d of a murine single-chain antibody fragment which recognizes CD19 and is fused to intracellular signaling domains from 4-1BB (CD137) and CD3 zeta. The CD3 zeta component is critical for initiating T-cell activation and antitumor activity, while 4-1BB enhances the expansion and persistence of KYMRIAH. Upon binding to CD19-expressing cells, the CAR transmits a signal to promote T-cell expansion, activation, target cell elimination, and persistence of the KYMRIAH cells.
12.3 Pharmacokinetics/Cellular Kinetics
Following infusion, KYMRIAH exhibited an initial rapid expansion followed by a bi-exponential decline in both pediatric and young adult relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) patients, and adult relapsed/refractory diffuse large B-cell lymphoma patients.
A summary of pharmacokinetic parameters of KYMRIAH is provided in Table 7 below.
Table 7. Pharmacokinetic Parameters of KYMRIAH in Pediatric and Young Adult r/r B-cell ALL and Adult r/r DLBCL
‡A total of 7 patients had an early Tmax (< 0.03 days), the next lowest Tmax occurred at 5.7 days. Early Tmax may not be representative of the true maximal expansion, but rather representative of the amount of transgene present in the catheter from which sample was collected.
Parameter Summary Statistics Pediatric ALL
Responding Patients
N = 62 Pediatric ALL
Non-Responding Patients
N = 8 r/r DLBCL
Responding Patients
(CR and PR)
N = 34 r/r DLBCL Non-
Responding Patients
(SD/PD/Unknown)
N = 34
Cmax (copies/mcg) Geometric mean (CV%), n 34,700 (155.4), 61 20,000 (71.6%), 7 5210 (256.5), 33 6450 (408.2), 32
Tmax (day) Median [min; max], n 9.91 [0.008; 27], 61 20.0 [0.03; 62.7], 7 9.83 [5.73, 16.8], 33 8.39 [3.04, 27.7], 32
AUC0-28d (copies/mcg*day) Geometric mean (CV%), n 318,000 (177.8), 61 156,000 (99.4), 6 58200 (165.1), 30 75800 (292.3), 25
T½ (day) Geometric mean (CV%), n 16.8 (155.9), 54 2.52 (171.9), 3 45.3 (157.7), 21 13.6 (167.0), 22
Description of Pharmacokinetics in Pediatric and Young Adult r/r B-cell ALL (up to 25 years of age)
The Cmax and AUC0-28d were approximately 2-fold higher in CR/CRi patients compared with non-responding (NR) patients.
KYMRIAH was present in the blood as well as bone marrow and was measurable beyond 2 years. Blood to bone marrow partitioning suggested that KYMRIAH distribution in bone marrow was 44% of that present in blood at Day 28 while at Months 3 and 6 KYMRIAH distributed at 67% and 69%, respectively, indicating high distribution to bone marrow.
Children < 10 years and between 10-18 years of age had 1.5- to 2-fold higher Cmax and AUC0-28d than adults. Due to small sample size and high variability, it is difficult to assess the impact of age on the pharmacokinetics of KYMRIAH.
Description of Pharmacokinetics in Adult r/r DLBCL
The Cmax and AUC0-28d were similar between responding and non-responding (NR) patients.
KYMRIAH was present in adult r/r DLBCL patients up to 18 months in peripheral blood and up to 9 months in the bone marrow for patients having a complete response. The median time of maximal expansion of transgene levels (Tmax) in peripheral blood occurred at 9-10 days in both responding and non-responding patients.
