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M. Robin et al.
patients with a matched related donor received ATG.22 ATG was used less frequently before 2010 (35% versus 51%). The majority of patients received a reduced intensi- ty conditioning regimen and the preferred source of stem cells was peripheral blood. Our study demonstrated that acute GvHD was decreased following the use of ATG but there was no impact on chronic GvHD. The lack of atten- uation of the risk of chronic GVHD is in contrast to the findings of the randomized trial comparing ATG versus no ATG in the setting of matched related donor HSCT pub- lished recently by Kröger et al.19 However, that study included patients with acute leukemia who were given myeloablative conditioning whereas our cohort received predominantly reduced intensity conditioning regimens and the study focused only on myelofibrosis. Of note, the rate of acute GvHD, even in patients who received ATG, was relatively high in our cohort (26%) as compared to that in the prospective study cited above but not dissimi- lar to the rates in other studies including only patients with myelofibrosis.17,18 The rates of chronic GvHD were significantly high even after ATG; indeed, they were high- er than previously reported in this disease setting. This raises the question of whether these myelofibrosis patients were more susceptible to developing chronic GvHD. We could postulate that these patients, who still had myelofibrosis slowly resolving in the first months after transplantation, had a pro-inflammatory profile able to trigger GvHD. Indeed, myelofibrosis is associated with elevated pro-inflammatory biomarkers such as those found in both autoimmune disease and immune dysregu- lation23–26 and it has been demonstrated that the bone mar- row remains fibrotic at 3 months following HSCT in approximately half of patients.27 Moreover, Hussain et al. reported that even in patients in whom fibrosis resolved following HSCT, the levels of pro-inflammatory cytokines and tissue remodeling factors could remain elevated.28 In contrast, other cytokines are downregulated following HSCT, such as the T-cell inhibitory receptor Tim-3 (T-cell
Table 2. Outcomes in patients with or without T-cell depletion (univariate).
Figure 2. Adjusted survival curves. From left to right, overall survival (OS), disease-free survival (DFS), and graft-versus-host disease-free, relapse-free survival (GRFS) in patients who were given antilymphocyte globulin (red) and patients who were not given antilymphocyte globulin (black) with the 95% confidence intervals (dotted lines). Curves have been adjusted according to multiple Cox models.
Outcomes: number of events
No ATG (n=152)
ATG (n=135)
130
96.3% (90.9-98.5)
108
80.3% (72.3-86.1)
32
26.2% (18.7-34.3)
20
15.1% (9.6-21.7)
62
54.6% (44.5-63.7)
33
28.3% (20.4-36.7)
29
24.4% (16.5-33.1)
31
31.0% (20.9-41.6)
P value Gray: P=0.35
Gray: P=0.09 Gray: P=0.0067 Gray : P=0.47 Gray: P=0.47 Gray: P=0.50 Gray: P=0.083 Gray: P=0.56
Neutrophil recovery 60-day cum incidence
Platelet recovery
180-day cum incidence
Grade II-IV acute GvHD 4-month cum incidence
Grade III-IV acute GVHD
4-month cum incidence
Chronic GvHD* 5-year cum incidence
Extensive chronic GvHD *
5-year cum incidence
Relapse
5-year cum incidence
Non-relapse mortality
5-year cum incidence
Death
Median (95% CI) 5-year OS
Cause of death
Relapse/progression Other
Unknown
Relapse or death Median (95% CI) 5-year DFS
GvHD relapse death Median (95% CI) 5-year GRFS
143
94.1% (88.7-96.9)
104
68.4% (60.3-75.2)
58
41.4% (33.1-49.5)
18
11.9% (7.3-17.6)
75
51.7% (43.1-59.6)
37
25.8% (18.9-33.3)
24
18.6% (12.1-26.1)
45
32.5% (24.4-40.7)
65
63.4 months (39.8-NA) 64 months (44.7-NA)
54.7% (45.1-63.1)
22 (34%) 35 (54%) 8 (12%)
44 Logrank P=0.43 52.8% (42.1-66.3)
69
59.5 months (29-NA) 38.1 months (23.6-NA)
*censored at donor lymphocyte infusion.ATG: antilymphocyte globulin; cum incidence: cumu- lative incidence; GvHD: graft-versus-host disease; OS: overall survival; DFS: disease-free survival; GRFS: GvHD-free, relapse-free survival.
Fisher exact: P=0.52
13 (29%) 28 (64%) 3 (7%)
60
49.0% (40.6-59.0) 44.7% (34.7-57.4)
95 86 Log-rank: P=0.12 9.9 months (8.2-17.7) 7.5 months (6.7-11.3)
29.3% (22.0-38.9) 23.6% (15.8-35.2)
Log-rank: P=0.46
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