TY - JOUR
T1 - Grading of neurological toxicity in patients treated with tisagenlecleucel in the JULIET trial
AU - Maziarz, Richard T.
AU - Schuster, Stephen J.
AU - Romanov, Vadim V.
AU - Rusch, Elisha S.
AU - Li, Junlong
AU - Signorovitch, James E.
AU - Maloney, David G.
AU - Locke, Frederick L.
N1 - Funding Information:
Medical writing support was provided by Ina Nikolaeva (Healthcare Consultancy Group) and was funded by Novartis Pharmaceuticals Corporation. Editorial assistance was provided by Marie Louise Edwards, Lei Yin, and Yichen Lu from Analysis Group, Inc., and was supported by Novartis Pharmaceuticals Corporation. The study was sponsored by Novartis Pharmaceuticals Corporation.
Funding Information:
Conflict-of-interest disclosure: R.T.M. received honoraria, membership on the board of directors or advisory committees, and research funding from Novartis; consultancy and honoraria from CRSPR Therapeutics, Incyte, and Juno Therapeutics; honoraria from Kite Therapeutics; patents and royalties from Athersys, Inc.; and is employed by Oregon Health & Science University. R.T.M. also provided consultant services to and received payment from Novartis. This potential conflict of interest has been reviewed and managed by Oregon Health & Science University. S.J.S. received
Publisher Copyright:
© 2020 by The American Society of Hematology
PY - 2020/4/14
Y1 - 2020/4/14
N2 - Chimeric antigen receptor-T (CAR-T) cell therapy achieves durable responses in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), but may be associated with neurological toxicity (NT). We retrospectively assessed differences and concordance among 3 available grading scales (the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03 [CTCAE], modified CAR-T Related Encephalopathy Syndrome [mCRES], and American Society for Transplantation and Cellular Therapy [ASTCT] scales) applied to the same set of NT data from the JULIET (A Phase 2, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Patients With Relapsed or Refractory DLBCL) trial. Individual patient-level NT data from the phase 2, single-group, global, pivotal JULIET trial (NCT02445248) were retrospectively and independently graded, using CTCAE, ASTCT, and mCRES, by 4 medical experts with experience managing patients with 3 different CD19-targeted CAR constructs. According to the US Food and Drug Administration definition of NT using CTCAE, 62 of 106 patients infused with tisagenlecleucel had NT as of September 2017. Among 111 patients infused with tisagenlecleucel (as of December 2017), the 4 experts identified 50 patients (45%) who had any-grade NT per CTCAE, 19 (17%) per mCRES, and 19 (17%) per ASTCT. Reevaluation according to the mCRES/ASTCT criteria downgraded 31 events deemed NT by CTCAE to grade 0. This is the first study to retrospectively apply CTCAE, mCRES, and ASTCT criteria to the same patient data set. We conclude that CTCAE v4.03 was not designed for, and is suboptimal for, grading CAR-T cell therapy-associated NT. The CRES and ASTCT scales, which measure immune effector cell-associated neurotoxicity syndrome, offer more accurate assessments of NT after CAR-T cell therapy.
AB - Chimeric antigen receptor-T (CAR-T) cell therapy achieves durable responses in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), but may be associated with neurological toxicity (NT). We retrospectively assessed differences and concordance among 3 available grading scales (the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03 [CTCAE], modified CAR-T Related Encephalopathy Syndrome [mCRES], and American Society for Transplantation and Cellular Therapy [ASTCT] scales) applied to the same set of NT data from the JULIET (A Phase 2, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Patients With Relapsed or Refractory DLBCL) trial. Individual patient-level NT data from the phase 2, single-group, global, pivotal JULIET trial (NCT02445248) were retrospectively and independently graded, using CTCAE, ASTCT, and mCRES, by 4 medical experts with experience managing patients with 3 different CD19-targeted CAR constructs. According to the US Food and Drug Administration definition of NT using CTCAE, 62 of 106 patients infused with tisagenlecleucel had NT as of September 2017. Among 111 patients infused with tisagenlecleucel (as of December 2017), the 4 experts identified 50 patients (45%) who had any-grade NT per CTCAE, 19 (17%) per mCRES, and 19 (17%) per ASTCT. Reevaluation according to the mCRES/ASTCT criteria downgraded 31 events deemed NT by CTCAE to grade 0. This is the first study to retrospectively apply CTCAE, mCRES, and ASTCT criteria to the same patient data set. We conclude that CTCAE v4.03 was not designed for, and is suboptimal for, grading CAR-T cell therapy-associated NT. The CRES and ASTCT scales, which measure immune effector cell-associated neurotoxicity syndrome, offer more accurate assessments of NT after CAR-T cell therapy.
UR - http://www.scopus.com/inward/record.url?scp=85083737188&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85083737188&partnerID=8YFLogxK
U2 - 10.1182/bloodadvances.2019001305
DO - 10.1182/bloodadvances.2019001305
M3 - Article
C2 - 32271898
AN - SCOPUS:85083737188
SN - 2473-9529
VL - 4
SP - 1440
EP - 1447
JO - Blood advances
JF - Blood advances
IS - 7
ER -