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High- vs low-dose antithymocyte globulin for pediatric patients with leukemia undergoing allo-PBSCT

Dec 22, 2020
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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved the survival outcomes of children with leukemia. Antithymocyte globulin (ATG) and anti-T lymphocyte globulin (ATLG) have been shown to reduce the risk and severity of acute and chronic graft-versus-host disease (GvHD) following allo-HSCT, thereby improving non-relapse mortality.

ATG and ATLG represent two distinct GvHD prophylaxis formulations that cannot be administered interchangeably. In pediatric patients, a dose of 15 mg/kg ATLG for myeloablative conditioning in sibling and unrelated transplants has been recommended internationally. However, there is insufficient data to support a uniform dose of ATG in pediatric patients undergoing allo-HSCT.

A study by Hyun Mi Kang et al.1 investigated the effects of different ATG dosages on the overall survival (OS), relapse outcomes, and infectious complications in pediatric patients undergoing allogeneic peripheral blood stem cell transplant (allo-PBSCT) for the treatment of leukemia.

Study design

  • Retrospective cohort study of patients aged < 18 years who received HSCT at Seoul St. Mary’s Hospital Pediatric Hemato-oncology Center, KR, between April 2009 and September 2018 (Figure 1).
  • High-dose ATG was defined as 7.5 mg/kg (unrelated donor) and 10.0 mg/kg (haploidentical donor), while low-dose ATG was 3.75 mg/kg (unrelated donor) and 5.0 mg/kg (haploidentical donor).
  • Primary outcomes: OS and relapse rate.
  • Secondary outcomes: acute and chronic GvHD severity and infectious complications due to delayed immune activation following allo-PBSCT.

Figure 1. Study cohort selection1

ATG, antithymocyte globulin; BM, bone marrow; HFD, haploidentical familial donor; HSCT, hematopoietic stem cell transplant; MUD, matched unrelated donor; PBSCT, peripheral blood stem cell transplant.

Results

Patient characteristics

Throughout the study period, 196 patients met the eligibility criteria, and the baseline patient characteristics are shown in Table 1.

Table 1. Patient characteristics1

ATG, antithymocyte globulin; CMV, cytomegalovirus; D, donor; EBMT, European Society for Blood and Marrow Transplantation; IQR, interquartile range; R, recipient.

Significant differences between groups are shown in bold.

*Lymphoid: acute lymphoblastic leukemia, mixed-phenotype acute leukemia; myeloid: acute myeloid, chronic myeloid, juvenile myelomonocytic leukemia.

Characteristic

ATG dose group

p value

Low (n = 78)

High (n = 118)

Male sex, %

65.4

61.0

0.536

Median age at transplant, years (IQR)

7.7 (5.0–13.6)

10.5 (3.6–14.7)

0.659

Median follow-up duration after transplant, years (IQR)

2.2 (1.2–3.7)

5.0 (0.5–7.4)

0.008

Type of leukemia, %*

 

 

0.415

  Lymphoid

50.0

44.1

 

  Myeloid

50.0

55.9

 

Donor type, %

 

 

0.976

  Haploidentical familial donor

26.9

27.1

 

  Matched unrelated donor

73.1

72.9

 

EBMT disease stage at transplant, %

 

 

0.259

  Early

67.9

65.3

 

  Intermediate

32.1

31.3

 

  Late

0.0

3.4

 

CMV serostatus (D/R)

 

 

0.323

  D+/R+

93.6

96.6

 

  D−/R+

6.4

3.4

 

ATG dose, survival, and relapse

  • Lower ATG doses and earlier EBMT diseas e stages at transplant significantly improved OS (p = 0.017) and relapse-free survival (p = 0.021).
  • By contrast, higher ATG doses increased the risk of relapse (p = 0.038) and death (p = 0.036).
  • The negative impact of higher ATG doses on relapse incidence was confirmed using multivariate analysis, as demonstrated in Tables 2 and 3.
  • Non-relapse mortality did not differ significantly between the low- vs high-dose ATG groups (Table 4).

Table 2. Univariate and multivariate analyses of the factors associated with OS in pediatric patients undergoing allo-PBSCT for the treatment of leukemia1

ATG, antithymocyte globulin; CI, confidence interval; EBMT, European Society for Blood and Marrow Transplantation; HR, hazard ratio; OS, overall survival.

Significant differences between groups are shown in bold.

 

OS

Univariate analysis

Multivariate analysis

Factor

HR (95% CI)

p value

HR (95% CI)

p value

Lymphoid vs myeloid

0.76 (0.44–1.30)

0.31

 

 

Age at transplant

1.00 (0.98–1.10)

0.19

 

 

EBMT disease stage at transplant

2.70 (1.70–4.30)

<0.001

2.59 (1.66–4.04)

<0.001

Donor type

1.60 (0.89–2.70)

0.12

 

 

ATG dose

0.91 (0.70–1.20)

0.02

2.02 (1.05–3.88)

0.036

Conditioning regimen

0.96 (0.72–1.30)

0.52

 

 

Table 3. Univariate and multivariate analyses of the factors associated with RI in pediatric patients undergoing allo-PBSCT for the treatment of leukemia1

ATG, antithymocyte globulin; CI, confidence interval; EBMT, European Society for Blood and Marrow Transplantation; HR, hazard ratio; RI, relapse incidence.

Significant differences between groups are shown in bold.

 

RI

Univariate analysis

Multivariate analysis

Factor

HR (95% CI)

p value

HR (95% CI)

p value

Lymphoid vs myeloid

0.79 (0.48–1.30)

0.35

 

 

Age at transplant

1.00 (0.95–1.00)

0.92

 

 

EBMT disease stage at transplant

2.20 (1.50–3.40)

<0.001

2.15 (1.42–3.26)

<0.001

Donor type

0.91 (0.52–1.60)

0.75

 

 

ATG dose

1.90 (1.10–3.30)

0.023

1.81 (1.03–3.17)

0.038

Conditioning regimen

1.0 (0.80–1.30)

0.87

 

 

Table 4. Patient outcomes1

aGvHD, acute graft-versus-host disease; ATG, antithymocyte globulin; cGvHD, chronic graft-versus-host disease; CI, cumulative incidence; NRM, non-relapse mortality; OS, overall survival; RI, relapse incidence.

Outcome, %

ATG dose group

p value

Low (n = 78)

High (n = 118)

2-year OS

83.3

71.4

 

1-year RI

18.1

32.2

 

2-year RI

22.2

34.8

0.022

1-year NRM

2.6

5.9

0.270

CI Day 100 aGvHD, %

59.0

51.7

0.096

CI 6-month cGvHD, %

18.8

20.2

0.672

ATG dose and GvHD

  • There was no significant difference in the cumulative incidences of acute GvHD between the high vs low groups (Table 4).
  • There was also no significant difference in the cumulative incidences of chronic GvHD between the high vs low groups at 6, 12 or 24 months post-transplant (Table 4). Nor was the severity of cGvHD at 12 months affected by ATG dose.

ATG dose and immune reconstitution

  • Reconstitution of T4 cells, T8 cells, NKT cells, and B cells was significantly delayed in the high-dose ATG group at 1-month post-transplant.

ATG dose and infectious complications

  • Infectious complications following allo-PBSCT were exacerbated in patients who received high vs low dose ATG, as illustrated in Table 5.

Table 5. Infectious complications1

ATG, antithymocyte globulin; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSCT, hematopoietic stem cell transplantation; IQR, interquartile range.

Significant differences between groups are shown in bold.

Infectious complication

ATG dose group

p value

 

Low (n = 78)

High (n = 118)

 

CMV DNAemia, %

51.3

70.3

0.007

Cases needing preemptive therapy

43.6

66.9

0.001

Onset after HSCT, median (IQR), days

26 (20–35.8)

20 (14–27)

0.022

CMV disease, %

10.3

3.4

0.097

EBV DNAemia, %

39.7

81.4

< 0.001

Invasive fungal infection, %

5.1

7.6

0.491

Invasive bacterial infection, %

0

12.7

0.001

Conclusion

In a cohort of pediatric patients undergoing allo-PBSCT for the treatment of leukemia, those who received low doses (3.75–5.0 mg/kg) of ATG demonstrated superior treatment outcomes when compared with those treated with higher ATG doses (7.5–10.0 mg/kg). Higher doses of ATG were also coupled with a significant increase in the rates of viral and bacterial infections and exhibited no benefit over low-dose ATG in preventing the incidence and severity of GvHD.

 

  1. Mi Kang H, Koo Kim S, Wook Lee J, et al. Efficacy of low dose antithymocyte globulin on overall survival, relapse rate, and infectious complications following allogeneic peripheral blood stem cell transplantation for leukemia in children. Bone Marrow Transplant. 2020. Online ahead of print. DOI: 10.1038/s41409-020-01121-9

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