TY - JOUR
T1 - Treosulfan, Fludarabine, and Low-Dose Total Body Irradiation for Children and Young Adults with Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation
T2 - Prospective Phase II Trial of the Pediatric Blood and Marrow Transplant Consortium
AU - Nemecek, Eneida R.
AU - Hilger, Ralf A.
AU - Adams, Alexia
AU - Shaw, Bronwen E.
AU - Kiefer, Deidre
AU - Le-Rademacher, Jennifer
AU - Levine, John E.
AU - Yanik, Gregory
AU - Leung, Wing
AU - Talano, Julie An
AU - Haut, Paul
AU - Delgado, David
AU - Kapoor, Neena
AU - Petrovic, Aleksandra
AU - Adams, Roberta
AU - Hanna, Rabi
AU - Rangarajan, Hemalatha
AU - Dalal, Jignesh
AU - Chewning, Joseph
AU - Verneris, Michael R.
AU - Epstein, Stacy
AU - Burroughs, Lauri
AU - Perez-Albuerne, Evelio D.
AU - Pulsipher, Michael A.
AU - Delaney, Colleen
N1 - Funding Information:
Financial disclosure: The study was supported in part by grants from the Johnny Crisstopher Children's Charitable Foundation St. Baldrick's Consortium Grant, and Medac GmbH . The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; a Grant/Cooperative Agreement (4U10HL069294) from NHLBI and NCI; a contract (HHSH250201200016C) with Health Resources and Services Administration (HRSA/DHHS); 2 grants (N00014-17-1-2388 and N0014-17-1-2850) from the Office of Naval Research; and grants from (asterisk represents corporate members) *Actinium Pharmaceuticals, Inc.; *Amgen, Inc.; *Amneal Biosciences; *Angiocrine Bioscience, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; Atara Biotherapeutics, Inc.; Be the Match Foundation; *bluebird bio, Inc.; *Bristol Myers Squibb Oncology; *Celgene Corporation; Cerus Corporation; *Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Gilead Sciences, Inc.; HistoGenetics, Inc.; Immucor; *Incyte Corporation; Janssen Scientific Affairs, LLC; *Jazz Pharmaceuticals, Inc.; Juno Therapeutics; Karyopharm Therapeutics, Inc.; Kite Pharma, Inc.; Medac, GmbH; MedImmune; The Medical College of Wisconsin; *Mediware; *Merck & Co, Inc.; *Mesoblast; MesoScale Diagnostics, Inc.; Millennium, the Takeda Oncology Co.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; *Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Otsuka Pharmaceutical Co, Ltd. – Japan; PCORI; *Pfizer, Inc; *Pharmacyclics, LLC; PIRCHE AG; *Sanofi Genzyme; *Seattle Genetics; Shire; Spectrum Pharmaceuticals, Inc.; St. Baldrick's Foundation; *Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; Telomere Diagnostics, Inc.; and University of Minnesota. The views expressed in in this article are the authors and not an official position of the institutions or sources of support (including the National Institutes of Health, the Department of the Navy, the Department of Defense, HRSA, or any other agency of the US Government).
Funding Information:
Financial disclosure: The study was supported in part by grants from the Johnny Crisstopher Children's Charitable Foundation St. Baldrick's Consortium Grant, and Medac GmbH. The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; a Grant/Cooperative Agreement (4U10HL069294) from NHLBI and NCI; a contract (HHSH250201200016C) with Health Resources and Services Administration (HRSA/DHHS); 2 grants (N00014-17-1-2388 and N0014-17-1-2850) from the Office of Naval Research; and grants from (asterisk represents corporate members) *Actinium Pharmaceuticals, Inc.; *Amgen, Inc.; *Amneal Biosciences; *Angiocrine Bioscience, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; Atara Biotherapeutics, Inc.; Be the Match Foundation; *bluebird bio, Inc.; *Bristol Myers Squibb Oncology; *Celgene Corporation; Cerus Corporation; *Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Gilead Sciences, Inc.; HistoGenetics, Inc.; Immucor; *Incyte Corporation; Janssen Scientific Affairs, LLC; *Jazz Pharmaceuticals, Inc.; Juno Therapeutics; Karyopharm Therapeutics, Inc.; Kite Pharma, Inc.; Medac, GmbH; MedImmune; The Medical College of Wisconsin; *Mediware; *Merck & Co, Inc.; *Mesoblast; MesoScale Diagnostics, Inc.; Millennium, the Takeda Oncology Co.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; *Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Otsuka Pharmaceutical Co, Ltd. ? Japan; PCORI; *Pfizer, Inc; *Pharmacyclics, LLC; PIRCHE AG; *Sanofi Genzyme; *Seattle Genetics; Shire; Spectrum Pharmaceuticals, Inc.; St. Baldrick's Foundation; *Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; Telomere Diagnostics, Inc.; and University of Minnesota. The views expressed in in this article are the authors and not an official position of the institutions or sources of support (including the National Institutes of Health, the Department of the Navy, the Department of Defense, HRSA, or any other agency of the US Government).
Publisher Copyright:
© 2018 The American Society for Blood and Marrow Transplantation
PY - 2018/8
Y1 - 2018/8
N2 - This multicenter study evaluated a treosulfan-based regimen in children and young adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplant (HCT). Forty patients with median age 11 years (range, 1 to 19) underwent allogeneic HCT for AML in first (n = 18), second (n = 11), and third or greater remission (n = 3) or MDS (n = 8) using bone marrow (n = 25), peripheral blood stem cells (n = 5), or cord blood (n = 9). The regimen consisted of body surface area (BSA)-based treosulfan 10 g/m 2 /day (BSA ≤.5 m 2 ), 12 g/m 2 /day (BSA >.5 to 1.0 m 2 ), or 14 g/m 2 /day (BSA > 1.0 m 2 ) on days −6 to −4; fludarabine 30 mg/m 2 /day on days −6 to −2; and a single fraction of 200 cGy total body irradiation on day −1. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and methotrexate for marrow and peripheral blood stem cell and cyclosporine/mycophenolate mofetil for cord blood. One-year overall survival, disease-free survival, and nonrelapse mortality were 80%, 73%, and 3%, respectively. One-year relapse was 38% for AML and 13% for MDS. No serious organ toxicities were observed. All 37 assessable patients engrafted. Cumulative incidences of grades II to IV acute GVHD and chronic GVHD were 22% and 40%, respectively. BSA-based treosulfan dosing resulted in predictable area under the curve and maximum concentration, which is required for dosing without measuring individual pharmacokinetic parameters. Observed differences in pharmacokinetics did not impact disease control or regimen toxicity. This BSA-based treosulfan regimen resulted in excellent engraftment and disease-free survival and minimal toxicity and transplant-related mortality (3%) in children and young adults with AML and MDS.
AB - This multicenter study evaluated a treosulfan-based regimen in children and young adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplant (HCT). Forty patients with median age 11 years (range, 1 to 19) underwent allogeneic HCT for AML in first (n = 18), second (n = 11), and third or greater remission (n = 3) or MDS (n = 8) using bone marrow (n = 25), peripheral blood stem cells (n = 5), or cord blood (n = 9). The regimen consisted of body surface area (BSA)-based treosulfan 10 g/m 2 /day (BSA ≤.5 m 2 ), 12 g/m 2 /day (BSA >.5 to 1.0 m 2 ), or 14 g/m 2 /day (BSA > 1.0 m 2 ) on days −6 to −4; fludarabine 30 mg/m 2 /day on days −6 to −2; and a single fraction of 200 cGy total body irradiation on day −1. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and methotrexate for marrow and peripheral blood stem cell and cyclosporine/mycophenolate mofetil for cord blood. One-year overall survival, disease-free survival, and nonrelapse mortality were 80%, 73%, and 3%, respectively. One-year relapse was 38% for AML and 13% for MDS. No serious organ toxicities were observed. All 37 assessable patients engrafted. Cumulative incidences of grades II to IV acute GVHD and chronic GVHD were 22% and 40%, respectively. BSA-based treosulfan dosing resulted in predictable area under the curve and maximum concentration, which is required for dosing without measuring individual pharmacokinetic parameters. Observed differences in pharmacokinetics did not impact disease control or regimen toxicity. This BSA-based treosulfan regimen resulted in excellent engraftment and disease-free survival and minimal toxicity and transplant-related mortality (3%) in children and young adults with AML and MDS.
KW - Acute myeloid leukemia
KW - Conditioning regimen
KW - Myelodysplastic syndromes
KW - Stem cell transplantation
UR - http://www.scopus.com/inward/record.url?scp=85047460893&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047460893&partnerID=8YFLogxK
U2 - 10.1016/j.bbmt.2018.04.025
DO - 10.1016/j.bbmt.2018.04.025
M3 - Article
C2 - 29753157
AN - SCOPUS:85047460893
SN - 1083-8791
VL - 24
SP - 1651
EP - 1656
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 8
ER -