@article{783dba318095442c93de2d6a8a1a606a,
title = "A Prospective Study of Peritransplant Sorafenib for Patients with FLT3-ITD Acute Myeloid Leukemia Undergoing Allogeneic Transplantation",
abstract = "FLT3-ITD-mutated acute myeloid leukemia (AML) remains a therapeutic challenge. FLT3 inhibition in the setting of minimal residual disease and a new immune system via allogeneic transplantation offers a promise of improved survival for these patients. We performed a prospective study of patients with FLT3-ITD AML undergoing allogeneic transplant that was conducted to evaluate the safety, tolerability, and outcome of sorafenib administered peritransplant. Sorafenib dosing was individualized, starting at 200 mg twice a day (BID), and titrated based on tolerability or toxicities until a tolerable dose was identified. Forty-four patients, with a median age of 52 years, undergoing allogeneic transplant were started on sorafenib in the peritransplant period (21 pretransplant). The median duration of post-transplant follow-up was 27.6 months (range, 5.2 to 60.4). Overall survival was 76% at both 24 and 36 months. Event-free survival at 24 and 36 months was 74% and 64%, respectively. Ten patients died in the post-transplant period, with 6 deaths due to relapsed leukemia and 4 from transplant-associated toxicity. Tolerable doses ranged from 200 mg every other day to 400 mg BID with similar exposure. Correlative studies evaluating FLT3 inhibition via a plasma inhibitory activity assay showed consistent inhibition of FLT3 at all tolerability-determined dosing levels. Sorafenib is well tolerated in the peritransplant setting irrespective of the conditioning intensity or the donor source. Our findings indicate that sorafenib dosing can be individualized in the post-transplantation setting according to patient tolerability. This approach results in effective in vivo FLT3 inhibition and yields encouraging survival results.",
keywords = "FLT3, Maintenance, Post-transplant",
author = "{ETCTN-8922 study team} and Pratz, {Keith W.} and Rudek, {Michelle A.} and Smith, {B. Douglas} and Judith Karp and Ivana Gojo and Amy Dezern and Jones, {Richard J.} and Jackie Greer and Christopher Gocke and Baer, {Maria R.} and Duong, {Vu H.} and Gary Rosner and Marianna Zahurak and Wright, {John J.} and Ashkan Emadi and Mark Levis",
note = "Funding Information: Financial disclosure: The project described was supported in part by National Cancer Institute (NCI) Cooperative Agreement U01CA070095 , P01 CA015396 , and UM1CA186691 and by the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (National Institutes of Health [NIH] grants P30CA006973 and UL1TR001079 ) and the University of Maryland Comprehensive Cancer Center Support Grant NCI P30CA134274. Grant UL1TR 001079 is from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH, and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the Johns Hopkins Institute for Clinical and Translational Research, NCATS, or NIH. Conflict of interest statement: K.W.P. received grant/research support from AbbVie, Agios, Astellas, and Millenium/Takeda and provided consulting for AbbVie, Astellas, and Boston Biomedical. M.A.R. received the following support: employment: Novavax (spouse); stock or other ownership: Novavax (spouse); research funding: Celgene (institution) and Taiho Pharmaceutical (institution); honoraria: UpToDate; travel, accommodations, expenses: Expert Medical Events; and advisory committee: National Comprehensive Cancer Network. B.D.S. received grant/research support from Novartis, Tolero, and Io Therapeutics and provided consulting for Celgene, Jazz, Pfizer, and Bristol Myers Squibb. J.K.: data safety monitoring committee's for Tolero Pharmaceuticals; Imago; Leukemia Lymphoma Society Beat AML. I.G. received research support from Merck and Amgen and is on the advisory board for Abbvie and Jazz. A.E.D. received grant/research support from Acceleron and Celegene. G.R. is a consultant for Novartis and has stock ownership in Johnson & Johnson. R.J., J.G., C.G., V.H.D., J.J.W., M.B., M.Z., and A.E. have nothing to disclose. M.L. received grant/research support from FujiFilm, Novartis, Astellas, and Takeda and provided consulting for Amgen, Agios, Daiichi-Sankyo, Novartis, Astellas, and FujiFilm. Authorship statement: K.W.P., J.K., R.J.J., G.R., J.J.W., and M.L. designed the study. B.D.S., I.G., A.D., J.G., M.R.B., V.H.D., and A.E. conducted the study and treated study participants. C.G. performed FLT3 and engraftment studies. G.R. and M.Z. performed statistical analysis. M.A.R. performed pharmacokinetic analysis. K.W.P. performed pharmacodynamic analysis and prepared the manuscript and figures for publication. All authors analyzed the data, reviewed the manuscript, and agreed to its submission for publication. Funding Information: Financial disclosure: The project described was supported in part by National Cancer Institute (NCI) Cooperative Agreement U01CA070095, P01 CA015396, and UM1CA186691 and by the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (National Institutes of Health [NIH] grants P30CA006973 and UL1TR001079) and the University of Maryland Comprehensive Cancer Center Support Grant NCI P30CA134274. Grant UL1TR 001079 is from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH, and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the Johns Hopkins Institute for Clinical and Translational Research, NCATS, or NIH. Conflict of interest statement: K.W.P. received grant/research support from AbbVie, Agios, Astellas, and Millenium/Takeda and provided consulting for AbbVie, Astellas, and Boston Biomedical. M.A.R. received the following support: employment: Novavax (spouse); stock or other ownership: Novavax (spouse); research funding: Celgene (institution) and Taiho Pharmaceutical (institution); honoraria: UpToDate; travel, accommodations, expenses: Expert Medical Events; and advisory committee: National Comprehensive Cancer Network. B.D.S. received grant/research support from Novartis, Tolero, and Io Therapeutics and provided consulting for Celgene, Jazz, Pfizer, and Bristol Myers Squibb. J.K.: data safety monitoring committee's for Tolero Pharmaceuticals; Imago; Leukemia Lymphoma Society Beat AML. I.G. received research support from Merck and Amgen and is on the advisory board for Abbvie and Jazz. A.E.D. received grant/research support from Acceleron and Celegene. G.R. is a consultant for Novartis and has stock ownership in Johnson & Johnson. R.J. J.G. C.G. V.H.D. J.J.W. M.B. M.Z. and A.E. have nothing to disclose. M.L. received grant/research support from FujiFilm, Novartis, Astellas, and Takeda and provided consulting for Amgen, Agios, Daiichi-Sankyo, Novartis, Astellas, and FujiFilm. Authorship statement: K.W.P. J.K. R.J.J. G.R. J.J.W. and M.L. designed the study. B.D.S. I.G. A.D. J.G. M.R.B. V.H.D. and A.E. conducted the study and treated study participants. C.G. performed FLT3 and engraftment studies. G.R. and M.Z. performed statistical analysis. M.A.R. performed pharmacokinetic analysis. K.W.P. performed pharmacodynamic analysis and prepared the manuscript and figures for publication. All authors analyzed the data, reviewed the manuscript, and agreed to its submission for publication. Financial disclosure: See Acknowledgments on page 305. Publisher Copyright: {\textcopyright} 2019",
year = "2020",
month = feb,
doi = "10.1016/j.bbmt.2019.09.023",
language = "English (US)",
volume = "26",
pages = "300--306",
journal = "Biology of Blood and Marrow Transplantation",
issn = "1083-8791",
publisher = "Elsevier Inc.",
number = "2",
}