Rabbit antithymocyte globulin and cyclosporine as first-line therapy for children with acquired aplastic anemia

To the editor:

Horse antithymocyte globulin (hATG) and cyclosporine have been used as standard therapy for children with acquired aplastic anemia (AA) for whom an HLA-matched family donor is unavailable. However, in 2009, hATG (lymphoglobulin; Genzyme) was withdrawn and replaced by rabbit ATG (rATG; thymoglobulin; Genzyme) in Japan. Many other countries in Europe and Asia are facing the same situation.¹  Marsh et al recently reported outcomes for 35 adult patients with AA who were treated with rATG and cyclosporine as a first-line therapy.²  Although the hematologic response rate was 40% at 6 months, several patients subsequently achieved late responses. The best response rate was 60% compared with 67% in a matched-pair control group of 105 patients treated with hATG. The overall and transplantation-free survival rates appeared to be significantly inferior with rATG compared with hATG at 68% versus 86% (P = .009) and 52% versus 76% (P = .002), respectively. These results are comparable to those from a prospective randomized study reported by Scheinberg et al comparing hATG and rATG.³  Both studies showed the superiority of hATG over rATG.^2,3 

We recently analyzed outcomes for 40 Japanese children (median age, 9 years; range, 1-15) with AA treated using rATG and cyclosporine. The median interval from diagnosis to treatment was 22 days (range, 1-203). The numbers of patients with very severe, severe, and nonsevere disease were 14, 10, and 16, respectively. The ATG dose was 3.5 mg/kg/day for 5 days. The median follow-up time for all patients was 22 months (range, 6-38). At 3 months, no patients had achieved a complete response (CR) and partial response (PR) was seen in only 8 patients (20.0%). At 6 months, the numbers of patients with CR and PR were 2 (5.0%) and 17 (42.5%), respectively. After 6 months, 5 patients with PR at 6 months had achieved CR and 4 patients with no response at 6 months had achieved PR, offering a total best response rate of 57.5%. Two patients relapsed at 16 and 19 months without receiving any second-line treatments. Two patients with no response received a second course of rATG at 13 and 17 months, but neither responded. Sixteen patients underwent hematopoietic stem cell transplantation (HSCT) from alternative donors (HLA-matched unrelated donors, n = 13; HLA-mismatched family donors, n = 3). Two deaths occurred after rATG therapy, but no patients died after HSCT. Causes of death were intracranial hemorrhage at 6 months and acute respiratory distress syndrome at 17 months. The overall 2-year survival rate was 93.8% and the 2-year transplantation-free survival rate was 50.3% (Figure 1).

In our previous prospective studies with hATG, the response rates after 6 months were 68% and 70%, respectively, with no increases in response rates observed after 6 months.^4,5  Our results support the notion that rATG is inferior to hATG for the treatment of AA in children. First-line HSCT from an alternative donor may be justified, considering the excellent outcomes in children who received salvage therapies using alternative donor HSCT.