Risk-Stratification Directed Prophylaxis with Additional Low-Dose of Methylprednisolone Can Reduce Acute Graft-Versus-Host Disease for Patients with Hematological Malignancies after Allogeneic SCT: A Randomized, Controlled, Clinical Trial

The major complication of allogeneic HSCT-graft-versus-host disease (GVHD)-remains lethal and limits use of this important procedure, especially after unmanipulated haploidentical HSCT. Several studies have provided evidence that universal addition of corticosteroids for prophylaxis of GVHD can reduce the risk for acute GvHD grade II-IV in HLA-matched transplantation. However, corticosteroid, a non-specific immunosuppressive agent, may also contribute to high rates of infections. Our previous data suggest that the ratio of CD4/CD8 in allografts from haploidentical donors can stratify patients into high-risk and low-risk ones who will develop GVHD after transplantation. Recently, we indicated that low-dose of methylprednisolone (MP, 0.5 mg/kg/day) might be a well-tolerated, effective and inexpensive regimen in combination of MTX for therapy of GVHD, suggesting that low-dose corticosteroid may be used for the prophylaxis of GVHD without increasing infection. To investigate whether risk-stratification directed prophylaxis strategy can reduce the incidence of GVHD and improve survival in a hemogenous patient population who underwent unmanipulated haploidentical HSCT, we performed a prospective, randomized, controlled, clinical trial. A total of 228 patients were enrolled in this trial. All of the patients completed the study and were stratified as high-risk (n=145) and low-risk arms (n=83) according to the ratio of CD4/CD8 in allografts. Patients of the high-risk arms were randomly assigned in a 1:1 ratio to additional low-dose glucocorticoid prophylaxis group (Group A, n=72) and control group (GroupB, n=73). The groups were balanced with respect to patient and donor characteristics. Our results showed that the cumulative incidence of grade II-IV acute GVHD on day 100 was 20.9%±4.8% in Group A, which was comparable to Group C (25.5%±4.8%, P=0.430) and both of which were significantly lower than that of Group B (48.1%±5.9%, P＜0.001). In addition, the onset time of grade II-IV acute GVHD was 25 (16-50) days, 15 (9-57) days, and 21 (10-58) days, respectively in Group A, Group B, and Group C (P＜0.05, Group A vs. Group B or Group C). There were no significant difference in grade Ⅲ-IV acute GVHD among these three groups. The ratio of patients who developed glucocorticoid refactory acute GVHD and treated with basiliximab (anti-CD25 antibody) were 13.9% (10/72), 17.8% (13/73), and 22.9% (19/83), respectively, in Group A, Group B, and Group C, there is a trend that the incidence of basiliximab treated patients in Group C is higher than that of Group A (P=0.109). The median time for myeloid engraftment in Group A was 11 days (range: 10-21 days), which was significantly faster that those of Group B (13 days, range from 10 to 33 days, P＜0.05) and Group C (13 days, range from 10 to 33 days, P＜0.05). The median time for platelet engraftment in Group A was 12 days (range: 10-22 days), which was significantly faster that those of Group B (17 days, range from 6 to 255 days, P＜0.01) and Group C (19 days, range from 8 to 260 days, P＜0.01). In addition, risk-stratification directed prophylaxis with additional low-dose of MP did not increase the incidence of CMV, EBV reactivation, PTLD, relapse and TRM, as well as delay immune recovery after unmanipulated haploidentical HSCT. The 100 day cumulative incidence relapse and transplant-related mortality was not significantly different among patients in Group A, Group B, and Group C, respectively. The 100 day probabilities of LFS and OS were comparable among these three patient groups. In conclusion, we for the first time demonstrated that risk-stratification directed prophylaxis for GVHD with additional low-dose of MP could significantly decrease the incidence and delay the onset of grade II-IV acute GVHD without increasing infections and delaying immune recovery. Our data indicated that addition of glucocorticoid early after unmanipulated haploidentical transplantation could also accelerate hematopietic recovery [This study was registered at http://clinicaltrials.gov/ NCT01607580].