title: Combination Therapy for Graft-versus-Host Disease Prophylaxis with Etanercept and Extracorporeal Photopheresis: Results of a Phase II Clinical Trial.
abstract: Reduced-intensity conditioning (RIC) regimens minimize early toxicity after allogeneic hematopoietic cell transplantation (HCT) by placing greater reliance on establishing a graft-versus-leukemia effect (GVL). Because graft-versus-host disease (GVHD) and GVL are tightly linked, inhibition of T cell populations that cause GVHD may lead to an unintended increased risk of relapse in the RIC setting. Although not completely understood, etanercept and extracorporeal photopheresis (ECP) are thought to ameliorate GVHD without direct T cell inhibition. We hypothesized that adding these 2 agents to a standard GVHD prophylaxis regimen of tacrolimus and mycophenolate mofetil (MMF) would improve survival by reducing GVHD-related mortality without increasing relapse rates. Therefore, we conducted a prospective phase II clinical trial that incorporated tacrolimus, MMF, etanercept, and ECP as GVHD prophylaxis in 48 patients undergoing RIC unrelated donor transplantation. The preferred RIC was fludarabine 160 mg/m(2) + busulfan 6.4 mg/kg to 12.8 mg/kg ± total body irradiation 200 cGy. Etanercept .4 mg/kg (maximum dose, 25 mg) was given subcutaneously twice weekly for 8 weeks after HCT and ECP was given for 12 treatments, starting weekly on day 28 weekly and tapering off by day 180. The median age of the study patients was 60 (range, 18 to 71) years. Donors were 7/8 (n = 14, 29%) or 8/8 (n = 34, 71%) HLA matched. All patients engrafted neutrophils at a median of 12 days. The cumulative incidence of grades II to IV acute GVHD at day 100 was 46%, but it was typically sensitive to initial steroid treatment (84% day 56 complete response/partial response rate). Overall survival at 1 year in this older, frequently mismatched unrelated donor setting was excellent (73%) because of low rates of nonrelapse mortality (21%) and relapse (19%). However, this strategy was not effective at preventing a high incidence of chronic GVHD and late deaths led to a drop in 2-year survival, declining to 56%, reflecting a high incidence of chronic GVHD.
authors.affiliation: Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan; Pediatric Stem Cell Transplant Program, Vanderbilt University, Nashville, Tennessee. Electronic address: carrie.l.kitko@vanderbilt.edu.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Kitko
authors.affiliation: Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan.
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.affiliation: Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Couriel
authors.affiliation: Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Sung W
authors.initials: SW
authors.lastname: Choi
authors.affiliation: Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan; Pediatric Stem Cell Transplant Program, Vanderbilt University, Nashville, Tennessee.
authors.forename: James
authors.initials: J
authors.lastname: Connelly
authors.affiliation: Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hoffmann
authors.affiliation: Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Steven
authors.initials: S
authors.lastname: Goldstein
authors.affiliation: Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: John
authors.initials: J
authors.lastname: Magenau
authors.affiliation: Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Attaphol
authors.initials: A
authors.lastname: Pawarode
authors.affiliation: Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Charles
authors.initials: C
authors.lastname: Schuler
authors.affiliation: Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Yanik
authors.affiliation: Blood and Marrow Transplant Program, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: James L
authors.initials: JL
authors.lastname: Ferrara
authors.affiliation: Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan; Blood and Marrow Transplant Program, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: John E
authors.initials: JE
authors.lastname: Levine
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D064591:Allografts; D018572:Disease-Free Survival; D000068800:Etanercept / Q000008:administration & dosage*; D005260:Female; D006086:Graft vs Host Disease / Q000097:blood / Q000401:mortality / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D017893:Photopheresis / Q000379:methods*; D011446:Prospective Studies; D015996:Survival Rate; D019172:Transplantation Conditioning
chemical_list: D000068800:Etanercept
keywords: Etanercept; Graft-versus-host disease; Photopheresis; Prophylaxis