A trial of unrelated donor marrow transplantation for children with severe sickle cell disease.
Children with sickle cell disease experience organ damage, impaired quality of life, and premature mortality. Allogeneic bone marrow transplant from an HLA-matched sibling can halt disease progression but is limited by donor availability. A Blood and Marrow Transplant Clinical Trials Network (BMT CTN) phase 2 trial conducted from 2008 to 2014 enrolled 30 children aged 4 to 19 years; 29 were eligible for evaluation. The primary objective was 1-year event-free survival (EFS) after HLA allele-matched (at HLA-A, -B, -C, and -DRB1 loci) unrelated donor transplant. The conditioning regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitor, short-course methotrexate, and methylprednisolone. Transplant indications included stroke (n = 12), transcranial Doppler velocity >200 cm/s (n = 2), ≥3 vaso-occlusive pain crises per year (n = 12), or ≥2 acute chest syndrome episodes (n = 4) in the 2 years preceding enrollment. Median follow-up was 26 months (range, 12-62 months); graft rejection was 10%. The 1- and 2-year EFS rates were 76% and 69%, respectively. The corresponding rates for overall survival were 86% and 79%. The day 100 incidence rate of grade II-IV acute GVHD was 28%, and the 1-year incidence rate of chronic GVHD was 62%; 38% classified as extensive. There were 7 GVHD-related deaths. A 34% incidence of posterior reversible encephalopathy syndrome was noted in the first 6 months. Although the 1-year EFS met the prespecified target of ≥75%, this regimen cannot be considered sufficiently safe for widespread adoption without modifications to achieve more effective GVHD prophylaxis. The BMT CTN #0601 trial was registered at www.clinicaltrials.gov as #NCT00745420.
Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO.
Shalini
S
Shenoy
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.
Mary
M
Eapen
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.|Children's Hospital of Wisconsin, Milwaukee, WI.
Julie A
JA
Panepinto
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.
Brent R
BR
Logan
The Emmes Corporation, Rockville, MD.
Juan
J
Wu
Children's National Medical Center, Washington, DC.
Allistair
A
Abraham
Steven and Alexandra Cohen Children's Medical Center, New Hyde Park, NY.
Joel
J
Brochstein
Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.
Sonali
S
Chaudhury
Department of Pediatrics, Virginia Commonwealth University, Richmond, VA.
Kamar
K
Godder
Department of Pediatrics, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA.
Ann E
AE
Haight
Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Kimberly A
KA
Kasow
Department of Pediatrics, Baylor College of Medicine, Houston, TX.
Kathryn
K
Leung
Department of Pediatrics, University of Miami, Miami, FL.
Martin
M
Andreansky
Columbia University Medical Center, New York, NY.
Monica
M
Bhatia
Children's Mercy Hospital and Clinics, Kansas City, KS.
Jignesh
J
Dalal
Department of Pediatrics, University of Alabama, Birmingham, AL.
Hilary
H
Haines
Department of Pediatrics, Medical University of South Carolina, Charleston, SC.
Jennifer
J
Jaroscak
Department of Internal Medicine, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH.
Hillard M
HM
Lazarus
Departments of Internal Medicine and Pediatrics, University of Michigan, Ann Arbor, MI.
John E
JE
Levine
Children's Hospital of Pittsburgh, Pittsburgh, PA.
Lakshmanan
L
Krishnamurti
Children's Hospital of Wisconsin, Milwaukee, WI.
David
D
Margolis
University of Mississippi Medical Center, Jackson, MS.
Gail C
GC
Megason
Louisiana State University Medical Center, Children's Hospital of New Orleans, New Orleans, LA.
Lolie C
LC
Yu
Pediatric Blood and Marrow Transplant Consortium, Salt Lake City, UT.
Michael A
MA
Pulsipher
The Emmes Corporation, Rockville, MD.
Iris
I
Gersten
National Heart, Lung, and Blood Institute, Bethesda, MD.
Nancy
N
DiFronzo
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.
Mary M
MM
Horowitz
UCSF Benioff Children's Hospital, Oakland, CA; and.
Mark C
MC
Walters
AABB Center for Cellular Therapies, Bethesda, MD.
Naynesh
N
Kamani
D000293:Adolescent; D064591:Allografts; D000755:Anemia, Sickle Cell / Q000401:mortality* / Q000503:physiopathology / Q000628:therapy*; D016026:Bone Marrow Transplantation; D065095:Calcineurin Inhibitors / Q000008:administration & dosage; D002648:Child; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000401:mortality / Q000517:prevention & control; D006801:Humans; D008297:Male; D015996:Survival Rate; D061349:Unrelated Donors
D065095:Calcineurin Inhibitors