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Antithymocyte globulin (ATG) is a drug used for the prevention and treatment of acute graft-versus-host disease (aGvHD). Conventional prophylaxis regimens using methotrexate (MTX), cyclosporine (CsA), and mycophenolate mofetil (MMF) have significantly reduced the incidence of aGvHD following allogeneic stem cell transplantation (allo-HSCT) in recent decades. However, rates of Grade 2–4 aGvHD remain ~30% in patients ≥ 40 years of age who have received human leukocyte antigen-matched sibling donor (HLA-MSD) transplantation.
Incorporation of ATG into standard GvHD prophylaxis protocols has reduced the prevalence of aGvHD and chronic GvHD (cGvHD) in patients receiving unrelated donor (UD) transplantation and haploidentical (haplo) donor transplantation, but the role of ATG in preventing aGvHD following MSD is up for debate.
Chang et al.1 sought to determine whether the addition of ATG to standard GvHD prophylaxis decreases incidence of aGvHD following MSDT compared with MTX + CsA + MMF alone. Results from this multicenter, open-label, randomized controlled trial were recently reported in the Journal of Clinical Oncology, and the GvHD Hub is happy to provide a summary.
* Acute leukemia in first complete remission, chronic myelogenous leukemia in the chronic phase, myelodysplastic syndrome with refractory anemia, refractory anemia with ring sideroblasts, refractory cytopenia with multilineage dysplasia, and refractory anemia with excess blasts.
Figure 1. Study consort diagram and patient randomization1
ATG, antithymocyte globulin
Table 1. Baseline patient characteristics1
ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; ATG, antithymocyte globulin; BM, bone marrow; Bu, busulfan; CML, chronic myeloid leukemia; Cy, cyclophosphamide; Flu, fludarabine; MDS, myelodysplastic syndromes; MNC, mononuclear cell; NHL, non-Hodgkin lymphoma; PB, peripheral blood; TBI, total body irradiation |
||
Characteristic, % (unless otherwise stated) |
ATG (n = 132) |
Control (n = 131) |
Median age, years (range) |
48 (40–61) |
46 (40–58) |
Male sex |
57.6 |
57.3 |
Disease |
|
|
AML |
66.7 |
67.2 |
ALL |
13.6 |
12.2 |
CML |
1.5 |
0.8 |
MDS |
18.2 |
17.6 |
NHL |
0.0 |
2.3 |
Graft |
|
|
BM + PB |
37.9 |
38.9 |
BM |
4.5 |
2.3 |
PB |
57.6 |
58.8 |
Conditioning regimen |
|
|
Bu + Cy |
97.7 |
90.1 |
TBI + Cy |
1.5 |
8.4 |
Bu + Flu |
0.8 |
1.5 |
Median MNC, × 108/kg |
9.07 |
9.21 |
Median CD34+ cells, × 106/kg |
3.12 |
3.36 |
Table 2. Patient outcomes to standard GvHD prophylaxis ± ATG1
aGvHD, acute graft-versus-host disease; ATG, antithymocyte globulin; BSI, blood stream infection; cGvHD, chronic graft-versus-host disease; CIR, cumulative incidence of relapse; CMV, cytomegalovirus; EBV, Epstein–Barr virus; GRFS, graft-versus-host disease relapse-free survival; IFD, invasive fungal disease; ISP, immunosuppressant; NRM, non-relapse mortality; OS, overall survival |
|||
Outcome, % (95% CI) |
ATG (n = 132) |
Control (n = 131) |
p value |
aGvHD at 100 days |
|
|
|
Grade 2–4 |
13.7 (13.5–13.9) |
27.0 (26.7–27.3) |
0.007 |
Grade 3–4 |
8.4 (8.3–8.5) |
14.2 (14.0–14.4) |
0.151 |
Organ-specific aGvHD |
|
|
|
Skin |
16.4 (16.2–16.6) |
19.9 (19.6–20.02) |
0.484 |
Intestine |
8.4 (8.0–8.8) |
24.3 (24.0–24.6) |
0.001 |
Liver |
4.1 (4.0–4.2) |
11.1 (10.0–12.2) |
0.053 |
2-year overall cGvHD |
27.9 (27.6–28.2) |
52.5 (52.1–52.9) |
0.001 |
Free of ISP at 2 years |
84.8 (56.0–66.0) |
57.4 (35.0–61.) |
0.001 |
CMV at Day 100 |
22.7 (22.4–23.0) |
23.9 (23.6–24.2) |
0.674 |
EBV at Day 180 |
7.8 (7.7–7.9) |
3.4 (3.3–3.5) |
0.289 |
Bacterial BSI at Day 30 |
3.8 (3.0–4.6) |
3.1 (3.0–3.2) |
0.769 |
IFD at 1 year |
13.7 (13.5–13.9) |
13.8 (13.6–14.0) |
0.843 |
3-year GRFS |
38.7 (29.9–47.5) |
24.5 (16.9–32.1) |
0.003 |
3-year OS |
69.0 (61.2–76.8) |
70.4 (62.0–78.8) |
0.937 |
3-year CIR |
20.8 (20.5–21.1) |
15.4 (15.2–15.6) |
0.362 |
3-year NRM |
9.9 (9.8–10.0) |
14.3 (14.1–14.5) |
0.552 |
Upon addition to CsA + MTX + MMF, Chang and team found that ATG reduced the frequency of aGvHD following MSD transplantation when compared with conventional prophylaxis alone. The group highlighted that previous studies have associated ATG with increased CIR—believed to be dose dependent. In agreement with other trials, the dose of 4.5 mg/kg ATG did not result in an increased CIR and could be suitable for patients undergoing MSD transplantation. Although further investigation is required, the authors conclude that this study suggests that the incorporation of ATG into transplantation regimens may improve the outlook of patients undergoing MSD transplantation for the treatment of hematological malignancies.
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