Antithymocyte Globulin for Matched Sibling Donor Transplantation in Patients With Hematologic Malignancies: A Multicenter, Open-Label, Randomized Controlled Study

Abstract

<jats:sec><jats:title>PURPOSE</jats:title><jats:p> The role of antithymocyte globulin (ATG) in preventing acute graft-versus-host disease (aGVHD) after HLA-matched sibling donor transplantation (MSDT) is still controversial. </jats:p></jats:sec><jats:sec><jats:title>PATIENTS AND METHODS</jats:title><jats:p> We performed a prospective, multicenter, open-label, randomized controlled trial (RCT) across 23 transplantation centers in China. Patients ages 40-60 years with standard-risk hematologic malignancies with an HLA-matched sibling donor were randomly assigned to an ATG group (4.5 mg/kg thymoglobulin plus cyclosporine [CsA], methotrexate [MTX], and mycophenolate mofetil [MMF]) and a control group (CsA, MTX, and MMF). The primary end point of this study was grade 2-4 aGVHD on day 100. </jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p> From November 2013 to April 2018, 263 patients were enrolled. The cumulative incidence rate of grade 2-4 aGVHD was significantly reduced in the ATG group (13.7%; 95% CI, 13.5% to 13.9%) compared with the control group (27.0%; 95% CI, 26.7% to 27.3%; P = .007). The ATG group had significantly lower incidences of 2-year overall chronic GVHD (27.9% [95% CI, 27.6% to 28.2%] v 52.5% [95% CI, 52.1% to 52.9%]; P &lt; .001) and 2-year extensive chronic GVHD (8.5% [95% CI, 8.4% to 8.6%] v 23.2% [95% CI, 22.9% to 23.5%]; P = .029) than the control group. There were no differences between the ATG and control groups with regard to cytomegalovirus reactivation, Epstein-Barr virus reactivation, 3-year nonrelapse mortality (NRM), 3-year cumulative incidence of relapse (CIR), 3-year overall survival, or 3-year leukemia-free survival. Three-year GVHD relapse-free survival was significantly improved in the ATG group (38.7%; 95% CI, 29.9% to 47.5%) compared with the control group (24.5%; 95% CI, 16.9% to 32.1%; P = .003). </jats:p></jats:sec><jats:sec><jats:title>CONCLUSION</jats:title><jats:p> Our study is the first prospective RCT in our knowledge to demonstrate that ATG can effectively decrease the incidence of aGVHD after MSDT in the CsA era without affecting the CIR or NRM. </jats:p></jats:sec>

<p>Impact of Low-Dose rATG Prior to Matched Sibling Donor Hematopoietic Stem Cell Transplantation for Hematologic Malignancies: Reduced Risk of Chronic Graft-versus-Host Disease and Improved Survival Outcomes</p>

“…Recently, a prospective multicenter open-label randomized controlled clinical trial by Chang et al showed that addition of 4.5 mg/kg ATG in MSD-HSCT, sources of graft including peripheral blood and bone marrow and peripheral blood + bone marrow, could reduce not only the risk of overall cGVHD (27.9% versus 52.5%, p<0.001) and extensive cGVHD (8.5% versus 23.2%, p=0.029) but also the risk of grade 2–4 aGVHD (13.7% versus 27.0%, p=0.007). 34 However, in regard to survival and efficacy, Kröger et al and Chang et al observed no significant between-group differences in relapse, NRM, LFS or OS, while GRFS in the study of Chang et al was much better in the ATG group than that in the non-ATG group (38.7% versus 24.5%, p=0.003). In cord blood transplantation (CBT), the use of ATG may need further confirmation and exploration.…”

“…The risk of relapse did not increase, and the OS was effectively improved, as were LFS and GRFS, although no statistical significance was found in the univariate or multivariate analyses (Tables 6 and 7 and Figure 2A-D). We have noticed that the benefit of ATG in preventing aGVHD after MSD-HSCT was once considered controversial, 15,33 but it has been confirmed recently in the study of Chang et al 34 Considering that the transplant procedures, including conditioning regimen and GVHD prophylaxis, were almost the same in our two studies, we analyzed whether the difference in the aGVHD result might be partly due to patient age (40-60 years old), which is thought to be associated with an increased risk of aGVHD. 32 Although many studies have confirmed the protective effects of ATG, the issue is that an insufficient dose of ATG cannot exert an effective immunosuppressive function, while high-dose ATG will produce an inhibitory effect on host immune function, resulting in delayed immune reconstruction, increasing the risk of infection and relapse, and ultimately negatively affecting survival.…”

Low-dose antithymocyte globulin plus low-dose posttransplant cyclophosphamide combined with cyclosporine and mycophenolate mofetil for prevention of graft-versus-host disease after HLA-matched unrelated donor peripheral blood stem cell transplantation

“…The median relapse time was 2 (2-4) months after transplantation, which indicated that the early relapse was related with the preconditioning effects, but not with graft-versus-leukemia (GVL) effects. Low-dose ATG for GvHD prophylaxis in MRD transplantation did not increase the relapse risk, which has been demonstrated in several clinical trials [30][31][32]. PTCy has been demonstrated in preclinical experiments that it could separate GvHD and a GVL effect [33] and did not increase the relapse risk in clinical studies [34,35].…”

Future perspective: precision medicine to improve treatment results in the settings of allogenic stem cell transplantation for acute myelogenous leukemia

“…Finally, strategies reducing the risk of GVHD, without reducing the GVL effect are strongly desired. A recent publication suggest antithymocyte globulin (ATG) may possess such properties, as it could reduce the risk of GVHD without compromising with increased risk for relapse [15].…”