Prospective, Randomized, Multicenter Study Comparing Antithymocyte Globulin (ATG) Alone with ATG Plus Cyclosporine (CsA) for Treatment of Children with Nonsevere Aplastic Anemia (nSAA).

In contrast to treatment for childhood severe aplastic anemia (SAA), there is no consensus on the treatment of childhood nSAA. Two thirds of patients progress to SAA, suggesting the need to consider early immunosuppressive therapy (IST). ATG+CsA was superior to ATG alone in a German randomized trial that enrolled both patients with SAA and nSAA. However, subgroup analysis revealed no advantage of adding CsA for patients with nSAA. These findings formed the basis for this prospective, randomized study comparing ATG alone with ATG+CsA for treatment of childhood nSAA. From 1997 to 2004, 62 children with newly diagnosed nSAA were enrolled. Interim analysis was done in April 2005. Patients were randomized to receive either horse ATG (Lymphoglobuline, 1.5vial/10kg/day for 5 days; n=31) or ATG+CsA (6mg/kg/day; n=31). CsA was added for non-responders at day+90 in ATG group. The endpoints were hematologic response at 6 months and failure-free survival (FFS). Complete response (CR) was defined as a neutrophil count > 1.5x 109/L, a platelet count > 100x109/L, and a hemoglobin level > 11.0g/dl. Partial response (PR) was defined as a neutrophil count > 1.0x 109/L, a platelet count > 30x109/L, and a hemoglobin level > 8.0g/dl. FFS was defined as survival with a response. Clinical profiles of two treatment groups were comparable. Median age was 11 years and 10 years in ATG+CsA group and ATG group, respectively. Median time from diagnosis to treatment was 20 days and 23 days in ATG+CsA group, and ATG group, respectively. After 6 months, CR was observed in ATG+CsA group in 5 patients (16%) and PR in 12 patients (39%). In ATG groups, 2 patients (6%) achieved CR and 13 patients (42%) achieved PR. However, 19 patients in the ATG group received additional CsA. There were 22 failures in ATG group and 14 failures in ATG+CsA group. A total of 10 patients who failed initial therapy (7 in ATG group and 3 in ATG+CsA group) received a second IST. Bone marrow transplant (BMT) was attempted in 4 non-responders in ATG group and 6 non-responders in ATG+CsA group. Requiring CsA was a cause of failure in 8 patients of ATG group. The probability of FFS was 54.8% in ATG+CsA group compared with 26.7% in the ATG group (p=0.001). There was 1 death in each group: 1 from BMT-related toxicity in ATG+CsA group and 1 from bacterimia in ATG group. The 5-year survival rate was 94.8% in ATG+CsA group and 96.7% in ATG group. Conclusion; the hematologic response rate at 6 months and overall survival rate are comparable between the two groups, however the combination of ATG and CsA is superior to ATG alone in term of FFS for children with nSAA.