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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
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
Both study arms were well balanced in their characteristics (Table 1).
Table 1. Selected patient characteristics*
Characteristic, % |
Study arm |
Control arm |
p value† |
||||
---|---|---|---|---|---|---|---|
Low-risk patients |
High-risk patients |
Total |
Low-risk patients |
High-risk patients |
Total |
||
Patient age, years, median (range) |
53 |
53 |
53 |
48 |
53 |
49 |
0.171 |
Donor age, years, median (range) |
30 |
31 |
32 |
34 |
31 |
30 |
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. |
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.
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).
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, % |
ATG arm |
No ATG arm |
p value |
---|---|---|---|
Age, recipient at allo-HSCT, median (range) |
47.5 |
44.5 |
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. |
Statistically significant study results are listed in Table 3.
Table 3. Treatment outcomes*
Characteristic, % (95% CI) |
ATG arm |
No ATG arm |
p value |
---|---|---|---|
cGvHD at 2 years |
|||
Overall grade mild to severe |
25.0 |
65.4 |
<0.001 |
Overall grade moderate to severe |
15.0 |
45.3 |
0.001 |
Skin involvement† |
26.3 |
0 |
0.027 |
Infectious complications |
|||
EBV viral reactivation (≥1000 IU/mL) |
21.8 |
5.1 |
0.013 |
ATG, antithymocyte globulin; cGvHD, chronic graft-versus-host disease; CI, confidence interval; EBV, Epstein Barr virus; NIH, National Institutes of Health. |
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.
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