Alternative Donor Transplantation with High-Dose Post-TransplantationCyclophosphamide for Refractory Severe Aplastic Anemia

摘要

Severe aplastic anemia (SAA) is a life-threatening hematopoietic stem cell disorder that is treated with bone marrow transplantation (BMT) or immunosuppressive therapy (IST). The management of patients with refractory SAA after IST is a major challenge. Alternative donor BMT is the best chance for cure in refractory SAA, but morbidity and mortality from graft failure and complications of graft-versus-host disease (GVHD) have limited enthusiasm for this approach. Here, we employed post-transplantation high-dose cyclophosphamide in an effort to safely expand the donor pool in 16 consecutive patients with refractory SAA who did not have a matched sibling donor. Between July 2011 and August 2016, 16 patients underwent allogeneic (allo) BMT for refractory SAA from 13 haploidentical donors and 3 unrelated donors. The nonmyeloablative conditioning regimen consisted of antithymocyte globulin, fludarabine, low-dose cyclophosphamide, and total body irradiation. Post-transplantation cyclophosphamide 50 mg/kg/day i.v. on days +3 and +4 was administered for GVHD prophylaxis. Additionally, patients received mycophenolate mofetil on days +5 through 35 and tacrolimus from day +5 through 1 year. The median age of the patients at the time of transplantation was 30(range, 11 to 69) years. The median time to neutrophil recovery over 1000× 10³/mm³ for 3 consecutive days was 19 (range, 16to 27) days, to red cell engraftment was 25 (range, 2 to 58) days, and to lastplatelet transfusion to keep platelets counts over 50 ×10³/mm³ was 27.5 (range, 22 to 108) days. Graftfailure, primary or secondary, was not seen in any of the patients. All 16patients are alive, transfusion independent, and without evidence of clonality.The median follow-up is 21 (range, 3 to 64) months. Two patients had grade 1 or2 skin-only acute GVHD. These same 2 also had mild chronic GVHD of theskin/mouth requiring systemic steroids. One of these GVHD patients was able tocome off all IST by 15 months and the other by 17 months. All other patientsstopped IST at 1 year. Nonmyeloablative alloBMT using post-transplantationcyclophosphamide allowed for safe expansion of the donor pool to includeHLA-haploidentical donors. This approach appears promising in refractory SAApatients. Importantly, engraftment was 100%, pre-existing clonal diseasewas eradicated, and the risk of GVHD was low.