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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the only curative treatment available for patients with myelodysplastic syndromes (MDS), and the efficacy of allo-HSCT is largely dependent on the intensity (and type) of pretransplantation conditioning regimen. Data from recent clinical trials are divided regarding conditioning regimens; however, in one study, better outcomes were seen in association with myeloablative conditioning (MAC), while in another, better outcomes were seen with reduced intensity conditioning (RIC). Similarly, conflicting results have been reported in the relapsed setting.1
While MAC regimens may be the best option for certain patients with MDS, it is important to keep in mind that many MDS patients are older and, due to concerns regarding comorbidities and unfitness, most will be treated with RIC regimens. In a recent study published in Transplantation and Cellular Therapy, Betül Oran et al. compared the two most commonly used RIC regimens—fludarabine + intermediate-dose melphalan (FluMel) and fludarabine + intermediate-dose busulfan (FluBu)—to determine which regimen is most effective in older patients with MDS.1
This was a retrospective cohort analysis of data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Results reported to the CIBMTR between 2007 and 2016 were included for patients with MDS age ≥60 years who underwent human leukocyte antigen (HLA)-matched related or unrelated donor HSCT following a RIC regimen (defined as fludarabine with either a total melphalan dose ≤150 mg/m2 or intravenous busulfan ≤7.2 mg/kg).
A total of 1,045 patients were included in the analysis (FluMel, n = 448; FluBu; n = 597) and were categorized according to disease characteristics using the revised International Prognostic Scoring System (IPSS-R) and CIBMTR risk scoring. The median patient age was 67 years in each treatment group (Table 1).
Table 1. Selected patient characteristics by RIC regimen*
Variable, % (unless otherwise stated) |
FluBu |
FluMel |
p value |
---|---|---|---|
Age, years |
0.005 |
||
60‒69 |
74 |
81 |
|
≥70 |
26 |
19 |
|
Median age (range), years |
67 (60‒83) |
67 (60‒77) |
0.23 |
KPS |
0.13 |
||
90‒100 |
15 |
13 |
|
<90 |
10 |
11 |
|
IPSS-R before HSCT |
0.71 |
||
Very low |
12 |
10 |
|
Low |
25 |
24 |
|
Intermediate |
31 |
30 |
|
High |
14 |
17 |
|
Very high |
6 |
6 |
|
CIBMTR MDS risk score |
0.18 |
||
Intermediate |
47 |
42 |
|
High |
31 |
31 |
|
Very high |
4 |
5 |
|
Donor type |
0.08 |
||
HLA-identical sibling |
26 |
31 |
|
Well-matched unrelated (8/8) |
74 |
69 |
|
Graft type |
0.002 |
||
Bone marrow |
3 |
7 |
|
Peripheral blood |
97 |
93 |
|
Median follow-up of survivors (range), months |
38 (4‒101) |
35 (6‒120) |
|
CIBMTR, Center for International Blood and Marrow Transplant Research; FluBu, fludarabine + busulfan; FluMel, fludarabine + melphalan; HLA, human leukocyte antigen; HSCT, hematopoietic stem cell transplantation; IPSS-R, revised International Prognostic Scoring System; KPS, Karnofsky performance status; MDS, myelodysplastic syndromes. |
No differences were observed between the groups regarding:
While treatment with graft-versus-host disease (GvHD) prophylaxis was uniform between the groups, the regimen more commonly included antithymocyte globulin (ATG) and alemtuzumab in the FluBu group vs the FluMel group (39% vs 31%; p<0.001).
On univariate analysis, estimates of overall survival (OS) at 1 year (FluBu, 61%; FluMel, 63%) and 2 years (FluBu, 49%; FluMel, 51%) posttransplantation were similar regardless of the conditioning regimen; a difference was observed at 3 years (FluBu, 39%; FluMel, 45%).
On multivariate analysis, FluMel was associated with a decrease in OS, but only in the first 3 months following transplantation; after this point, it was associated with improved OS (p<0.001). After adjusting for MDS risk group by CIBMTR and HCT-CI, FluMel was associated with improved OS compared with FluBu (46% vs 39%; p = 0.03) as shown in Table 2.
Table 2. Adjusted probabilities of transplantation outcomes by conditioning regimen*
Outcome |
FluBu regimen |
FluMel regimen |
p value |
---|---|---|---|
Overall survival, years |
|||
1 |
61 (57‒65) |
63 (59‒68) |
0.4 |
2 |
48 (44‒52) |
52 (47‒57) |
0.24 |
3 |
39 (34‒43) |
46 (41‒51) |
0.03 |
Disease-free survival, years |
|||
1 |
40 (36‒44) |
48 (43‒52) |
0.02 |
2 |
32 (29‒36) |
40 (36‒45) |
0.01 |
3 |
27 (23‒31) |
35 (30‒40) |
0.01 |
Relapse incidence, years |
|||
1 |
44 (40‒47) |
26 (22‒30) |
<0.0001 |
2 |
47 (43‒51) |
28 (24‒33) |
<0.0001 |
3 |
50 (46‒54) |
32 (27‒37) |
<0.0001 |
Treatment-related mortality, years |
|||
1 |
16 (13‒19) |
26 (22‒30) |
<0.0001 |
2 |
22 (19‒26) |
33 (28‒38) |
0.0005 |
3 |
28 (24‒33) |
36 (31‒41) |
0.03 |
aGvHD grade |
|
|
|
II‒IV at 60 days |
24 (21‒28) |
35 (30‒39) |
0.0003 |
II‒IV at 6 months |
40 (36‒44) |
44 (39‒48) |
0.19 |
III‒IV at 60 days |
9 (7‒11) |
16 (13‒20) |
0.0004 |
III‒IV at 6 months |
17 (14‒20) |
19 (15‒22) |
0.48 |
cGvHD, years |
|||
1 |
42 (38‒46) |
35 (30‒39) |
0.02 |
2 |
49 (45‒53) |
45 (40‒50) |
0.18 |
3 |
49 (45‒53) |
48 (43‒53) |
0.75 |
GRFS |
|
|
|
60 days |
84 (81‒87) |
76 (71‒80) |
0.0005 |
6 months |
40 (36‒44) |
43 (38‒48) |
0.37 |
1 year |
14 (11‒17) |
22 (18‒26) |
0.0009 |
2 years |
7 (5‒10) |
14 (11‒18) |
0.002 |
3 years |
6 (4‒9) |
10 (7‒13) |
0.1 |
aGvHD; acute GvHD; cGvHD, chronic GvHD; FluBu, fludarabine + busulfan; FluMel, fludarabine + melphalan; GRFS, GvHD relapse-free survival; GvHD, graft-versus-host disease. |
Regarding cause of death:
Disease-free survival (DFS) was lower in the FluBu cohort compared with the FluMel cohort, even after adjusting for CIBMTR risk category; multivariate analysis showed that the favorable impact of FluMel was only apparent after 3 months posttransplantation (p<0.001; Table 2).
In this comparison of two RIC regimens in older (≥60 years) patients with MDS, FluMel was associated with a significant improvement in DFS, and a decreased risk of relapse compared with FluBu. An improvement was also seen in OS, despite a higher incidence of TRM in the first 3 months posttransplantation. These improvements were observed across disease risk categories.
Despite comparison groups that were similar in most patient, disease, and transplantation characteristics (excepting the use of ATG or alemtuzumab for GvHD prophylaxis), this study had several limitations, including the inability to account for certain variables (reasons for selecting one regimen over the other, dosing details, and molecular information, in particular). Recent retrospective data have shown that pharmacokinetic-guided busulfan dosing may result in more standardized systemic exposure and better leukemia control, but patients receiving busulfan in this way were unable to be identified. Based on the improved outcomes seen in this study, however, the authors concluded that FluMel should be considered the RIC regimen of choice for older patients with MDS, barring any contraindication.
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