Prospective Multicenter Trial Comparing Repeated Immunosuppressive Therapy (IST) with Stem Cell Transplantation (SCT) from an Alternative Donor as a Second-Line Treatment for Children with Acquired Aplastic Anemia (AA).

Immunosuppressive therapy (IST) has been shown to be an effective therapy for aplastic anemia (AA) patients without HLA-matched family donors. However, a significant proportion of patients are refractory to IST. Although the efficacy of repeated IST and stem cell transplantation (SCT) from an alternative donor has been confirmed, a direct comparison between these two procedures has not yet been conducted. In this study, we prospectively compared the efficacy of these two treatments. Between Oct. 1997 and Apr. 2003, 231 patients (125 male, 106 female; median age, 9 y; range, 0 to 17 y) were enrolled in the AA-97 study. Analysis was performed in April 2004. A total of 103 very severe AA and 74 severe AA patients received first-line IST consisting of antithymocyte globulin (ATG; Lymphoglobulin), Cyclosporin (CyA) and methylprednisolone (Mepred), while 54 non-severe AA patients received IST consisting of ATG and Mepred with or without CyA. G-CSF was administered only to patients with very severe AA. Sixty patients (26%) were non-responders to first-line IST and were eligible for 2 ^nd -line therapies. Of these, 29 patients lacking suitable donors received 2 ^nd-line IST with ATG (Lymphoglobulin), CyA and Mepred. Four developed severe anaphylactoid reactions and could not complete the 2 ^nd-line treatment. Twenty-nine patients received SCT as follows: BMT from an unrelated donor (n=22), BMT from an HLA-mismatched family donor (n=4) and cord blood SCT from an unrelated donor (n=3). Two patients did not receive any 2 ^nd-line treatment. Median interval between 1 ^st -line IST and 2 ^nd-line treatment was 8 mo for the SCT group (range: 4–20 mo) and 7 mo for the IST group (range: 5–14 mo). One patient receiving 2 ^nd-line IST and 5 patients receiving SCT died of infections. The overall probability of survival at 5 y from the start of 2 ^nd-line treatment was 82 ± 10% in the SCT group and 97 ± 5% in the IST group (p:0.08 ). However, trilineage response to a 2 ^nd course of IST was seen in only 3 of 25 evaluable patients (12%), and 10 non-responders to 2 ^nd-line IST later received BMT from an unrelated donor as a 3 ^rd -line therapy. Blood counts normalized in all patients following SCT. Failure-free survival (FFS) was defined as survival with treatment response. The estimated FFS at 5 y was significantly better (p <0.01) in the SCT group (81 ± 15%) than in the IST group (13 ± 12%). The probability of survival at 6 y from the start of 1 ^st treatments was 90 ± 6% in the 103 very severe AA patients, 97 ± 3% in the 74 severe AA patients and 95±4% in the non-severe 54 AA patients.

Conclusion: SCT from alternative donors offers a better chance of FFS than 2 ^nd-line IST in non-responders to 1 ^st -line IST. However, overall survival rate is not different between two approaches.