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Prevention of graft-versus-host disease (GvHD) represents the most important factor in the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and posttransplant cyclophosphamide (PTCy) is an effective prophylactic treatment for GvHD after haploidentical (haplo) HSCT.
Two retrospective studies, published in September last year, suggested that PTCy represents a good alternative to the standard GvHD prophylaxis with antithymocyte globulin (ATG) in the human leukocyte antigen (HLA)-mismatched, unrelated donor (9/10 MMUD) allo-HSCT setting, and may improve outcomes in a HLA disparity transplant setting. However, there is not much information on the impact of donor types using PTCy prophylaxis.
In May 2020, two retrospective studies were published evaluating the impact of donor type on the outcome of patients with acute leukemia who underwent allo-HSCT, using PTCy for GvHD prophylaxis. The first study, published in the Journal of Hematology & Oncology by Jaime Sanz and colleagues, investigated the outcomes of patients with acute myeloid leukemia (AML) in first complete remission (CR1) who received allo-HSCT, with PTCy for GvHD prophylaxis, from matched sibling donors (MSD), matched unrelated donors (MUD), and haplo donors.1 The second study, published in Leukemia by Francesca Lorentino and colleagues, compared the outcomes of patients with acute leukemia receiving 10/10 or 9/10 HLA allele-matched unrelated donors HSCT (UD-HSCT) with PTCy-based GvHD prophylaxis.2
The main designs of both studies are highlighted in Table 1.
Table 1. Study design
aGvHD, acute GvHD; ALL, acute lymphoblastic leukemia; ALWP, acute leukaemia working party; AML, acute myeloid leukemia; cGvHD, chronic GvHD; CR1, first complete remission; EBMT, European Society for Blood and Marrow Transplantation; GRFS, graft-versus-host disease and relapse-free survival; GvHD, graft-versus-host disease; haplo, haploidentical; HSCT, hematopoietic stem cell transplantation; LFS, leukemia-free survival; MSD, matched sibling donor; MUD, matched unrelated donor; NRM, non-relapse mortality; OS, overall survival; PTCy, posttransplant cyclophosphamide; UD, unrelated donor. *Haplo defined as recipient-donor number of human leukocyte antigen (HLA) mismatches ≥ 2 |
||
|
Sanz et al.1 |
Lorentino et al.2 |
---|---|---|
Study |
Retrospective registry-based analysis on behalf of the ALWP of the EBMT |
Retrospective registry-based study on behalf of the ALWP and the Cellular Therapy and Immunobiology Working Party of the EBMT |
Eligibility criteria |
Adult (≥ 18 years) patients with AML in CR1 at transplantation, who underwent first allogeneic HSCT, from haplo*, MUD, or MSD donors between 2010 and 2017, using PTCy either alone or in combination with other immunosuppressive drugs as GvHD prophylaxis |
Adult (≥ 18 years) patients with AML or ALL at all disease stages, who received a first allogeneic HSCT from 10/10 or 9/10 UD between 2010 and 2017, using PTCy either alone or in combination with other immunosuppressive drugs as GvHD prophylaxis |
Primary endpoint |
LFS |
LFS |
Secondary endpoints |
Neutrophil engraftment, aGvHD and cGvHD, relapse incidence, NRM, GRFS, and OS |
aGvHD, cGvHD, NRM, relapse, OS and GRFS |
Patient characteristics from both studies are summarized in Table 2. In both studies, the vast majority of patients received PTCy combined with one or two additional immunosuppressive drugs as GvHD prophylaxis, while PTCy without any additional immunosuppressive drug was adopted only in a small number of patients.
Table 2. Patient characteristics
ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; GvHD, graft-versus-host disease; haplo, haploidentical; MAC, myeloablative conditioning; MSD, matched sibling donor; MUD, matched unrelated donor; PTCy, posttransplant cyclophosphamide; RIC, reduced intensity conditioning; UD, unrelated donor. |
|||||
Characteristic |
Sanz et al.1 (N = 1239) |
Lorentino et al.2 (N = 464) |
|||
---|---|---|---|---|---|
MSD (n = 215) |
MUD (n = 235) |
Haplo (n = 789) |
10/10 UD (n = 305) |
9/10 UD (n = 159) |
|
Median age, years (range) |
48 (18–71) |
47 (18–74) |
54 (18–75) |
41 (18–76) |
47 (19–73) |
Diagnosis, n (%) |
|||||
AML |
|
|
|
218 (71.0) |
113 (71.0) |
ALL |
|
|
|
87 (29.0) |
46 (29.0) |
Conditioning, n (%) |
|||||
RIC |
87 (42.0) |
115 (50.0) |
298 (38.0) |
144 (47.0) |
70 (44.0) |
MAC |
122 (58.0) |
116 (50.0) |
487 (62.0) |
161 (53.0) |
89 (56.0) |
Missing |
6 |
4 |
4 |
|
|
Cell source, n (%) |
|||||
Bone Marrow |
62 (29.0) |
22 (9.0) |
341 (43.0) |
36 (12.0) |
19 (12.0) |
Peripheral blood |
152 (71.0) |
213 (91.0) |
448 (57.0) |
269 (88.0) |
140 (88.0) |
GvHD prophylaxis, n (%) |
|||||
PTCy + 2 drugs |
56 (26.0) |
111 (47.0) |
730 (93.0) |
165 (54.0) |
113 (71.0) |
PTCy + 1 drug |
108 (50.0) |
111 (47.0) |
46 (6.0) |
111 (36.0) |
38 (24.0) |
PTCy only |
51 (24.0) |
13 (6.0) |
13 (2.0) |
24 (8.0) |
4 (2.5) |
Other |
|
|
|
5 (2.0) |
4 (2.5) |
The results from the univariate analysis of transplant outcomes are reported in Table 3.
Table 3. Univariate analysis of transplant outcomes
aGvHD, acute graft-versus-host disease; cGvHD, cronic graft-versus-host disease; CI, confidence interval; GRFS, graft-versus-host disease and relapse-free survival; Haplo, haploidentical; LFS, leukemia-free survival; MSD, matched sibling donor; MUD, matched unrelated donor; NRM, non-relapse mortality; OS, overall survival; UD, unrelated donor. |
|||||||
Outcome, % (95% CI) |
Sanz et al.1 |
Lorentino et al.2 |
|||||
---|---|---|---|---|---|---|---|
MSD |
MUD |
Haplo |
p value |
10/10 UD |
9/10 UD |
p value |
|
100-day cumulative incidence of aGvHD |
|||||||
Grades II–IV |
17 (12–23) |
28 (22–34) |
26 (23–29) |
0.03 |
28 (23–33) |
28 (21–35) |
0.84 |
Grades III–IV |
6 (4–10) |
8 (5–11) |
9 (7–12) |
0.2 |
10 (7–14) |
8 (5–13) |
0.51 |
2-year cumulative incidence of: |
|||||||
cGvHD |
|
|
|
|
|
|
|
Overall |
34 (26–41) |
32 (25–39) |
30 (26–33) |
0.3 |
35 (28–42) |
44 (34–54) |
0.21 |
Extensive type |
14 (9–20) |
18 (13–25) |
10 (8–13) |
0.003 |
21 (15–27) |
20 (12–28) |
0.60 |
NRM |
10 (6–15) |
14 (9–19) |
23 (20–26) |
< 0.001 |
20 (15–26) |
16 (9–24) |
0.15 |
Relapse |
33 (26–40) |
25 (19–31) |
23 (20–26) |
0.02 |
24 (19–30) |
28 (21–37) |
0.42 |
2-year probability of: |
|||||||
OS |
64 (56–72) |
68 (62–75) |
61 (58–65) |
0.1 |
62 (55–69) |
59 (49–69) |
0.86 |
LFS |
57 (49–65) |
62 (55–69) |
54 (51–58) |
0.2 |
56 (49–62) |
56 (46–65) |
0.64 |
GRFS |
45 (37–53) |
42 (35–50) |
46 (42–50) |
0.9 |
40 (33–47) |
43 (33–52) |
0.33 |
Lorentino et al. found no difference in the outcome of the 10/10 and 9/10 HLA-matched UD groups stratifying for the total number of immunosuppressive drugs used for GvHD prophylaxis.2
The multivariate analysis of transplant outcomes showed that:
Sanz et al. showed that the use of PTCy for GvHD prophylaxis, in patients with AML in CR1 receiving HSC from haplo donors, led to higher rates of aGVHD and NRM but lower relapse incidence, compared with MSD. Although all patients received PTCy prophylaxis, only a very small number of patients in the haplo group received PTCy alone. In fact, the vast majority of patients (93%) in the haplo group received PTCy plus two additional immunosuppressive drugs and this might have enhanced the effect of PTCy, leading to a reduction in the risk of severe cGvHD. In conclusion, haplo-HSCT offers a good alternative to matched donor transplants but, when available, HLA-matched donors should remain the first choice.
Lorentino and colleagues, found a higher risk of cGvHD in the 9/10 compared with the 10/10 HLA-matched group but similar survival outcomes between the two groups. These results could have important implications, since they could allow a donor pool expansion for high-risk patients who lack an identical sibling or a well-matched UD.
Both studies had the limitations of retrospective studies. In addition, although all patients received PTCy prophylaxis, conditioning regimens were heterogeneous and different immunosuppressive drugs were added to PTCy.
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