TY - JOUR
T1 - Ibrutinib Treatment of Pediatric Chronic Graft-versus-Host Disease
T2 - Primary Results from the Phase 1/2 iMAGINE Study
AU - Carpenter, Paul A.
AU - Kang, Hyoung Jin
AU - Yoo, Keon Hee
AU - Zecca, Marco
AU - Cho, Bin
AU - Lucchini, Giovanna
AU - Nemecek, Eneida R.
AU - Schultz, Kirk R.
AU - Stepensky, Polina
AU - Chaudhury, Sonali
AU - Oshrine, Benjamin
AU - Khaw, Seong Lin
AU - Harris, Andrew C.
AU - Verna, Marta
AU - Zubarovskaya, Liudmila
AU - Lee, Yihua
AU - Wahlstrom, Justin
AU - Styles, Lori
AU - Shaw, Peter J.
AU - Dalle, Jean Hugues
N1 - Funding Information:
The authors thank the patients who participated in this study and their supportive families, as well as the investigators, sub-investigators, and coordinators at each of the study sites. The authors also thank Harisha Atluri, PhD (employed by AbbVie; may own AbbVie stock), for assistance with pharmacokinetic data analysis. Editorial support was provided by Cindi A. Hoover, PhD, and funded by Pharmacyclics LLC, an AbbVie Company. Financial disclosure: This study was sponsored by Pharmacyclics LLC, an AbbVie Company, South San Francisco, CA, USA, and Janssen Pharmaceuticals. Conflict of interest statement: P.A.C. reports honoraria from Johnson & Johnson; a consultancy/advisory role with Fate Therapeutics and Intellisphere; and research funding from Incyte and Pharmacyclics LLC, an AbbVie Company. H.J.K. reports a consultancy/advisory role with Amgen, Cartexell, and Novartis and research funding from Amgen. K.H.Y. reports a consultancy/advisory role with Amgen. M.Z. reports a consultancy/advisory role with Bluebird Bio, Jazz Pharmaceuticals, and Medac; speakers’ bureau for Amgen and Medac; support from Ricerca Corrente to Fondazione IRCCS Policlinico San Matteo (RCR 0845818 and 08069119); and travel/accommodations/expenses from Jazz Pharmaceuticals. G.L. reports research funding from Autolus, GlaxoSmithKline, and Pharmacyclics LLC, an AbbVie Company. E.R.N. reports honoraria from Atara Biotherapeutics, Medexus, Medac, and Novartis. K.R.S. reports a consultancy/advisory role with Bristol Myers Squibb and Seres and travel/accommodations/expenses from Jazz Pharmaceuticals. S.C. reports a consultancy/advisory role with AbbVie, Bluebird Bio, and Mesoblast Ltd and research funding from Bristol Myers Squibb and Karius. B.O. reports part-time employment with Clinipace. S.L.K. reports honoraria from Novartis; a consultancy/advisory role with Amgen and Novartis; research funding from AbbVie, Bristol Myers Squibb, and Jazz Pharmaceuticals; patents/royalties/other intellectual property with WEHI; and travel/accommodations/expenses from Novartis. A.C.H. reports a consultancy/advisory role with Horizon Therapeutics and Mesoblast Ltd. Y.L. reports employment and stock or other ownership with AbbVie. J.W. reports previous employment and stock or other ownership with Pharmacyclics LLC, an AbbVie Company and current employment with Atara Biotherapeutics. L.S. reports previous employment with AbbVie and current employment with Summit Therapeutics and stock or other ownership with AbbVie. P.J.S. reports a consultancy/advisory role with Novartis. J.-H.D. reports employment and stock or other ownership with Teva Pharmaceuticals; honoraria from and a consultancy/advisory role with Bluebird Bio, Jazz Pharmaceuticals, Novartis, Orchard Therapeutics, and Sanofi; and travel/accommodations/expenses from Gilead and Jazz Pharmaceuticals. The other authors have no conflicts of interest to report. Authorship statement: P.A.C. J.W. and L.S. designed the study; P.A.C. H.J.K. K.H.Y. M.Z. G.L. E.R.N. K.R.S. P.S. S.C. B.O. S.L.K. A.C.H. M.V. L.Z. P.J.S. and J.-H.D. collected data; Y.L. J.W. and L.S. confirmed the accuracy of the data, interpreted the data, and compiled it for analysis; and Y.L. performed statistical analysis. All authors had access to the data and were involved in the interpretation of data. All authors contributed to the manuscript preparation and approved the final version of the manuscript for submission. Financial disclosure: See Acknowledgments on page XXX.
Funding Information:
The authors thank the patients who participated in this study and their supportive families, as well as the investigators, sub-investigators, and coordinators at each of the study sites. The authors also thank Harisha Atluri, PhD (employed by AbbVie; may own AbbVie stock), for assistance with pharmacokinetic data analysis. Editorial support was provided by Cindi A. Hoover, PhD, and funded by Pharmacyclics LLC, an AbbVie Company.
Publisher Copyright:
© 2022 The American Society for Transplantation and Cellular Therapy
PY - 2022/11
Y1 - 2022/11
N2 - Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. Clinical data surrounding cGVHD therapies in younger children are limited and critically needed. Primary endpoints were to determine the recommended pediatric equivalent dose (RPED) and assess pharmacokinetics (PK) and safety. Secondary endpoints included overall response rate (ORR; comprising complete response and partial response) according to the 2014 National Institutes of Health criteria at 24 weeks, overall survival, and duration of response (DOR). Here we present the primary results from the open-label, multicenter, international phase 1/2 iMAGINE study (PCYC-1146-IM), which evaluated the PK, safety, and efficacy of ibrutinib in patients age ≥1 to <22 years with treatment-naive (TN) or relapsed/refractory (R/R) moderate/severe cGVHD. Patients age <12 years received once-daily ibrutinib starting at 120 mg/m2 and escalating to 240 mg/m2 (full adult dose equivalent) after 14 days if free from ibrutinib-related grade ≥3 toxicity; patients age ≥12 years received once-daily ibrutinib 420 mg. Fifty-nine patients (12 TN and 47 with R/R cGVHD; median age, 13 years; range, 1 to 19 years) were enrolled. Plasma concentration-time profiles for ibrutinib 240 mg/m2 (the RPED) were comparable to those observed in adults with cGVHD at a dose of 420 mg/day. Safety was consistent with the known profile of ibrutinib in cGVHD. ORR by 24 weeks was 64% (38 of 59), including 83% (10 of 12) for the TN subgroup and 60% (28 of 47) for R/R. Among 46 responders (median follow-up, 20 months; range, 2 to 32 months), 12-month DOR for each subgroup was 60% (95% confidence interval [CI], 25% to 83%) in TN patients and 58% (95% CI, 35% to 75%) in R/R patients. Responses were durable, with numerically higher rates than those previously observed with ibrutinib in adults, demonstrating that ibrutinib provides clinically meaningful activity with acceptable safety in children with moderate/severe cGVHD.
AB - Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. Clinical data surrounding cGVHD therapies in younger children are limited and critically needed. Primary endpoints were to determine the recommended pediatric equivalent dose (RPED) and assess pharmacokinetics (PK) and safety. Secondary endpoints included overall response rate (ORR; comprising complete response and partial response) according to the 2014 National Institutes of Health criteria at 24 weeks, overall survival, and duration of response (DOR). Here we present the primary results from the open-label, multicenter, international phase 1/2 iMAGINE study (PCYC-1146-IM), which evaluated the PK, safety, and efficacy of ibrutinib in patients age ≥1 to <22 years with treatment-naive (TN) or relapsed/refractory (R/R) moderate/severe cGVHD. Patients age <12 years received once-daily ibrutinib starting at 120 mg/m2 and escalating to 240 mg/m2 (full adult dose equivalent) after 14 days if free from ibrutinib-related grade ≥3 toxicity; patients age ≥12 years received once-daily ibrutinib 420 mg. Fifty-nine patients (12 TN and 47 with R/R cGVHD; median age, 13 years; range, 1 to 19 years) were enrolled. Plasma concentration-time profiles for ibrutinib 240 mg/m2 (the RPED) were comparable to those observed in adults with cGVHD at a dose of 420 mg/day. Safety was consistent with the known profile of ibrutinib in cGVHD. ORR by 24 weeks was 64% (38 of 59), including 83% (10 of 12) for the TN subgroup and 60% (28 of 47) for R/R. Among 46 responders (median follow-up, 20 months; range, 2 to 32 months), 12-month DOR for each subgroup was 60% (95% confidence interval [CI], 25% to 83%) in TN patients and 58% (95% CI, 35% to 75%) in R/R patients. Responses were durable, with numerically higher rates than those previously observed with ibrutinib in adults, demonstrating that ibrutinib provides clinically meaningful activity with acceptable safety in children with moderate/severe cGVHD.
KW - Bruton's tyrosine kinase inhibitor
KW - Chronic graft-versus-host disease
KW - Ibrutinib
KW - Pediatric
UR - http://www.scopus.com/inward/record.url?scp=85139336459&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85139336459&partnerID=8YFLogxK
U2 - 10.1016/j.jtct.2022.08.021
DO - 10.1016/j.jtct.2022.08.021
M3 - Article
C2 - 36044977
AN - SCOPUS:85139336459
SN - 2666-6375
VL - 28
SP - 771.e1-771.e10
JO - Transplantation and Cellular Therapy
JF - Transplantation and Cellular Therapy
IS - 11
ER -