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

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.

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

Characteristic	ATG dose group		p value
Low (n = 78)	High (n = 118)
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.
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

	OS
Univariate analysis		Multivariate analysis
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.
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

	RI
Univariate analysis		Multivariate analysis
Factor	HR (95% CI)	p value	HR (95% CI)	p value
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.
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

Outcome, %	ATG dose group		p value
Low (n = 78)	High (n = 118)
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.
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

Infectious complication	ATG dose group		p value
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.
	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.