Influence of two different doses of antithymocyte globulin in patients with standard-risk disease following haploidentical transplantation: a randomized trial

Abstract

To evaluate the effect of the different doses of antithymocyte globulin (ATG) on the incidence of acute GVHD among patients receiving hematopoietic SCT without ex vivo T-cell-depletion from haploidentical donors, 224 patients with standard-risk hematological malignancy were randomized in this study. One hundred and twelve patients received 6 mg/kg ATG, whereas the remaining patients received 10 mg/kg ATG. This study was registered at http://www.chictr.org as No. ChiCTR-TRC-11001761. The incidence of grade III-IV acute GVHD was higher in the ATG-6 group (16.1%, 95% confidence interval (CI), 9.1-23.1%) than in the ATG-10 group (4.5%, CI, 0.7-8.3%, P ¼ 0.005, 95% CI for the difference, À 19.4% to À 3.8%). EBV reactivation occurred more frequently in the ATG-10 group (25.3%, 17.1-33.5%) than in the ATG-6 group (9.6% (4.0-15.2%), P ¼ 0.001). The 1-year disease-free survival rates were 84.3% (77.3-91.3%) and 86.0% (79.2-92.8%) for the ATG-6 group and ATG-10 groups, respectively (P ¼ 0.88). In conclusion, although 6 mg/kg ATG applied in haploidentical transplantation decreased the risk of EBV reactivation compared with 10 mg/kg ATG, this treatment exposes patients to a higher risk for severe acute GVHD. INTRODUCTIONAntithymocyte globulin (ATG) has been used in the conditioning regimen to prevent severe GVHD in haploidentical hematopoietic SCT (HSCT), and our previous study presented encouraging results. 1 However, the limitations associated with the use of ATG as a regimen for in vivo T-cell depletion (TCD) include the occurrence of delayed immune reconstitution and an increased risk of severe infections, depending on the dose of ATG administered. 2 Several previous studies have suggested suitable doses of ATG in matched unrelated transplantations. 3,4 However, to date, the optimal dose of ATG with respect to the prevention of severe GVHD following the haploidentical transplantation is unknown.In our recently reported retrospective study, we reduced the total dose of ATG from the traditional 10 mg/kg in our classic regimen to 6 mg/kg for refractory/relapsed patients undergoing haploidentical HSCT. We observed that the reduction of the total dose of ATG to 6 mg/kg produced similar rates of engraftment, GVHD and survival compared with the 10 mg/kg dose of ATG. 5 Based on these findings, we set out to extend the use of 6 mg/kg ATG to standard-risk patients. Therefore, we initiated the current prospective randomized study to evaluate the effect of the two different doses of ATG in conditioning regimens on graft failure, GVHD, relapse and survival among standard-risk patients receiving haploidentical HSCT. We postulated that the use of 6 mg/kg ATG might reduce adverse events without increasing the risk of GVHD.

Lower dose anti-thymocyte globulin for GvHD prophylaxis results in improved survival after allogeneic stem cell transplantation

“…7,10,12,13 In our study, we found that lower dose ATG-F decreased the incidence of cGvHD without influencing aGvHD. Similar results have been reported by Bonifazi et al…”

“…However, with the exception of one study with matched-related HSCT only, 21 these studies did not reach statistical significance. [7][8][9][10]13,22 The survival benefit shown here may be due to an improved selection of patients receiving ATG. Although the imbalance of known risk factors was adjusted for by statistical analysis, larger series of patients need to be analyzed for confirmation.…”

“…Other groups had similar findings, for example, Bacigalupo et al, 10 who found more lethal infections with ATG, but others did not find any difference in infection-related mortality. 7,13,22 Previous studies had only analyzed fatal infections or patients with 41 any infectious episode without further differentiation. We analyzed infections as viral reactivation, symptomatic viral infection, bacterial and fungal infection within 6 months from transplantation.…”

“…ATG has been shown in randomized clinical trials to decrease mainly chronic GvHD (cGvHD) but not to prolong survival. [7][8][9][10][11][12][13] However, studies were possibly underpowered and without sufficient follow-up to detect survival differences. ATG-Fresenius (ATG-F) at a dose of 60 mg/kg (20 mg/kg on days − 3, − 2 and − 1) was studied in one of the largest randomized trials with ATG 7 and became therefore standard GvHD prophylaxis in unrelated donor HSCT at our institution.…”

Prophylactic use of low-dose interleukin-2 and the clinical outcomes of hematopoietic stem cell transplantation: A randomized study

“…31,36,37 aGVHD was defined and graded from 0 to 4 based on the Seattle criteria. 38 cGVHD was defined and graded according to the NIH criteria.…”