Pharmacokinetics and pharmacodynamics of anti-thymocyte globulin in recipients of partially HLA-matched blood hematopoietic progenitor cell transplantation.
Polyclonal anti-thymocyte globulin (ATG) administered before allogeneic blood hematopoietic progenitor cell transplantation reduces the risks of graft rejection and graft-versus-host disease, but may delay posttransplant immune reconstitution caused by delayed clearance of ATG from the blood. We studied graft-versus-host disease, infections, and the kinetics of immune reconstitution in 28 patients with very poor-risk hematologic malignancies who received lymphocyte-depleted, CD34(+) cell-enriched hematopoietic progenitor cell grafts from partially HLA-matched related donors (PMRD). The incidence of these clinical events was correlated with blood ATG levels in 19 transplant recipients who received rabbit ATG (r-ATG, thymoglobulin) during conditioning. Total r-ATG and the fraction of ATG antibodies that bind human cells (active ATG) were measured for up to 45 days posttransplantation using enzyme-linked immunosorbent assay and flow cytometry assays. Three patients received equine ATG (e-ATG; total dose of 60 mg/kg/day), 3 patients received 10 mg/kg r-ATG, and 22 patients received 6 mg/kg r-ATG during conditioning. All evaluable patients engrafted. Median numbers of blood CD4(+) and CD8(+) T cells at 100 days posttransplantation were 15 and 8 cells/microL, respectively. Acute graft-versus-host disease developed in 3 of 3 recipients of e-ATG and 1 of 25 recipients of r-ATG. Rapid T-cell reconstitution was seen only in younger patients. Overall mortality was 93% (26/28 patients) with poor immune reconstitution contributing to death in 21 of 28 patients. Recipients of 6 mg/kg r-ATG had peak levels of total and active r-ATG of 64+/-20 microg/mL and 9.2+/-5.8 microg/mL, respectively, with clearance of active r-ATG (t(1/2)6 days) to sub-therapeutic levels (<1 microg/mL) by a median of 15 days posttransplantation (range, 8-38 days). Delayed immune reconstitution is likely a consequence of ex vivo and in vivo purging of donor T cells in the graft coupled with inadequate thymic function rather than persistence of active r-ATG in the blood for months posttransplantation.
Waller
Edmund K
EK
Winship Cancer Institute, Emory University, 1701 Uppergate Dr, Atlanta, GA 30322, USA. ewaller@emory.edu
Langston
Amelia A
AA
Lonial
Sagar
S
Cherry
Judy
J
Somani
Jyoti
J
Allen
Andrew J
AJ
Rosenthal
Hilary
H
Redei
Istvan
I
D000328:Adult; D000818:Animals; D000961:Antilymphocyte Serum / Q000097:blood* / Q000494:pharmacology*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology*; D019337:Hematologic Neoplasms / Q000601:surgery*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections / Q000276:immunology; D011817:Rabbits; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D019172:Transplantation Conditioning / Q000379:methods; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D000961:Antilymphocyte Serum; D006680:HLA Antigens