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ATG in myelofibrosis patients
immunoglobulin and mucin-domain containing-3), which may play a role in the control of GvHD.28,29
While ATG clearly decreased the risk of acute GvHD, the adjusted model showed a trend towards improved overall survival in patients who received ATG (P=0.05). This higher risk of mortality without ATG may be explained by higher risk of acute GvHD even if the excess of mortality was not observed only in the first months post-transplant corresponding to GvHD. Treatment of GvHD and steroid-refractory GvHD may have con- tributed to mortality in patients who did not receive ATG. Of note, the definitions of acute and chronic GvHD in the registry were still restricted to the time of development of the disease, such that GvHD occurring in the 100 first days was considered as acute GvHD but we had no data regarding late acute GvHD which is considered as chronic GvHD in this study. Indeed, the classification of acute and chronic GvHD was not made according to the latest National Institutes of Health (NIH) consensus and chronic GvHD may have been overestimated because of the inclu- sion of cases of late acute GvHD.30 Our analysis was based on registry data and GvHD was not recoded a posteriori according to the NIH classification. GRFS, which captures both severe acute and severe chronic GvHD, is an impor- tant endpoint in this setting and showed no difference according to the use or not of ATG. Of note, even if the risk of chronic GvHD is mostly influenced by previous acute GvHD, other variables, such as the management of immunosuppressive therapy and cellular therapy may influence the risk of chronic GvHD. Finally, this is the first study that shows a trend to lower mortality in patients receiving ATG. Four prospective trials conducted in the setting of transplantation from unrelated donors and the aforementioned study in the matched sibling donor set- ting did not find a significant overall survival advantage in patients given ATG.19,31–33 In contrast, one large prospective randomized trial found that overall survival was lower in patients receiving ATG in the setting of unrelated donor transplantation (whether given reduced intensity or mye- loablative conditioning).34 It must be considered however that the dose of ATG and the manufacturing process of these products may also have an impact on outcomes and differ in the various prospective trials. In the present
Table 3. Adjusted effect of antilymphocyte globulin on outcomes; adjustment for age at transplant, Lille score, Karnofsky Performance Status, splenectomy, conditioning regimen intensity and source of stem cells.
Overall survival
Relapse
Non-relapse mortality
Grade II-IV acute GvHD
Grade III-IV acute GvHD
Chronic extensive GvHD
Disease-free survival
GRFS
Hazard ratio (96% CI) ATG versus none
0.66 (0.43-1.00)
1.31 (0.71-2.42)
0.64 (0.39-1.07)
0.54 (0.34-0.86)
1.11 (0.54-2.28)
1.17 (0.72-1.91)
0.86 (0.59-1.27)
1.05 (0.76-1.46)
P value 0.05
0.39
0.09
0.01
0.77
0.52
0.46
0.74
References
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ATG: antilymphocyte globulin; GvHD: graft-versus-host disease; GRFS: GvHD-free, relapse-free survival.
EBMT study, we were able to identify patients who received Thymoglobulin® or Grafalon® but due to small numbers in the subgroups, we could not draw conclusions regarding the specific impact of the individual products on outcomes. Absolute lymphocyte count may also con- tribute to the efficiency of ATG and this factor could not be studied here from the registry data.34 We can only pos- tulate that myelofibrosis patients, who usually have not received intensive chemotherapy, may arrive at transplan- tation with subnormal lymphocyte counts, which can be targeted by ATG. With regards to relapse risk, it was not confirmed in the multivariable model that ATG increased the risk of relapse; however, relapse continued to occur late after HSCT without a real plateau occurring, high- lighting the importance of long-term monitoring in myelofibrosis patients who undergo HSCT.
In conclusion, this retrospective data analysis of myelofibrosis patients undergoing HSCT whose data were included in the EBMT registry confirms that in vivo ATG is able to protect against acute GvHD and possibly may decrease mortality rates. A prospective study is need- ed to confirm the role of ATG in myelofibrosis patients transplanted from an HLA-matched related donor.
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