Treatment of severe aplastic anemia with a combination of horse antithymocyte globulin and cyclosporine, with or without sirolimus: a prospective randomized study.
BACKGROUND
We hypothesized that the addition of sirolimus to standard horse antithymocyte globulin (h-ATG) and cyclosporine (CsA) would improve response rates in severe aplastic anemia, due to its complementary and synergistic properties to cyclosporine A.


METHODS
To test this hypothesis, we conducted a prospective randomized study comparing hATG/CsA/sirolimus to standard h-ATG/CsA. A total of 77 patients were treated from June 2003 to November 2005; 35 received h-ATG/CsA/sirolimus and 42 h-ATG/CsA. The two groups were well matched demographically and in blood counts prior to therapy. The primary end-point was hematologic response rate at 3 months, defined as no longer meeting the criteria for severe aplastic anemia. The study was powered to show a superior hematologic response rate of h-ATG/CsA/sirolimus compared to standard h-ATG/CsA.


RESULTS
The overall response rate at 3 months was 37% for h-ATG/CsA/sirolimus and 50% for h-ATG/CsA and at 6 months 51% for h-ATG/CsA/sirolimus and 62% for h-ATG/CsA. After a planned interim analysis of 30 evaluable patients in each arm, accrual to the h-ATG/CsA/sirolimus arm was closed, as the conditional power for rejecting the null hypothesis was less than 1%. The rate of relapse, clonal evolution, and survival (secondary outcomes) did not differ significantly between patients treated with the two different regimens.


CONCLUSIONS
Despite a theoretical rationale for its use, sirolimus did not improve the response rate in patients with severe aplastic anemia when compared to standard h-ATG/CsA.
Scheinberg
Phillip
P
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1202, USA. scheinbp@mail.nih.gov
Wu
Colin O
CO
Nunez
Olga
O
Scheinberg
Priscila
P
Boss
Carol
C
Sloand
Elaine M
EM
Young
Neal S
NS
D000293:Adolescent; D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000961:Antilymphocyte Serum / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D006736:Horses; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012008:Recurrence; D020123:Sirolimus / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020123:Sirolimus