Some patients required tocilizumab and corticosteroids for the management of CRS. KYMRIAH continues to expand and persist following tocilizumab administration. Patients who have higher expansion tended to have higher CRS Grades [see Warnings and Precautions (5.1)]. 

Pediatric and young adult r/r B-cell ALL patients (n = 18) treated with tocilizumab had 265% and 183% higher KYMRIAH AUC0-28d and Cmax, respectively, as compared to patients (n = 44) who did not receive tocilizumab. In addition, patients who received corticosteroids had 89% higher AUC0-28d compared with patients who did not receive corticosteroids.

Adult /r/r DLBCL patients treated with tocilizumab (N = 15) had 199% (n = 11) and 257% (n = 13) higher KYMRIAH AUC0-28d and Cmax, respectively, as compared to patients (N = 90) who did not receive tocilizumab. In addition, patients who received corticosteroids (N = 11) had 122% and 161% higher AUC0-28d and Cmax, respectively, as compared with patients who did not receive corticosteroids (N = 94). Hepatic and renal impairment studies of KYMRIAH were not conducted.

13     NONCLINICAL TOXICOLOGY 

13.1     Carcinogenesis, Mutagenesis, Impairment of Fertility

Genotoxicity assays and carcinogenicity assessment in rodent models were not performed for KYMRIAH. In vitro expansion studies with transduced T cells (KYMRIAH) from healthy donors and patients showed no evidence for transformation and/or immortalization of T cells. In vivo studies in immunocompromised mice did not show signs of abnormal cell growth or signs of clonal cell expansion for up to 7 months after cell injection. A genomic insertion site analysis was performed on KYMRIAH products from 14 individual donors (12 patients and 2 healthy volunteers). There was no evidence for preferential integration near genes of concern, or preferential outgrowth of cells harboring integration sites of concern

No studies on the effects of KYMRIAH on fertility have been conducted.

14     CLINICAL STUDIES 

14.1     Relapsed or Refractory (r/r) B-cell Acute Lymphoblastic Leukemia (ALL) 

The efficacy of KYMRIAH in pediatric and young adults with r/r B-cell precursor ALL was eva luated in an open-label, multicenter single-arm trial (ELIANA, NCT02228096). In total, 107 patients were screened, 88 were enrolled, 68 were treated, and 63 were eva luable for efficacy. Nine percent of the enrolled patients did not receive the product due to manufacturing failure. The 63 eva luable patients included 35 males and 28 females of median age 12 years (range: 3-23 years). Seventy-three percent of patients were White, 10% were Asian, and 17% were of other races. Six (10%) had primary refractory disease, 30 (48%) had one prior stem cell transplantation, 5 patients (8%) had two stem cell transplantations. Treatment consisted of lymphodepleting chemotherapy (fludarabine 30 mg/m2 daily for 4 days and cyclophosphamide 500 mg/m2 daily for 2 days) followed by a single dose of KYMRIAH. Of the 22 patients who had a WBC count < 1000/µL, 20 received lymphodepleting chemotherapy prior to KYMRIAH while 2 received KYMRIAH infusion without lymphodepleting chemotherapy. Fifty-three patients received bridging chemotherapy between time of enrollment and lymphodepleting chemotherapy.