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An overview of the role of ATG in preventing acute and chronic GvHD after allo-HSCT

Sep 15, 2021
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Graft-versus-host disease (GvHD) can significantly impact the morbidity, mortality, and quality of life (QoL) of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. The immunologic graft-versus-host response that precedes acute GvHD (aGvHD) occurs within hours following HSCT, long before the disease is clinically evident. Chronic GvHD (cGvHD) arises in the days after HSCT and can be challenging to manage without compromising the graft-versus-leukemia (GvL) effect.

Rabbit antithymocyte globulin (ATG) has proven to be an effective prophylaxis for the prevention of GvHD, however, intensified immunosuppressive treatment may cause serious side effects and therefore, it is suggested only for high-risk patients. Despite this, only a few studies have touched upon ATG dosing protocols and its effects on relapse and infection, especially so in the case of HLA-matched sibling donor transplantations (MSD-T).

Two recent studies have assessed the impact of ATG on high-risk patients1 and on patients who have undergone MSD-T.2

Khanolkar et al. examined whether GvHD could be reduced in patients with high serum soluble interleukin-2 receptor alpha (sIL2Ra) or low interleukin-15 (IL-15) on Day 7 by pre-emptively administering ATG on Day 8.1 The two biomarkers indicate a high risk of developing clinically significant GvHD (sGvHD), defined as Grade 2−4 aGvHD or moderate to severe cGvHD.

Cho et al. investigated the ability of low-dose ATG to prevent cGvHD for patients with acute leukemia who underwent MSD-T.2

Study by Khanolkar et al. on biomarker-guided, prophylactic ATG therapy1

Study design

This was a phase II, prospective, open-label, non-randomized, single-center trial. A diagram depicting the study design is shown in Figure 1.

The HSCT conditioning regimen comprised of intravenous (IV) fludarabine (50 mg/m2/day on Day −6 to Day −2), IV busulfan (3.2 mg/kg/day on Day −5 to Day −2), and total body irradiation (TBI) (4 Gy in two fractions on Day −1 and Day 0). GvHD prophylaxis included IV ATG (0.5 mg/kg on Day −2, 2.0 mg/kg on Day −1, and 2.0 mg/kg on Day 0) and methotrexate on Day 1, Day 3, Day 6, and Day 11 and cyclosporine from Day −1 to 84.

Figure 1. Study flowchart*

ATG, antithymocyte globulin; HSCT, hematopoietic stem cell transplantation; IL-15, interleukin-15; sIL2Ra, serum soluble interleukin-2 receptor alpha.
*Adapted by Khanolkar et al.1

  • Major inclusion criteria were:
    • Age ≥ 18 years
    • Myeloablative conditioning (MAC)
    • Filgrastim-mobilized blood stem cell graft
    • GvHD prophylaxis with ATG (4.5 mg/kg given between Day −2 and 0), methotrexate and, cyclosporine
  • Primary endpoint was the cumulative incidence of sGvHD.
  • Secondary endpoints included:
    • Overall survival (OS)
    • Nonrelapse mortality (NRM)
    • Cumulative incidence of relapse (CIR)

Both study arms were well balanced in their characteristics (Table 1).

Table 1. Selected patient characteristics*

Characteristic, %
(unless otherwise stated)

Study arm

Control arm

p value

Low-risk patients
(n = 34)

High-risk patients
(n = 34)

Total
(N = 68)

Low-risk patients
(n = 74)

High-risk patients
(n = 69)

Total
(N = 143)

Patient age, years, median (range)

53
(22−66)

53
(20−65)

53
(20−66)

48
(18−67)

53
(18−66)

49
(18−67)

0.171

Donor age, years, median (range)

30
(16−67)

31
(17−61)

32
(17−62)

34
(19−62)

31
(13−69)

30
(13−69)

0.577

Graft type

N/A

PBSCs

100

100

100

100

100

100

 

Conditioning

1.000

Flu-Bup-ATG-TBI

100

97

99

97

100

99

 

Flu-Cy-ATG-TBI 2

0

3

1

3

0

1

 

Disease risk

0.656

Low/intermediate

94

79

87

85

83

84

 

High/very high

6

15

10

9

17

13

 

Unknown

0

6

3

5

0

3

 

Median follow-up, days (range)

1451 (53−2257)

1389 (53−2257)

1455 (53−2257)

1783 (24−3266)

1654 (27−3189)

1743 (24−3266)

0.003

Median follow-up of surviving patients, days (range)

1813 (1033−2257)

1611 (1364−2257)

1839 (1033−2257)

2261 (141−3266)

2250 (89−3189)

2250 (89−3266)

< 0.001

ATG, antithymocyte globulin; Bup, busulfan; Cy, cyclophosphamide; Flu, fludarabine; N/A, not applicable; PBSCs, peripheral blood stem cells; TBI, total body irradiation.
*Adapted from Khanolkar et al.1
Calculated for the difference between the 2011−2016 total control patients and 2014−2016 total study patients. For characteristics that included an ‘unknown’ subcategory, the unknowns were excluded.

Results

  • The prevalence of clinically sGvHD was significantly lower in high-risk patients who had Day 8 ATG compared with high-risk controls (subdistribution hazard ratio [SHR] = 0.48; p = 0.045).
  • There was no statistically significant difference in OS between low-risk (hazard ratio [HR] = 0.97; p = 0.971) or high-risk (HR = 1.66; p = 0.101) study patients and controls.
  • High-risk study patients had a significantly higher incidence of non-GvHD-associated NRM compared with high-risk controls (SHR = 3.73; p = 0.032), usually related to infection
  • Despite the significant decrease in sGvHD incidence in the high-risk study patients compared with the high-risk controls, no significant difference was found in GvHD-associated NRM, due to Day 8 ATG reducing Grade 2 aGvHD, which is usually non-fatal, but not Grade 3−4 aGvHD or moderate to severe cGvHD.
  • There was no significant difference between high-risk trial patients and high-risk controls in CIR.
  • When comparing high- and low-risk controls, no significant difference was found in the incidence of sGvHD (SHR = 1.18; p = 0.519). This suggested that sIL-2Ra and IL-15 levels no longer effectively stratified sGvHD risk in the 2011−2016 patient cohort even though they had predicted a 2.5-fold difference in sGvHD incidence in the 2004−2010 group.

Study by Cho et al. on low-dose ATG in MSD-T setting2

Study design

A prospective, single-center, open-label, randomized, phase III study of 120 adult patients randomly assigned to receive or not receive ATG (1.25 mg/kg/day) on Days −3 and −2 was carried out.

Taking into account age and/or comorbidities, patients were treated with either MAC or reduced-intensity conditioning (RIC) regimens.

  • MAC: Cyclophosphamide (120 mg/kg) combined with 1,320 cGy of fractionated TBI or busulfex (12.8 mg/kg).
  • RIC: Busulfex (6.4 mg/kg) and fludarabine (150 mg/m2) with 400 cGy of fractionated TBI or busulfex (9.6 mg/kg) and fludarabine (150 mg/m2).

All patients received GvHD prophylaxis with cyclosporine (target serum trough level of 150−300 ng/mL) and methotrexate (10 mg/m2 on Days 1, 3, 6, and 11).

  • Primary endpoint was the cumulative incidence of cGvHD at 2 years according to the National Institutes of Health (NIH) criteria.
  • Secondary endpoints included:
    • Engraftment
    • Immune reconstitution
    • Cumulative incidence of aGvHD
    • Infectious complications
    • Relapse (CIR)
    • NRM
    • Disease-free survival (DFS)
    • OS
    • cGvHD-free and relapse-free survival (cGRFS)
    • Recipient reported outcomes with the Short Form (36) Health Survey (SF-36) questionnaire

Patients were eligible if they were 19 to 65 years of age, had acute myeloid or lymphoblastic leukemia (AML/ALL) in complete morphologic remission (CR), and had an Eastern Cooperative Oncology Group (ECOG) performance score < 2. Selected clinical characteristics of the enrolled patients are presented in Table 2 below. There were no significant differences between the two groups other than gender.

Table 2. Patient characteristics by ATG use*

Characteristic, %
(unless otherwise stated)

ATG arm
(n = 60)

No ATG arm
(n = 60)

p value

Age, recipient at allo-HSCT, median (range)

47.5
(20–64)

44.5
(18–64)

0.362

Gender, recipient, male

61.0

39.0

0.018

Refined DRI, high risk

15.0

13.3

0.793

Cytogenetic risk, high risk

45.0

41.7

0.713

Disease type

1.000

              AML

55.0

55.0

              ALL

45.0

45.0

Conditioning regimen

0.613

              CY + TBI 1320 cGy

38.3

41.7

              CY + BU

25.0

28.3

              FLU + BU

25.0

25.0

              FLU + BU + TBI 400 cGy

11.7

5.0

Conditioning intensity

0.562

              MAC

63.3

70.0

              RIC

36.7

30.0

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; ATG, antithymocyte globulin; BU, busulfex; CY, cyclophosphamide; DRI, disease risk index; FLU, fludarabine; HSCT, hematopoietic stem cell transplantation; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; TBI, total body irradiation.
*Adapted from Cho, et al.2
Cytogenetic risk was defined according to National Comprehensive Cancer Network consensus guidelines.

Results

Statistically significant study results are listed in Table 3.

Table 3. Treatment outcomes*

Characteristic, % (95% CI)
(unless otherwise stated)

ATG arm

No ATG arm

p value

cGvHD at 2 years

              Overall grade mild to severe

25.0
(14.8−36.5)

65.4
(50.8−76.7)

<0.001

              Overall grade moderate to severe

15.0
(7.3−25.2)

45.3
(31.6−58.0)

0.001

              Skin involvement

26.3

0

0.027

Infectious complications

              EBV viral reactivation (≥1000 IU/mL)

21.8
(11.8−33.7)

5.1
(1.3−12.9)

0.013

ATG, antithymocyte globulin; cGvHD, chronic graft-versus-host disease; CI, confidence interval; EBV, Epstein Barr virus; NIH, National Institutes of Health.
*Adapted from Cho, et al.2
According to the NIH criteria for organ involvement.

  • Immune reconstitution:
    • The ATG group had significantly fewer CD4 T-cells posttransplant compared with the non-ATG group.
  • Acute and chronic GvHD:
    • The difference in the cumulative incidence of cGvHD in the ATG and non-ATG groups remained significant when adjusted by refined disease risk index (DRI) and conditioning intensity.
    • 33% of patients in the ATG group were free from immunosuppressive treatment at 12 months compared with 12% in the non-ATG group (p = 0.004). Median time to stop all immunosuppressive treatment without resumption was 5.3 months (range, 2.3−11.8 months) in the ATG group and 9.6 months (range, 4.3−17.8 months) in the non-ATG group.
  • Toxicity:
    • The Grade > 2 infusion reactions in the ATG group were 33%.
  • NRM and relapse:
    • Older age was the only significant factor associated with increased NRM (p = 0.035).
    • The 2-year CIR was higher in the ATG group (20.0%; 95% CI: 11.0−31.0) than in the non-ATG group (9.3%; 95% CI: 3.3−19.0; p = 0.055), with risk differing according to cytogenetic subgroup (non-high-risk, 12.2% vs 9.2%, p = 0.596; high-risk, 29.6% vs 9.3%, p = 0.042).
    • Refined DRI was the only significant factor associated with increased CIR (p = 0.038).
  • Survival outcomes:
    • Older age was the only significant factor associated with inferior OS (p = 0.024).
    • Improvement in cGRFS was significant in the non-high-risk cytogenetic subgroup (ATG group 45.5% vs non-ATG group 0%; p = 0.038)
  • Impact of absolute lymphocyte count (ALC) at the time of ATG administration:
    • ATG use reduced cGvHD more efficiently in patients with Day −3 ALC ≤ 0.1 × 109/L (ATG group 66.7% vs non-ATG group 9.7%; p < 0.001) than patients with Day −3 ALC > 0.1 × 109/L (63.2% vs 41.4%; p= 0.261).
    • cGRFS was significantly improved by ATG use in patients with Day −3 ALC ≤ 0.1 × 109/L (67.7% vs 18.0%; p = 0.002) with no difference in the −3 ALC > 0.1 × 109/L (24.1% vs 21.0%; p = 0.410).
    • TBI conditioning had significant effects on ALC on Day −3 with 66.7% of patients who received TBI having an ALC ≤ 0.1 × 109/L compared with 31.8% of patients who received non-TBI regimens (p < 0.001).
    • Multivariate analysis for the effects of ATG on cGvHD and cGRFS adjusted by TBI conditioning in each ALC group confirmed the benefit of ATG in patients with Day −3 ALC ≤ 0.1 × 109/L, whereas no benefit in patients with day −3 ALC > 0.1 × 109/L.
  • QoL:
    • At 12 months after allo-HSCT, the ATG group reported better scores for the physical components of the survey, including physical role and function, body pain, and general health.

Conclusion

Results from the first study showed that biomarker-guided, pre-emptive ATG therapy is achievable and effective at lowering sGvHD without increasing relapse, thus, improving the morbidity and poor QoL associated with GvHD. Though, the authors noted a heightened risk of fatal infections, and a lack of benefit in survival. The main limitation of the study was the lack of randomization. In the second study, low-dose ATG successfully reduced the incidence of cGvHD in MSD-T, resulting in improvement in QoL. This was more noticeable in patients with acute leukemia without adverse cytogenetic characteristics and with low absolute lymphocyte count on the first day of administration, in whom cGRFS was significantly superior. However, for patients with high-risk acute leukemia, treating physicians should ensure that the increased risk of relapse does not outweigh the benefit. Furthermore, low-dose ATG had no significant impact on aGvHD. Future randomized trials should focus on strategies to decrease the risk of infections associated with intensified GvHD prophylaxis, on personalized optimal ATG dosing and administration schedules, as well as more conclusively determining which patients may be better suited for intensified preventative GvHD treatment. The use of validated biomarkers may prove to be helpful in stratifying patients according to their risk of developing GvHD; hence allowing for tailored management approaches that inhibit adverse outcomes.

  1. Khanolkar RA, Kalra A, Kinzel M, et al. A biomarker-guided, prospective, phase 2 trial of pre-emptive graft-versus-host disease therapy using anti-thymocyte globulin. Cytotherapy. 2021; S1465-3249(21)00711-8. DOI: 1016/j.jcyt.2021.06.003
  2. Cho B-S, Min G-J, Park S-S, et al. Low-dose thymoglobulin for prevention of chronic graft-versus-host disease in transplantation from an HLA-matched sibling donor. Am J Hematol. 2021;1-9. DOI: 1002/ajh.26320

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