Antithymocyte Globulin (ATG), Cyclosporine (CyA), and Danazol Versus ATG and CyA As Treatment for Children with Aplastic Anemia: Result of Matched-Pair Analysis

Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) plus cyclosporine A (CyA) has been the standard therapy for aplastic anemia (AA) patients. Recently, telomerase shortening was observed in constitutional marrow failure and some acquired AA patients. In addition, constitutional marrow failure syndrome of variable severity may be present in otherwise phenotypically normal individuals and can masquerade as acquired AA. Calado et al. reported that androgens increased telomerase activity in vitro. The addition of androgens to immunosuppressive therapy may increase the response rate by the effect for these hidden patients. Because all patients in the AA-92 study received danazol and patients in AA 97 study did not receive danazol, we have a unique chance to evaluate the effects of androgen. In this report we present results comparing AA-92 (ATG+CyA+danazol) with AA-97 (ATG+CyA) protocol for children with AA using a matched-pair analysis. Patients and Methods: We conducted two prospective multicenter studies: the AA-92 and AA-97, which began in November 1992 and October 1997, respectively. From 1992 to 2009, 530 children with AA were treated with IST. IST consisted of horse ATG (15 mg/kg/day, days 1 to 5), CyA (6 mg/kg/day, days 1 to 180) and methylprednisolone. All patients in the AA-92 study received danazol at a dose of 5 mg/kg/day for 6 months. We selected pairs of patients treated with either AA-92 or AA-97 by matching the variables of disease severity, age, sex, and duration from diagnosis to IST. We assessed hematologic response at 3 and 6 months after initiation of therapy as well as overall survival and failure-free survival. Definition of treatment failure was death, relapse, disease progression requiring stem cell transplantation or second IST, and clonal evolution. Results: Among 530 patients, 104 pairs were matched and their disease severity was very severe (VSAA) (n=43), severe (SAA) (n=34), and non-severe (NSAA) (n=27). Median age was 8 years (1–15) and 53 (51.0%) were male. In the AA-92 study, the response rates at 3 and 6 months were 48/104 (46.2%) and 71/104 (68.3%), respectively. In the AA-97 study, the response rates at 3 and 6 months were 49/103 (47.6%) and 59/104 (56.7%), respectively. The overall 10-year survival rates in AA-92 and AA-97 were 82.7% and 93.6%, respectively. In VSAA patients, the response rate at 6 months in AA-92 was significantly higher than in AA-97 (69.8% vs 46.5%, p=0.029). However, the overall 10-year survival rates for patients with VSAA in AA-92 and AA-97 were 81.4% and 90.4%, respectively. The failure-free 7-year survival rates for patients with VSAA in AA-92 and AA-97 were 55.5% and 61.5%, respectively. The cumulative incidence of clonal evolution between studies did not differ. Conclusions: Our results showed that the response rate of VSAA patients at 6 months in the danazol group was significantly higher than in those not receiving danazol, but overall survival and failure-free survival were not different. There is a possibility that a number of cases with androgen-responsive congenital bone marrow failure syndrome, such as dyskeratosis congenita, were hidden in our series of AA patients, which may explain the higher response rate with danazol in AA-92.

No relevant conflicts of interest to declare.