Improved Outcome of Reduced Toxicity Fludarabine, Cyclophosphamide Plus Thymoglobulin Conditioning Regimen for Unrelated Donor Transplantation in Severe Aplastic Anemia: Comparison of Two Multicenter Prospective Studies

Hematopoietic stem cell transplantation (HSCT) is a curative therapeutic modality for severe aplastic anemia, but optimal conditioning regimen for the HSCT with an unrelated donor has not been defined yet. As the thymoglobulin had been found to be more effective among many kinds of anti-thymocyte globulins, and fludarabine based conditioning regimens without total body irradiation have been reported to be promising for transplantation from unrelated donors in SAA, combination of fludarabine, cyclophosphamide and thymoglobulin conditioning regimens had been tried to reduce GVHD and to allow good engraftment. Our previous phase II study (study 1) of fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen resulted in successful engraftment (100%), but treatment-related mortality (TRM) occurred in 9 (32.1%) patients (NCT00737685, Biol Blood Marrow Transplant. 2010.16;1582). As cyclophosphamide is more toxic than fludarabine with similar effect, then we performed a new phase II study (study 2) with reduced toxicity fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen by reducing dosage of cyclophosphamide and increasing dosage of fludarabine (NCT00882323).

Twenty-eight and 31 patients were enrolled in study 1 and 2, respectively. In study 1, cyclophosphamide (50 mg/kg once daily i.v. on days −9, −8, −7 & −6), fludarabine (30 mg/m2̂ once daily i.v. on days −5, −4, −3 & −2) and thymoglobulin (2.5 mg/kg once daily i.v. on days −3, −2 & −1) were used for the conditioning regimen. For study 2, cyclophosphamide was reduced to 60 mg/kg once daily i.v. on days −8 & −7, and fludarabine was increased to 40 mg/m2̂ once daily i.v. on days −6, −5, −4, −3 & −2. Thymoglobulin (2.5 mg/kg once daily i.v. on days −4, −3 & −2) was also used.

Donor type hematologic recovery was achieved in all patients of study 1 (100%) and study 2 (100%). Events were occurred in 10 patients of study 1. Nine patients developed TRM, which included thrombotic microangiopathy (N=2), pneumonia (N=1), myocardiac infarction (N=1), post-transplantation lymphoprolifarative disease (N=3), and chronic GVHD-associated complications (N=2). Delayed graft failure occurred in 1 patient at 37 months after HSCT. In study 2, 2 patients had events. One patient developed TRM (pneumonia) and delayed graft failure occurred in 1 patient at 4 months after HSCT. Overall survival rate of study 2 (96.7%) was significantly higher than that of study 1 (67.9%) (P=0.005). Event free survival of patients was significantly better in study 2 (93.3%) compared to that of study 1 (64.3%) (P=0.014).

Reduced toxicity fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen showed promising results with same successful engraftment and less TRM compared to the previous combination and was optimal for the unrelated donor transplantation in severe aplastic anemia.

No relevant conflicts of interest to declare.