The Outcome of Unrelated Hematopoietic Stem Cell Transplants with Total Body Irradiation (800 cGy) and Cyclophosphamide (120 mg/kg) in Adult Patients with Severe Aplastic Anemia.

We had reported the results of a pilot prospective study demonstrating the superiority of 800 cGy of total body irradiation (TBI) in combination with a 120 mg/kg of cyclophosphamide (CY) [TBI-800/CY-120] compared to the higher doses of TBI (1000 and 1200 cGy) as a conditioning regimen for unrelated stem cell transplantation (SCT) in adult patients with severe aplastic anemia (SAA) [Biology of Blood and Marrow Transplant 2007;13:836-870].

To analyze the long-term results of unrelated SCT with TBI-800/CY-120 for adult SAA who failed to respond to immunosuppressive treatment, we prospectively enrolled 50 adult patients with SAA [median age, 28 years (range, 15-53)], including 26 patients of a previous pilot study. All patients received fractionated TBI (400 cGy/day) for 2 days followed by CY (60mg/kg/day, 2 days). Nine patients (18%) were very SAA. Enrolled patients had received multiple transfusions (median 64 units, range, 10-363) and long disease duration (median 48 months, range 2-323). High resolution DNA typing was done at HLA-A, -B, -C, -DR level. Seventeen patients (34%) received HLA-mismatched SCT at allele level. Thirty-eight patients (76%) received bone marrow and 12 (24%) peripheral blood stem cells (PBSC). All patients received tacrolimus and short-course of methotrexate as GVHD prophylaxis.

All patients achieved engraftment and the median day of neutrophil and platelet recovery was 13 days (range, 8-30) and 20 days (range, 9-200), respectively. There was one case of delayed platelet recovery, but platelet count rose slowly to the normal level thereafter. At a median follow-up of 38 months (range, 1-84), the estimated 3-year overall survival was 87.8%. The cumulative incidence of acute GVHD (aGVHD) over grade II (6/23, grade III and IV) and chronic GVHD (cGVHD) were 46.0% and 50.3% [limited (39%) vs. extensive (61%)], respectively. Among 7 patients who died, 4 patients and 1 patient died of severe aGVHD (grade III and IV) and cGVHD, respectively, 1 patient multi-organ failure, and 2 patient sepsis. Univariate analysis revealed the following risk factors: very SAA (P=0.018), HLA-mismatched donor at allele level (P=0.012), and older donor age (P=0.080) for aGVHD and previous aGVHD (P=0.030) and PBSC (P=0.024) for cGVHD. Multivariate analysis showed that only a HLA-mismatched donor at allele level (hazard ratio: 2.7, 95% CI: 1.2-6.2, P=0.018) was a significant factor associated with higher cumulative incidence of aGVHD over grade II.

TBI-800/CY-120 conditioning resulted in excellent outcome of unrelated transplants in adult patients with SAA who had received multiple transfusions and long disease duration, which was comparable to those of matched sibling transplants. Additional strategies to prevent severe GVHD, for example, adding anti-thymocyte globulin, particularly for HLA-mismatched transplant and in case of PBSC as a stem cell source, will be helpful to improve the outcome in the future.

No relevant conflicts of interest to declare.