Several clinical trials established treatment with horse ATG (hATG) and cyclosporine A (CsA) as standard treatment of AA in patients (pts) who are not candidates for stem cell transplantation (SCT). In 2007 the hATG brand Lymphoglobulin® was withdrawn from the market. As the hATG brand ATGAM®, is not approved in Europe, hATG was replaced by rabbit ATG (rATG). Recently a large prospective randomized one-center study from NIH, USA comparing hATG ATGAM®/CsA and rATG Thymoglobulin®/CsA in untreated AA showed significantly lower response rates and survival with rATG. To obtain further information on rATG treatment in an unselected AA population, especially with a higher median of age and use of different rATG dosages we performed a retrospective data collection of first line rATG therapy on several centers. This shall reflect outcome after rATG in a real-world situation. Methods: Retrospective data collection and analysis of first line rATG treatment of AA after approval by Ethical Committee. Results: Up to now retrospective data of 64 pts from 18 centres in Germany were analysed. Characteristics of the pts: 30 male, 34 female; median age at time of therapy 54 years (6–80 years); 87.5% of pts had idiopathic AA. 51.6% of pts had severe AA, 32.8% very severe AA and 15.6% non-severe AA. Median granulocyte count was 0.3 G/l. 86% of the pts required red blood cell and 92% platelet transfusions. 56 of the evaluable pts received Thymoglobulin® and 5 pts Fresenius ATG S®. 52 of the 56 Thymoglobulin®-treated pts got this therapy in the years 2007–2011, i.e. not as deliberate primary choice of rATG but because hATG was no longer available. Median daily dose of Thymoglobulin® was 3.5 mg/kg (range from 2.5 – 3.75 mg/kg) for 5 days. 62 of 64 pts received additional immunosuppressive therapy with CsA and 19 of 64 pts received G-CSF. The median follow-up for surviving pts was 558.5 days (range, 78–3800 days). Response rates at time of best response of pts were CR in 10/58 pts (17%), PR in 18/58 pts (31%) and NR in 30/58 pts (52%) (only surviving patients with a minimum follow-up of 120 days were analyzed). Median interval to best response was 217 days. Response rate (PR+CR) was 16/33 (48.5%) in pts who received a Thymoglobulin® dose of > 3.5 –3.75 mg/kg/day versus only 4/14 (28.6%) group of 14 pts with a dose of > 2.5 to < 3.5 mg/kg/day (p=0.17; Fisher`s exact test). Relapses occurred in 3/28 responders and clonal evolution was observed in 3 pts (2 PNH, 1 MDS). Eighteen of 63 evaluable pts received allogenic SCT after ATG-therapy and were censored at the date of SCT. 23% of 44 pts without SCT died. In 6 of these 10 pts death was caused by infections. Other causes of death were bleeding, cardiac event, acute respiratory distress syndrome, adynamia. Overall probability of survival at 3 years was 75.8% (95% confidence interval (CI): 61.8 – 89.9%) and survival censored for SCT was 79.9% (CI: 66.0–92.8%). Survival was significantly better in responders (PR and CR) (94.1% at 3 years; CI: 82.9–100%) than in non-responders (58.0% at 3 years; CI 34.0 – 81.3%) (p=0.04; log-rank test). Adverse events were reported in 79.4% of 63 evaluable pts consisting of anaphylaxis/allergy in 27.3%, serum sickness in 12.7%, fever/chills in 34.5%, and bacterial/viral/fungal infections in 54.5% of pts. Conclusion: Response rate and survival after rATG+CsA in this retrospective analysis is lower than in historical controls (e.g. hATG+CsA treatment in previous controlled studies of the German AA Study Group and the EBMT AA Working Party; Frickhofen et al., Blood 2003; Tichelli et al., Blood 2011) and rate of (early) infections seem to be high. Our results are in accordance with recent reports from other groups. Additionally the results of this retrospective data analysis suggest a benefit for the patient group treated with a Thymoglobulin® dosage of > 3.5 –3.75 mg/kg/day compared to lower doses (< 3.5 mg/kg/day). There is growing evidence that best results in terms of response and survival are obtained by hATG-based immunosuppression. hATG can not be replaced by rATG without negative impact on patient outcome. There is need for action to achieve availability of hATG worldwide. If hATG is not available, treatment with rATG should be considered instead of no treatment or treatment with CsA alone since still about half of the patients respond to rATG.
Höchsmann:Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: The use of the horse ATG ATGAM in Aplastic Anemia is off-label in Europe. At the moment no horse ATG with approval is available in Europe. Schrezenmeier:Genzyme: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Research Funding.
Asterisk with author names denotes non-ASH members.