Phase II Study of Thymglobulin, Cyclosporin, and G-CSF for the Initial Treatment of Aplastic Anemia and Low Risk Myelodysplastic Syndrome.

Standard therapy of aplastic anemia (AA) involves the use of equine anti-thymocyte globulin (ATG) in combination with cyclosporine. Hematological responses occur in 40% to 50% of patients treated with ATG alone. The addition of cyclosporine to ATG has improved response and survival; response rates have been up to 65%, and the 5-year survival rate in the responding patients has been over 80%. Several lines of observation have also implicated an autoimmune mechanism in at least a subset of patients with myelodysplastic syndrome (MDS) whose disease process may overlap AA. The rationale for treating refractory or relapsing patients with ATG from a different animal has been the lower risk of potentially life-threatening allergic reactions. In a recent study, most patients who received rabbit ATG (Thymoglobulin) after unsuccessful treatment with ATG became transfusion independent (Di bonna E, Br J Haematol, 1999). Another study has reported high responses to Thymoglobulin in patients with relapsed AA (Scheinberg P, Br J Haematol, 2006). We are conducting a clinical trial of Thymoglobulin in combination with cyclosporin and GCSF in the first line therapy of patients with AA or low-risk MDS. Patients receive Thymoglobulin 3.5 or 2.5 (if they were 55 years or older) mg/kg/day IV for 4 days, methyl prednisone 1 mg/kg/day IV for 4 days followed by a tapering dose of oral prednisone, cyclosporine 5 mg/kg orally, and G-CSF 5 μg/kg daily for up to 3 months at the discretion of the treating physician. All patients receive prophylactic broad-spectrum antibiotics. We have enrolled 13 patients in the study including 7 patients with AA and 6 patients with MDS. The median age for AA patients was 61 years (range 45 – 73 years), and for MDS patients 60 years (range, 41 – 71 years). The median absolute neutrophil count (ANC) for AA patients was 0.74 × 10⁹/L (range, 0.1 – 1.0 × 10⁹/L) and for MDS patients 2.0 × 10⁹/L (range, 1.1 – 8.1 × 10⁹/L). The median Hgb for AA patients was 6.9 g/dL (range, 3.9 – 7.9 g/dL) and for MDS patients 8.1 g/dL (range 6.4 – 10.7 g/dL). The median platelet count for AA patients was 8 × 10⁹/L (range, 0 – 153 × 10⁹/L) and for MDS patients 10 × 10⁹/L (range, 6 – 16 × 10⁹/L). Flow cytometry for a PNH clone was negative in all patients. Seven patients (4 AA, 3 MDS) were positive for HLA-DR15. So far, 6 patients with AA have responded including 3 CRs, 2 PRs and 1 HI. One patient with MDS had a PR. Toxicity has been acceptable with no grade 3 or 4 side effects. Other side effects (grade 1 and 2) included infusion-related reactions, hypomagnesemia, elevation of serum creatinine, and hyperbilirubinemia. We conclude that Thymoglobulin can be administered safely in combination with cyclosporin and GCSF to treat patients with untreated AA and MDS.