First LINE Treatment of Aplastic Anemia with Thymoglobuline in Europe and ASIA: Outcome of 976 Patients Treated 2001-2012.

Background. Recent studies have suggested inferior outcome of patients treated with rabbit ATG (Thymoglobulin) as compared to horse ATG (ATGAM , Pfizer or Lymphoglobulin, Genzyme- the latter no longer available); other studies have shown comparable responses and survival. However these studies are based on a relatively small number of patients and a short follow up.

Aim of the study. The aim of this study was to assess real life outcome of a large number of AA patients , treated in Europe and Asia with rabbit ATG (Thymoglobulin, SANOFI) and cyclosporin, as first line treatment .

Methods and patients Eligible for this study were patients with AA treated with Thymoglobulin between 2001 and 2008 (n=501) and 2009-2012 (n=473) in Europe (n=519) or Asia (n=457). Median year of treatment was 2008 : median age (20 and 21 years), interval diagnosis treatment (23 and 25 days) and severity of the disease (46% and 48% with vSAA) were comparable in the 2 time periods.

Early mortality. Mortality <90 days was 5,5% and 2.1% in the time period 2001-2008 and 2009-2012 (p=0.007). In patients aged 0-60 early mortality was reduced from 3.5% to 1.4% and in patients over 60 , from 22% to 9%.

Response. Overall response was recorded in 799 patients. At 6 months , responses were comparable in the 2 time periods: 56% vs 57%, and at 1 year, 75% vs 73%. Response rates at 6 months were age dependent: 60%, 58%, 52%, 40% respectively in patients aged 0-20, 21-40, 41-60, >60. When non responders at 3 months were re-evaluated at 1 year, 59% had responded , 26% were non responders , 5% had died, and 10% had received other treatment.

Survival: The actuarial 10 year survival for the entire population was 73%, and 72%, when patients were censored as surviving at transplant. The actuarial survival has significantly improved after year 2008, from 71% to 81% , not because of more transplants, which have remained stable (29% vs 30% before or after 2008). Other predictors of 10 year survival in univariate analysis were the following : 89%, 86%, 59% for complete, partial responders and non responders (p<0.01), 68% vs 80% for males versus females (p=0.07); 69%, 77%, 78% in patients with neutrophils <0.2x10^9/L, 02-05x10^9/L and >0.5x10^9/L (p<0.001); 77%, 75%, 68% for patients with an interval diagnosis-treatment of <30 days, 31-60 days or > 60 days (p=0.002); 82%, 72%, 66%, 27% in patients aged 0-20, 21-40, 41-60, > 60 years (p<0.001). Survival at 5 years for patients aged 1-60 in the recent period (2009-2012) was 83% and 62% for patients over 60 years; for patients treated within 60 days from diagnosis these figures are 86% and 83%. In multivariate Cox analysis the following variables remained independent predictors of survival : patient age, year of treatment , severity of the disease, interval diagnosis treatment, gender.

Conclusions. With a current overall early mortality (<day 90) of 1.4% , a response rate at 6 months of 58% and 5 year survival of 81%, the combination of CsA and Thymoglobulin appears to be safe and effective as first line treatment in patients aged 1-60. In patients over 60 years of age, early mortality is higher , response rate and 5 year survival is lower, but results have improved after year 2008 , and current 5 year survival is 69%, for older patients treated within 2 months from diagnosis. Finally, response rates and survival, in this large retrospective analysis are quite favourable , compared to other recent publications, although a comparison with horse ATG was not the aim of the present study.