Background: Hematopoietic stem cell transplantation (HSCT) is the most effective curative option for patients with thalassemia major(TM). Early post-transplant mixed chimerism (MC) has known to be a predictor of secondary graft rejection. However, the impact of the persisting mixed chimerism on transplant outcome remains controversial. Recently Thiotepa(TT) has been decreased to reduce toxicity.There was no data available on reduced intensity conditioning on mixed chimersim in a large group of patients with thalassemia to date.
Aims: To assess risk factors of mixed chimerism and to evaluate possible correlations between mixed chimerism and the development of complications after HSCT, in terms of graft versus host disease (GVHD) development, OS, TFS and GR.
Patients and methods:
From December2008 until December 2019, 618 patients with TM underwent HSCT at our center with median age of 6 (1-23) and median follow up time of 70 months(1-135), from HLA-identical sibling donors (SD) (n=212; 34.3%), unrelated donors (UD, n=313; 50.6%),sibling Cord blood(CB, n=49,7.9%)and parent donors (PD, n=44,7.1%). Source of graft were 538 (87.1%) from peripheral stem cells, 32(5.2%) from bone marrow and 48(7.8%)from sibling cord blood. Cy+Bu+Flu+TT+ATG conditioning regimen was used in 416 pts while a reduced conditioning regimen Cy+Bu+Flu+ATG was used for 167pts and Cy+Bu+Flu for the other 35 pts.
Results
Overall Survival (OS), Thalassemia-Free survival (TFS), Transplantation-related mortality (TRM) and graft rejection (GR) for the entire group were 94.8%, 92.7% ,5.2% and 2.4% respectively.
MC was presented in 70 pts with 52 male and 18 female, defined as the presence of >5% residual recipient cells. Cumulative incidence of MC was 12.4% (Figure1). 5 pts had secondary graft failure and another 5 patients persisting MC post-transplant refractory to DLI following a second HSCT. There were two deaths ineffective to DLI and one die of idiopathic pneumonia and one of hemolytic uremic syndrome.
The median MC present time was 4 months (1-59 months).No significant difference was observed in OS and Thalassemia-Free survival (TFS) between MC and PC pts. The cumulative probability of OS, TFS between MC pts and FC pts was 97.1% vs. 94.4% (P=0.343) and 89.6% vs. 93.2% (P=0.272). However, the incidence of MC was significantly associated with the development of graft failure/rejection. Graft failure occurred in 5 pts in the MC group vs.7 pts in the full donor chimerism (PC) group, the corresponding incidence were 7.6% vs. 1.6 % respectively. (P =0.001, Figure 2).
Acute GVHD incidence was much lower in MC pts than in PC pts (2.9% vs. 12.7%, P=0.022, Figure 3 A), whereas MC pts had significantly higher chronic GVHD(16.8% vs. 4.2%, P=0.000 Figure 3 B). 2 of 70 MC pts developed I-II aGVHD. No MC pts develop II-IV aGVHD. MC patients were unlikely to have severe acute GVHD. MC was associated with an increased risk of chronic GVHD, mostly were DLI derived
Patients receiving stem cells from cord blood of matched sibling donors had a high risk of MC.MC incidence of stem cell source from peripheral blood(PB), bone marrow(BM), cord blood (CB)were 10.6%, 10%, 34.2% respectively.(P=0.000, Figure 4). Unrelated donors had a lower risk of MC than sibling donors. Incidence of MC from unrelated donors was 9.5% vs. 16.1% from sibling donors (P=0.007, Figure 5)
Intravenous Thiotepa (TT) in combination with Busulfan (Bu) , cyclophosphamide (Cy) anti-thymocyte globulin(ATG) on HSCT could reduce the risk of MC. The corresponding incidence of MC in Cy+Bu+Flu+TT+ATG, Cy+Bu+Flu+ATG, Cy+Bu+Flu conditioning regimen were 9.2%,15.9%,40.9% resepectively(P=0.000, Figure 6).
There was also a significant difference in chimerism based on donor-recipient gender pairing (P = 0.041): male grafts into male patients having the greatest risk of MC and female grafts into female patients having the least. Patients who under 9 years old had a higher risk of MC than that of pts>9 years old (P=0.018, Figure 7),
Summary:
Our results show that patients who presented mixed chimerism showed a similar post-transplant outcome in OS and TFS but was associated with higher risk of graft failue.Patients receiving stem cells from CB had a high risk of MC than from PBSC. Reduced nonmyeloablative approach capable of achieving allogeneic mixed hematopoietic chimerism. Our data suggests that Cy+Bu+Flu+TT+ATG is a preferred conditioning regimenfor TM patients could reduce the risk of mixed chimerism.
No relevant conflicts of interest to declare.
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