Randomized Trial On GvHD Prophylaxis with or without Anti T Cell Globulin ATG Fresenius (ATG-F) in Allogeneic Hematopoietic Cell Transplantation From Matched Unrelated Donors: Updated Results and Evaluation of the European Group for Blood and Marrow Transplantation (EBMT) Risk Score.

Previously, in 201 adult patients with allogeneic hematopoietic cell transplantation from matched unrelated donors, we demonstrated that addition of ATG-F to standard cyclosporine, methotrexate GvHD prophylaxis (control) significantly reduces acute and chronic GvHD without negatively affecting non-relapse mortality (NRM), relapse, disease-free survival (DFS) and overall survival (OS) [1,2].

Now, we present updated results of extended follow-up (median 5.5, Q1 5.0, Q3 6.5 years). Furthermore, we investigated whether the European Group for Blood and Marrow Transplantation (EBMT) risk score (0 to 7 points) based on the sum of points for patient age (20–40y: 1 point, >40y: 2 points), disease stage (intermediate: 1 point, late: 2 points), time interval from diagnosis to transplant (>12m: 1 point), donor type (unrelated: 1 point), and donor-patient sex combination (donor female, patient male: 1 point) [3] was able to predict outcome with respect to OS in our trial. The explained variation R² of the risk score was calculated by setting the prediction error (Integrated Brier Score) of the score in relation to the prediction error of an overall estimate of OS without dividing the patients into different risk groups.

The incidence of extensive chronic GvHD after 5 years was 13.6% in the ATG-F group vs 48.9% in the control group (p<0.0001). The 5-year rates with respect to outcome were: DFS 44.3% vs 37.2% (p=0.67), relapse 35.2% vs 29.9% (p=0.46), relapse mortality 29.7% vs 27.7% (p=0.99), NRM 20.5% vs 32.9% (p=0.15), and OS 49.8% vs 39.1% (p=0.28), ATG-F vs control respectively. Patients' distribution to the EBMT risk score was 1 point 2, 2 points 43, 3 points 59, 4 points 43, 5 points 32, 6 points19, 7 points 1, unknown 2.

The trend test for increasing risk with increasing risk score resulted in p=0.006. The risk score is able to separate patients with regard to OS, but in univariate and multivariate analyses of the factors building the score (age, disease stage, time from diagnosis, patient/donor sex) only disease stage showed a significant and relevant effect on OS (hazard ratio: intermediate vs early 1.54 95%-CI [0.92,2.56], late vs early 1.98 [1.30,3.02], trend test p=0.001). Thus, the addition of points to the risk score for factors that do not have a prognostic effect results in a dilution of its prognostic ability. In fact, the explained variation of the factor disease stage alone was higher than that of the risk score (R²=3.8% vs R²=3.4%).

The main prognostic factor in our trial besides disease stage was donor age [4]. We therefore analyse the effect of a new risk score based on the sum of points for these two factors: donor age (>40y: 1 point) and disease stage (intermediate: 1 point, late: 2 points).

The trend test for increasing risk with increasing score resulted in p<0.0001, and the explained variation was R²=8.1%.

After a long-term follow-up of 5.5 years, it could be confirmed that ATG-F GvHD prophylaxis provides a sustained protective effect without compromising relapse and survival. The EBMT risk score is able to separate patients with regard to OS, but in our trial another risk score based on disease stage and donor age can be defined leading to a better prediction of OS. As this score was derived in the same dataset, the assessment of its predictive ability is overoptimistic and it has to be validated in an independent study.

Finke:Fresenius Biotech GmbH: Honoraria, Research Funding. Bethge:Fresenius Biotech GmbH: Lecture remuneration Other. Bertz:Fresenius Biotech GmbH: Lecture remuneration Other.