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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment option in many hematological malignancies, but it remains challenging due to the associated high morbidity and mortality rates. Posttransplant cyclophosphamide (PTCy) and antithymocyte globulin (ATG) as individual treatment regimens have been found to reduce graft-versus-host-disease (GvHD) following allo-HSCT. Recently, two studies have assessed the combined effect of PTCy plus ATG as GvHD prophylaxis in patients with hematological malignancies receiving reduced intensity conditioning (RIC) before allo-HSCT.1, 2
Maria Queralt Salas, Shruti Prem, and colleagues aimed to assess the safety and efficacy of PTCy + ATG for patients who underwent allo-HSCT using peripheral blood from different donor types. They published their findings in Bone Marrow Transplantation.1
Dhon Roméo Makanga et al. previously reported on GvHD rates when using PTCy in RIC haploidentical (h)-HSCT.3 Their more recent publication in The Journal of Immunology aimed to assess combination treatment with PTCy + ATG as GvHD prophylaxis in a new cohort of patients who had received h-HSCT, and compare the findings with the outcomes of the previously reported cohort.2
Table 1. Patient and donor characteristics
|
Salas and Prem et al.1 |
Makanga et al.2 |
ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; HL, Hodgkin lymphoma; MDS, myelodysplastic syndrome; MMUD, mismatched unrelated donor (HLA match 9/10); MPN, myeloproliferative neoplasm; MRD, matched related donor; MUD, matched unrelated donor (HLA match 10/10); NHL, non-Hodgkin lymphoma; PTCy, posttransplant cyclophosphamide. |
||
Median age, year (range) |
58 (18.0–74.5) |
PTCy arm: 61 (32–71) |
% male |
57 |
63 |
Diagnosis, % |
|
|
AML |
53 |
47 |
MDS |
18 |
19 |
MPN |
10 |
7 |
ALL |
5 |
3 |
Lymphoproliferative disease |
9 |
0 |
NHL |
0 |
16 |
HL |
0 |
5 |
other |
6 |
4 |
Donor type, % |
|
|
MRD |
19 |
0 |
MUD |
46 |
0 |
MMUD |
16 |
0 |
Haploidentical |
19 |
100 |
Disease risk index, % |
|
|
Not available |
3 |
— |
Low + intermediate |
77 |
67 |
High + very high |
20 |
33 |
Table 2. Outcomes between the different groups included in the studies
|
Salas and Prem et al.1 |
Makanga et al.2 |
||||||
ATG, antithymocyte globulin; CIR, cumulative incidence of relapse; CMV, cytomegalovirus; DFS, disease free survival; EBV, Epstein–Barr virus; GRFS, GvHD-free RFS; GvHD, graft-versus-host-disease; haplo, haploidentical; MMUD, mismatched unrelated donor (HLA match 9/10); MRD, matched related donor; MUD, matched unrelated donor (HLA match 10/10); NRM, non-relapse mortality; OS, overall survival; PTCy, posttransplantation cyclophosphamide; PTLD, posttransplant lymphoproliferative disorder; RFS, relapse free survival. Statistically significant values are indicated in bold. |
||||||||
|
MRD |
MUD |
MMUD |
haplo |
p value |
PTCy |
PTCy + ATG |
p value |
Graft failure, % |
2.0 |
3.0 |
21.0 |
17.0 |
— |
0 |
19.3 |
0.03 |
OS, % |
|
|
|
|
0.0022 |
|
|
0.75 |
1 year |
60.3 |
77.3 |
44.7 |
58.8 |
|
71.5 |
61.5 |
|
2 years |
56.2 |
66.9 |
39.0 |
49.9 |
|
58.5 |
57.4 |
|
RFS, % |
|
|
|
|
< 0.0001 |
|
|
— |
1 year |
46.3 |
71.3 |
32.7 |
53.3 |
|
— |
— |
|
2 years |
37.4 |
64.8 |
29.7 |
34.8 |
|
— |
— |
|
DFS, % |
|
|
|
|
|
|
|
0.98 |
1 year |
— |
— |
— |
— |
|
59.3 |
53.8 |
|
2 years |
— |
— |
— |
— |
|
46.8 |
49.3 |
|
GRFS, % |
|
|
|
|
< 0.0001 |
|
|
0.24 |
1 year |
33.0 |
64.1 |
30.8 |
37.8 |
|
43.7 |
53.5 |
|
2 years |
30.5 |
59.5 |
28.0 |
20.9 |
|
31.2 |
49.3 |
|
NRM, % |
|
|
|
|
0.0030 |
|
|
— |
Day +100 |
7.7 |
6.5 |
16.7 |
9.6 |
|
— |
— |
|
1 year |
23.6 |
13.3 |
38.4 |
31.0 |
|
— |
— |
|
Over course of study |
— |
— |
— |
— |
|
18.7 |
19.2 |
1.00 |
Death from relapse, % |
17 |
14 |
17 |
10 |
|
25 |
23 |
1.00 |
CIR, % |
|
|
|
|
0.1169 |
|
|
— |
1 year |
23.5 |
13.2 |
38.4 |
31.0 |
|
— |
— |
|
2 years |
23.5 |
15.3 |
41.4 |
37.2 |
|
— |
— |
|
Relapses |
— |
— |
— |
— |
|
37.5 |
30.7 |
0.79 |
Acute GvHD, % |
|
|
|
|
|
|
|
|
Grade 2-4 |
26.9 |
19.5 |
11.9 |
21.2 |
0.4400 |
59.3 |
23.8 |
0.004 |
Grade 3-4 |
— |
— |
— |
— |
|
18.7 |
4.7 |
0.29 |
Chronic GvHD |
|
|
|
|
|
|
|
|
Moderate/severe |
13.9 |
10.0 |
14.3 |
13.5 |
0.7375 |
20.6 |
11.1 |
0.65 |
Infectious complications |
|
|
|
|
|
|
|
|
CMV reactivation |
50 |
48 |
71 |
77 |
|
— |
— |
|
EBV reactivation |
75 |
59 |
67 |
60 |
|
— |
— |
|
PTLD |
6 |
11 |
2 |
12 |
|
— |
— |
|
BK cystitis |
17 |
21 |
19 |
27 |
|
— |
— |
|
Other viral |
19 |
34 |
24 |
35 |
|
— |
— |
|
Fungal |
6 |
7 |
7 |
14 |
|
— |
— |
|
The use of combined PTCy and ATG for GvHD prophylaxis in both studies resulted in low rates of acute GvHD, without apparent increase in relapse rates. However, this did not translate into improved survival for patients who had received mismatched donor stem cells (haploidentical or mismatched unrelated donor), possibly due to very high rates of graft failure in both studies which may be linked to delayed T-cell engraftment. The best survival using the combination treatment was seen in patients who had received a matched unrelated donor transpant.1 Salas and Prem et al.1 also commented on the high infection rates in their PTCy + ATG cohort and felt that reducing the ATG dose could reduce the infectious toxicity of this regimen.
Combined treatment with PTCy + ATG caused longer T-cell depletion,1 as supported by the findings of Makanga et al. demonstrating a significantly lower percentage of T cells at Day 30 compared to PTCy alone.2 However, there are differential subsets of NK cells present with the different prophylactic treatments, and Makanga et al.2 postulate that better knowledge of these subsets may enable prognostication of patients.
The authors acknowledge that the studies had limitations, namely their retrospective nature, the heterogeneity of the groups (i.e., AML and ALL being combined as a subset)2 and sample sizes,1 and in the Makanga et al. study, the low number of participants.
References
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