Abstract
Background:
Plasmatic Levels of TIM-3 and ST-2 at the time of onset of acute GVHD predict prognosis after allogeneic transplantation. Based on previous data (Exp Hem 2015, 43:430), we hypothesized that may be possible to identify earlier, at the time of engraftment, patients having distinctive degrees of alloreactivity and prognosis.
Methods:
In a prospective study, we determined, the prognostic value of 5 plasma cytokines (IL-2-rec, TIM-3, ST2, IFN-gamma, IL-6) assayed in plasma at day+18/+19 after allogeneic hematopoietic transplantation. Eighty-five patients were studied, mean age was 45 years (18-67), 63 patients were affected by myeloid malignancies, 22 by lymphoma or myeloma, donor type for allogeneic hematopoietic transplantation was in 38% an HLA-identical sibling and in 62% an alternative donor (MUD or HAPLO). ST2 and TIM-3 were assayed by R-D ELISA kits, IFN-gamma high sensitivity, IL-6 and IL-2R were assayed by Diaclone ELISA kits. Data were analyzed by R statistical software.
Results:
In univariate analysis, negative factors important for Overall Survival (OS) were an alternative donor, advanced stage of disease, high level of Interleukin-2 receptor and high level of TIM-3 in plasma. In patients having a level of IL2-rec lower than median value (7600 pg/ml), OS at 2 y was 72% versus 18% in the group having IL-2-rec over the median (log-rank: p=0.0001). In the same way grouping patients according to TIM-3 (below or over the 25th percentile or 950 pg/ml), two groups having different OS could be identified. The first group, had a 2y OS of 90% while OS was 30% in patients having TIM-3 over the 25th percentile (p=0.0004). When IL-2-rec, TIM-3, Stage of disease and Donor type were entered a Cox proportional hazard multivariable analysis, risk factors retained as independently important for OS were: TIM-3 over 25th percentile (HR: 8.735 CI:1.870-40.802) and IL-2-rec over the median (HR: 3.477, CI: 1.366-8.848). In a ROC assay, a threshold level of IL-2-rec in plasma at day +18 of 8200 pg/ml had, a sensitivity of 0.76 and a specificity of 0.66 in predicting the risk of death attributed to TRM, (AUC 0.744 95% CI 0.61 - 0.879). Combining TIM-3 and IL-2-rec, different groups of patients were identified. Group A represented 28% of patients, they had an OS of 90% and a TRM of 0%, Group B represented 33% of patients they had an OS of 60% and a TRM of 20% and Group C represented 38% of all patients, they had an OS of 20% and a TRM of 50% (Gray test for differences in TRM, p=0.003, Log-rank test for difference in OS, p=0.0001).
Conclusion:
By the assay of IL-2-rec and TIM-3 in plasma at day +18 after allogeneic transplantation, it is possible to early identify patients having a high risk of TRM and to implement in these patients actions aimed to modulate alloreactivity.
No relevant conflicts of interest to declare.
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