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Antithymocyte globulin decreases acute graft-versus-host disease following HLA-matched sibling donor transplantation

Aug 17, 2020

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. 1sought 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.

Study design

Methods

  • Patients aged 40–60 years receiving HLA-MSD transplantation for the treatment of standard-risk hematologic malignancies* were recruited from 23 transplant centers across China
  • Patients were randomly assigned to receive GvHD prophylaxis with CsA + MTX + MMF ± 4.5 mg/kg ATG ( Figure 1)
  • Primary endpoint: Grade 2–4 aGvHD on Day 100 posttransplant

* 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 randomization 1

  

ATG, antithymocyte globulin

Results

Patient characteristics

  • Characteristics between the two cohorts were well balanced ( Table 1)

Table 1.Baseline patient characteristics 1

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, × 10 8/kg

9.07

9.21

Median CD34 +cells, × 10 6/kg

3.12

3.36

 Efficacy

  • Patients in the ATG group demonstrated significantly lower rates of Grade 2–4 aGvHD and overall cGvHD at 2 years vsthe control group ( Table 2)
    • Significance was not observed in rates of Grade 3–4 aGvHD between the two groups
  • No differences in cumulative incidence of disease relapse (CIR), non-relapse mortality, overall survival, or rates of infection were observed between groups ( Table 2)

Table 2.Patient outcomes to standard GvHD prophylaxis ± ATG 1

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

Conclusion

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.

  1. Chang YJ, Wu DP, Lai YR, et al. Antithymocyte globulin for matched sibling donor transplantation in patients with hematologic malignancies: A multicenter, open-label, randomized controlled study. J Clin OncolHy.2020. Online ahead of print. DOI: 10.1200/JCO.20.00150