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

Abstract

▪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. DisclosuresBacigalupo:PIERRE FABRE: Speakers Bureau; SANOFI: Speakers Bureau. Carlo:Pfizer, Novartis: Consultancy. Kojima:SANOFI: Honoraria, Research Funding.