title: Efficacy of tacrolimus/mycophenolate mofetil as acute graft-versus-host disease prophylaxis and the impact of subtherapeutic tacrolimus levels in children after matched sibling donor allogeneic hematopoietic cell transplantation.
abstract: Only a few studies in children have evaluated the efficacy of prophylactic regimens using tacrolimus on acute graft-versus-host disease (aGVHD). As a result, optimal tacrolimus levels in children after matched sibling donor allogeneic hematopoietic cell transplantation (alloHCT) are not well defined. We measured the association between subtherapeutic levels (<10 ng/mL) during weeks 1 to 4 after alloHCT and the cumulative incidence of grades II to IV aGVHD in children. Additionally, we identified optimal lower cutoff levels for tacrolimus. Sixty patients (median age, 8 years) received tacrolimus/mycophenolate mofetil between March 2003 and September 2012. Twenty-three had a malignant disease and 37 nonmalignant disorders. The stem cell source included peripheral blood stem cells (n = 12) and bone marrow or cord blood (n = 48). Conditioning regimen varied. Specifically, 38.3% received a myeloablative regimen, 36.7% receiving a reduced-toxicity regimen, and 25% receiving a reduced-intensity regimen. Tacrolimus was initiated at .03 mg/kg/day via continuous i.v. infusion or .12 mg/kg/day orally. The dose was adjusted to maintain daily steady state concentrations within a range of 10 to 20 ng/mL. The overall incidence of grades II to IV aGVHD was 33.3%. On multivariate analysis, a mean tacrolimus level < 10 ng/mL during week 3 (P = .042; 95% confidence interval, 1.051 to 14.28) was significantly associated with increased incidence of grades II to IV aGVHD. Using weekly receiver operator curves, the optimal lower cutoff for tacrolimus levels was 10 to 11.2 ng/mL. Further prospective studies are warranted to study the incidence of aGVHD comparing the conventional tacrolimus levels of 5 to 15 versus 10 to 15 ng/mL.
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York.
authors.forename: Katharine
authors.initials: K
authors.lastname: Offer
authors.affiliation: Department of Nursing, New York-Presbyterian Morgan Stanley Children's Hospital, New York, New York.
authors.forename: Michelle
authors.initials: M
authors.lastname: Kolb
authors.affiliation: Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York.
authors.forename: Zhezhen
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York.
authors.forename: Monica
authors.initials: M
authors.lastname: Bhatia
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York.
authors.forename: Diane
authors.initials: D
authors.lastname: George
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York.
authors.forename: James H
authors.initials: JH
authors.lastname: Garvin
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York.
authors.forename: Chalitha
authors.initials: C
authors.lastname: Robinson
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York.
authors.forename: Jean
authors.initials: J
authors.lastname: Sosna
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York.
authors.forename: Esra
authors.initials: E
authors.lastname: Karamehmet
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York. Electronic address: ps2087@columbia.edu.
authors.forename: Prakash
authors.initials: P
authors.lastname: Satwani
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006086:Graft vs Host Disease / Q000401:mortality / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007223:Infant; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D009369:Neoplasms / Q000401:mortality / Q000628:therapy; D012189:Retrospective Studies; D035781:Siblings; D015996:Survival Rate; D016559:Tacrolimus / Q000008:administration & dosage*; D019172:Transplantation Conditioning
chemical_list: D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus
keywords: Acute GVHD; ROC curve; Tacrolimus level