 patients with r/r DLBCL who had CRS, 16 (21%) received systemic tocilizumab or corticosteroids. Six (8%) patients received a single dose of tocilizumab, 10 (13%) patients received two doses of tocilizumab, and 10 (13%) patients received corticosteroids in addition to tocilizumab. Two patients with r/r DLBCL received corticosteroids for CRS without concomitant tocilizumab, and two patients received corticosteroids for persistent neurotoxicity after resolution of CRS.
Five deaths occurred within 30 days of KYMRIAH infusion. One patient with r/r ALL died with CRS and progressive leukemia, and one patient had resolving CRS with abdominal compartment syndrome, coagulopathy, and renal failure when an intracranial hemorrhage occurred. Of the 3 r/r DLBCL patients who died within 30 days of infusion, all had CRS in the setting of stable to progressive underlying disease, one of whom developed bowel necrosis. Among patients with CRS, key manifestations include fever (92% in r/r ALL and r/r DLBCL), hypotension (67% in r/r ALL; 47% in r/r DLBCL), hypoxia (20% in r/r ALL; 35% in r/r DLBCL) and tachycardia (30% in r/r ALL; 14% in r/r DLBCL). CRS may be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy.
Delay the infusion of KYMRIAH after lymphodepleting chemotherapy if the patient has unresolved serious adverse reactions from preceding chemotherapies (including pulmonary toxicity, cardiac toxicity, or hypotension), active uncontrolled infection, active graft versus host disease (GVHD), or worsening of leukemia burden [see Dosage and Administration (2.3)].
Ensure that two doses of tocilizumab are available on site prior to infusion of KYMRIAH. Monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment with KYMRIAH. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see Patient Counseling Information (17)]. At the first sign of CRS, immediately eva luate patient for hospitalization and institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated [see Dosage and Administration (2.3, 2.4)].
Risk factors for severe CRS in the pediatric and young adult r/r B-cell ALL population are high pre-infusion tumor burden (greater than 50% blasts in bone marrow), uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy, active infections, and/or inflammatory processes. Risk factors for developing severe CRS in adult r/r DLBCL are not known.
5.2 Neurological Toxicities
Neurological toxicities including severe or life-threatening reactions, occurred in 49 (72%) of the 68 patients with r/r ALL and 62 (58%) of the 106 patients with r/r DLBCL following treatment with KYMRIAH, including ≥ Grade 3 in 21% of patients with r/r ALL and 18% of patients with r/r DLBCL. Among patients wh
