Abstract
Background: Thalassemia major (TM) is a fatal genetic disease currently only curable with allogeneic stem cell transplantation. This is limited by the lack of suitable donors and the quantity of collected stem cells, and is often complicated by graft rejection and graft versus host disease (GVHD).
Methods: The aim of the study was to compare the outcomes of TM patients transplanted with matched sibling cord blood (CB) and bone marrow (BM) grafts vs. matched sibling peripheral blood (PB) stem cell and BM grafts. The trial was designed as a prospective, open-label, single-center clinical protocol, where 204 TM patients were enrolled between January 2007 and November 2015 and transplanted with either PB + BM (n=99) or CB+BM (n=105), from an HLA-identical sibling donor. This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University and was registered at the Chinese Bone Marrow Transplant Registry (CBMTR). The primary end point was 2-year thalassemia free survival(TFS). Secondary end points included 2-year overall survival (OS), the cumulative incidence of GVHD, transplant related mortality (TRM), graft rejection (GF).The conditioning regimen were:1) busulphan (BU) (1.25 mg/kg) given orally four times per day for 4 days or 1mg/kg given intravenously (IV) four times per day for 4 days (day -9 to day -6); 2) fludarabine (FLU) (50mg/m2/day) given IV for 3 days (day -12 to day -11); 3) cyclophosphamide (CTX) (50 mg/kg/day) given IV for 4 days (day -5 to day -4); 4) anti-thymocytes globulin (ATG, Genzyme ) (2.5 mg/kg/day) given IV for 4 days (days -4 and day -1). All patients were placed on 30 mg/kg hydroxyurea orally once daily for 2-3 months before transplantation.GVHD prophylaxis consisted of a combination of cyclosporin A, methotrexate and mycophenolate mofetil regimen. [BMT 2009; 43(1):61-67].
Results: Patient and donor characteristics, and transplantation outcomes are listed in Tables 1 and 2, respectively. Data cut off for survival follow-up was March 31, 2016. The median follow-up time was 26 months (range, 4 months -105 months). Both neutrophil as well as platelet engraftment occurred significantly faster in the PB+ BM group than the CB+BM group (11 days vs. 13 days, P=0.001 and 15 days vs. 25 days, P=0.001, respectively). The rate of GF was the same in both groups (1.0%). The cumulative incidence of grade II-IV acute (a) GVHD and extensive chronic (c)GVHD in the PB+ BM group was higher than the CB+BM group: aGVHD=15.5% vs 1.0%, P=0.001; cGVHD= 6.4% vs. 0%, P=0.013. The cumulative rates of TRM at 2 years remained significantly lower in the PB+BM group compared to the CB+BM group with 2.0% and 12.5%,(P=0.005), respectively . Both OS and TFS at 2 years favored the PB +BM group compared to the CB+BM group : OS=98% vs. 86.5%,P=0.003;TFS= 97% vs. 86.5%, P=0.008.(Fig 1)
Conclusion: Our results demonstrate that grafts composed of PB + BM had superior overall outcomes compared to CB + BM grafts, as evidenced by faster engraftment and lower TRM of the former despite substantially lower aGVHD and cGVHD rates of the latter. The mixed stem cell populaitons and the high cell dose achieved with the use of 2 different graft sources, toghether with the conditioning regimen used likely contributed to the superior outcomes seen with this regiem. This strategy could be of great benefit for the treatment of patient with TM and other benign hematologic disease.
No relevant conflicts of interest to declare.
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