Optimization of conditioning for marrow transplantation from unrelated donors for patients with aplastic anemia after failure of immunosuppressive therapy

Abstract

In 87 patients with aplastic anemia who failed to respond to immunosuppressive treatment, we determined the minimal dose of total body irradiation (TBI) required when added to antithymocyte globulin (ATG, 30 mg/kg x 3) plus cyclophosphamide (CY, 50 mg/kg x 4) to achieve engraftment of unrelated donor marrow. TBI was started at 3 x 200 cGy, to be escalated or deescalated in steps of 200 cGy depending on graft failure or toxicity. Patients were aged 1.3 to 53.5 years (median, 18.6 years). The interval from diagnosis to transplantation was 3 to 328 months (median, 14.6 months). Donors were HLA-A, -B, -C, -DR, and -DQ identical for 62 patients, and nonidentical for 1 to 3 HLA loci at the antigen or allele level for 25. The dose-limiting toxicity was diffuse pulmonary injury. The optimum TBI dose was 1 x 200 cGy. Nine patients did not tolerate ATG and were prepared with CY + TBI. Graft failure occurred in 5% of patients. With a median follow-up of 7 years, 38 (61%) of 62 HLA-identical, and 10 (40%) of 25 HLA-nonidentical transplant recipients are surviving. The highest survival rate with HLA-identical transplants was observed at 200 cGy TBI. Thus, low-dose TBI + CY + ATG conditioning resulted in excellent outcome of unrelated transplants in patients with aplastic anemia who had received multiple transfusions.

Figures

Figure 1.

Actual conditioning regimen given. Among the 87 patients who received a transplant, 78 (55 from HLA-identical and 23 from HLA-nonidentical donors) were conditioned with CY + ATG + TBI at the doses shown. *Nine patients (7 from HLA-identical and 2 from HLA-nonidentical donors) were unable to receive ATG and were conditioned with CY (120 mg/kg) and TBI (6 × 200 over 3 days) only.

Figure 2.

Survival by TBI dose in patients who were able to receive ATG. Shown separately are patients with HLA-identical (A) and HLA-nonidentical donors (B). Results with TBI doses of 400 cGy and 600 cGy were pooled.

Figure 3.

Effect of patient age on survival among patients conditioned with CY/ATG/TBI and who received a transplant from HLA-identical donors. (A) Five-year survival among 33 patients 20 years old or younger was 73%, compared with 46% among 22 patients older than 20 years (P = .05). (B) Among patients conditioned with 200 cGy TBI, the survival figures were 78% and 50% for patients 20 years old or younger and for patients older than 20 years, respectively. (C) Survival among 23 patients aged 20 years or younger, conditioned with 200 cGy TBI, with disease duration of 1 year or less (70%) or longer than 1 year (85%).