Phase II Study of Thymoglobulin, Cyclosporine and G-CSF for Initial Treatment of Aplastic Anemia and Low Risk Myelodysplastic Syndrome

Aplastic anemia (AA) is treated with equine anti-thymocyte globulin (hATG) and cyclosporine with response rates up to 65%. Rabbit anti-thymocyte globulin (rATG, Thymoglobulin^®) has been used successfully in relapsed and refractory patients with AA, reducing the risk associated with readministration of equine preparations. Immunosuppressive therapy is also effective in some subsets of patients with Myelodysplastic syndrome (MDS).

To evaluate if the combination of rATG, cyclosporine and G-CSF is safe and effective as first-line treatment of AA and low-risk MDS.

In this single-arm, phase II study, we investigated the efficacy (primary endpoint) and safety (secondary endpoint) of combined rATG, cyclosporine and G-CSF as first-line therapy for patients with AA and Hypoplastic MDS. After 8 patients were enrolled, the study was modified to also include patients with low/intermediate-1 per the International Prognostic Scoring System. Thymoglobulin 3.5 mg/kg (or 2.5 mg/kg/day for patients ≥55 years) was given for 4 days in the first 10 patients and for 5 days in the remaining patients. Methylprednisolone (1 mg/kg/day) was given for 5 days followed by a tapering dose of oral prednisone. G-CSF (5 μg/kg) was given subcutaneously daily for up to 3 months starting after thymoglobulin. Cyclosporine (5 mg/kg) was given daily and continued for 6 months or longer at the discretion of the treating physician. All patients received prophylactic broad-spectrum antimicrobials. Responses were assessed about 3 months after initiating therapy.

Thirty-six patients have been enrolled on study with 3 patients choosing alternate therapies and 1 patient dying before initiation of therapy. Among the thirty-two patients treated, 4 have been on study for less than 2 months; therefore 14 patients with AA and 14 with MDS were evaluable for a response. The median age was 62 years (20–83) for patients with AA and 63 (42–80) for patients with MDS. Thirteen of the fourteen (93%) patients with AA responded (5 CR, 7 PR, 1 HI-N), while four of 14 (29%) patients with MDS responded (1 CR, 3 PR). For patients with AA, the median time to response (TTR) was 93 days (79–623). For patients with MDS, the median TTR was 111 days (77–139). The median response duration for both groups has not been reached. Side effects were listed for 30 of 36 patients on treatment. The main grade 3/4 toxicities included thrombocytopenia in 20 patients (67%), anemia in 8 (27%), leukopenia in 17 (57%), and neutropenic fever in 4 (13%). Other grade 3/4 toxicities included renal failure, hypertension, pneumonia, urinary tract infection, fever, leukocytosis, increased liver function tests, hyperglycemia, and syncope (in 1 patient each).

The combination of rabbit thymoglobulin (rATG), cyclosporine and G-CSF is safe and effective in first-line treatment of AA and has significant activity in low-risk MDS.