Prevention of Chronic GvHD after HLA-Identical Sibling Peripheral Hematopietic Stem Cell Transplantation with or without Anti-Lymphocyte Globulin (ATG). Results from a Prospective, Multicenter Randomized Phase III Trial (ATGfamilystudy)

Introduction

Allogeneic stem cell transplantation is a curative and increasingly used treatment approach for a variety of hematological malignancies. Late complications such a chronic graft-versus-host disease (cGvHD) is a major risk factor, which significantly influences morbidity and mortality after allogeneic stem cell transplantation (ASCT). The incidence of cGvHD is higher when peripheral blood stem cells are used as stem cell source. There is a strong need for preventing cGvHD after ASCT without increasing the risk of relapse.

Patients and Methods

We performed a multicenter, multinational, open-label, randomized study comparing anti-lymphocyte globulin (ATG-Neovii®) 10mg/kg on day -3,-2 and -1 with no ATG in 155 patients with acute myeloid (n=110) or lymphoblastic leukemia (n=45) in 1^st complete remission (CR; n= 139) or 2^nd CR (n=16) who received peripheral blood stem cells from their HLA-identical sibling (n=148) or relatives (n=7) after standard TBI (12Gy)/Cyclophosphamide (120mg/kg) or Busulfan (16mg/kg)/Cy (120mg/kg) based myeloablative conditioning regimen and sufficient organ function. Standard GvHD prophylaxis consisted of cyclosporine A and a short course of MTX (10mg/m² on day +1,+3,+6 and +11). Major inclusion criteria were: acute myeloid or lymphoblastic leukemia in 1^st or 2^ndCR, age 18-65 years, HLA-identical sibling or relatives, peripheral blood stem cell as stem cell source, and a myeloablative conditioning regimen. The primary study aim was to compare the cumulative incidence of cGvHD at 2 years after ASCT.

Results

Out of 161 randomized patients from 27 centers and 4 nations, 6 were withdrawn before conditioning and ASCT due to leukemia progression, or cancellation of the donor. 155 patients were analyzed for safety and efficacy; 83 were randomized to ATG and 72 to non-ATG. The treatment groups were comparable regarding recipient and donor age and sex, CMV serostatus, disease (AML vs ALL), 1^st or 2^ndCR. The median time to leukocyte (>1.0x10e9/l) and platelet (> 20x 10e9/l) engraftment was significantly delayed in the ATG group (18 vs 15 days, p< 0.001 and 20 vs 13 days, p<0.001). The incidence of acute GvHD grade I-IV was 25% for the ATG arm and 36% for the non-ATG arm (p=0.32) and for severe grade III/IV acute GvHD 2% and 7%, respectively (p=0.2). Regarding the primary endpoint, the cumulative incidence of cGvHD at 2 years was 36% % (95% CI 26-51%) in the ATG and 73% (95% CI 63-84% ) in the non-ATG arm (p<0.0001). In the ATG group 74% of the patients with any cGvHD had only limited episodes and 26% had an extensive episode, compared to 49% and 51% for non-ATG (p=0.04). There was no higher rate of infectious complications (58% for ATG vs 54% for non-ATG), CMV reactivation (22 vs 24%) and of EBV reactivation (2.4 vs 1.4%). The cumulative incidence of therapy related mortality at 2 years was 13% (95% CI 7-22%) for the ATG arm and 10% (95% CI 5-20%) for the non-ATG arm (p=0.57), resulting in 2 year relapse-free and overall survival of 59%% (95%CI 49-70%) and 75% (95% CI 66-85%) for the ATG group and of 65% (95% CI 52-77%) and 79% (95% CI 69-89%) for the non-ATG group (p=0.44 and p=0.20, respectively).

Conclusion

This randomized cGvHD prevention study provides evidence that ATG-Neovii® 3x 10mg/kg within a myeloablative preparative conditioning regimen for HLA-identical sibling peripheral blood stem cell transplantation is highly effective in preventing limited and extensive cGvHD without obvious increase of infectious complications and relapse, resulting in similar overall survival rates.