Use of Antilymphocyte Globulin Appears to Reduce Chronic Graft-vs-Host Disease After Allogeneic Stem Cell Transplantation in Acute Leukemia
In a European phase III study reported in The New England Journal of Medicine, Kröger et al found that inclusion of antihuman T-lymphocyte immune globulin (ATG) in the myeloablative conditioning regimen in patients with acute myeloid or lymphoid leukemia resulted in a significant reduction in chronic graft-vs-host disease 2 years after allogeneic peripheral blood stem cell transplantation from HLA-identical siblings. There were no differences in 2-year relapse-free or overall survival between the ATG and no-ATG groups.
Study Details
In the open-label trial, 155 evaluable patients (aged 18–65 years) with acute myeloid or lymphoblastic leukemia in first or subsequent complete remission and indicated for an allogeneic hematopoietic stem cell transplantation from 27 sites were randomized between December 2006 and February 2012 to receive ATG (n = 83) or no ATG (n = 72). The conditioning regimen consisted of cyclophosphamide (120 mg/kg) and total-body irradiation (12 Gy) or busulfan (16 mg/kg orally or 12.8 mg/kg IV) with or without etoposide (30–60 mg/kg). ATG was given at 10 mg/kg on 3, 2, and 1 days before transplantation from an HLA-identical donor.
All siblings were matched serologically for HLA-A and HLA-B and for HLA-DRB1 and HLA-DQB1 alleles. Graft-vs-host disease prophylaxis consisted of cyclosporine and a short course of methotrexate. The primary endpoint was cumulative incidence of chronic graft-vs-host disease at 2 years.
Patients in the ATG and no-ATG groups had a median age of 39 and 44 years, 64% and 56% were male, 66% and 76% had acute myeloid leukemia, 37% and 31% were at high cytogenetic risk, 88% and 92% were in first complete remission, and 68% and 71% received the busulfan/cyclophosphamide conditioning regimen.
After a median follow-up of 24 months, the cumulative incidence of chronic graft-vs-host disease was 32.2% (95% confidence interval [CI] = 22.1%–46.7%) in the ATG group vs 68.7% (95% CI = 58.4%–80.7%) in the no-ATG group (P < .001). Two-year rates were 59.4% vs 64.6% (P = .21) for relapse-free survival and 74.1% vs 77.9% (P = .46) for overall survival.
On multivariate analysis, only diagnosis of acute lymphoblastic leukemia vs acute myeloid leukemia was significantly associated with survival (hazard ratio [HR] = 2.64, P = .02); the hazard ratio for survival for ATG vs no ATG was 0.74 (P = 0.47). The rate of the composite endpoint of 2-year survival free from chronic graft-vs-host disease and free from relapse was 36.6% vs 16.8% (P = .005).
Toxicity, Nonrelapse-Related Death
Infectious complications occurred in 57.8% vs 54.2% of patients (P = .65), with no differences in cytomegalovirus reactivation (21.7% vs 25.0%), Epstein–Barr virus reactivation (3.6% vs 1.4%), or fungal infection (3.6% vs 4.2%). The rate of nonrelapse-related death at 2 years was 14.0% vs 12.0% (P = .60).
The investigator concluded: “The inclusion of ATG resulted in a significantly lower rate of chronic graft-vs-host disease after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic graft-vs-host disease–free survival and relapse-free survival was higher with ATG.”
The study was funded by Neovii Biotech and European Society for Blood and Marrow Transplantation.
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