Prognosis Risk Factors After Stem Cell Transplantation In Childhood With Severe Thalassemia

ObjectiveTo investigate whether human leukocyte antigen(HLA)-mismatched donors can achieve similar therapeutic effects as HLA fully-matched donors in hematopoietic stem cell transplantation(HSCT)for severe thalassemia based on the same conditioning regimen and identify the risk factors for prognosis.MethodRetrospect 257 cases diagnosed of severe thalassemia who had agreed and received allogeneic hematopoietic stem cell(Allo-HCT)transplantation in the blood transplant center of Guangzhou Women and Children’s Medical Center in Guangdong province from September 2013 to September 2019.Log-Rank and Cox regression analysis were adopted to the risk factor of survival prognosis after Allo-HSCT in children with severe thalassemia.Rrisk classification,spleen size,left heart ejection fraction,gender,age,serum ferritin level,liver size in patients before transplantation,human leukocyte antigen(HLA)compatibility and relationship between donor and patient,donor gender status,transplantation,infusion volume of mononuclear cells and CD34 cells,time of neutrophil and platelet graft after transplantation,whether post-transplant complications occur(acute graft-versus-host,chronic graft-versus-host,veno occlusive disease,posterior reversible encephalopathy syndrome,hemorrhagic cystitis,autoimmune hemolysis,bronchiolitis obliterans,lymphoproliferative diseases,cytomegalovirus infection,Epstein-Barr virus infection)were brought into analysis of risk factors after all-HSCT.Each risk factor was analyzed for overall survival rate(OS),thalassemia free survival rate(TFS),transplantation-related mortality(TRM),and transplant rejection(GR)as well.OS,TFS,TRM,GR were estimated by Kaplan-Meier method.ResultOf the 257 patients included,172 were male and 85 were female.3 patients developed rejection and underwent secondary transplantation,of which 2 were male and 1 female.The median age at transplantation was 6 years.A total of 20 deaths and 237 survived.The cumulative overall survival rate(OS)was 92.08%.the cumulative thalassemia free survival rate(TFS)was 90.89.The cumulative graft rejection rate(GR)was 1.24% and the transplantation related mortality rate(TRM)was 8.01%.The OS of HLA full matched and mismatched donor transplantation were 92.71%,90.23%,TFS were 91.11%,90.23%,TRM were 7.41%,9.77%,GR were 1.64%,0,and the difference was not statistically significant(P> 0.05).The OS of HLA full matched related donor,HLA full matched unrelated donor,HLA mismatched related donor and HLA mismatched unrelated donor transplantation were 93.35%,91.93%,88.74%,91.23%,respectively and TFS were 92.31%,89.67%,88.74%,91.23%,respectively;TRM were6.72%,8.26%,11.27%,8.77%,respectively;GR were 1.11%,2.25%,0,0,the difference was not statistically significant(P > 0.05).Log-Rank test analysis indicated that the patient’s risk classification,bronchiolitis obliterans,acute graft-versus-host disease,and cytomegalovirus infection after transplantation were all associated with not only the overall survival but also the thalassemia free survival rate.Risk classification of patient,acute graft-versus-host disease,cytomegalovirus infection,and bronchiolitis obliterans were significantly associated with TRM;Acute graft-versus-host,bronchiolitis obliterans were associated with GR.The higher the patient’s risk classification,the lower the overall survival rate and thalassemia-free survival rate,and the difference is statistically significant(OS: Grade I : 100%,Grade II 92.26%,Grade III:83.33%,P= 0.032)(TFS: Grade I: 100%,Grade II 90.79%,Grade III: 83.33%,P = 0.047);patients develpoed bronchiolitis obliterans after transplantation was significantly lived shorter than those without bronchiolitis obliterans(OS: 67.50% VS 93.74%,P <0.0002;TFS: 55.56% VS 93.33%,P <0.0001);patients developed acute graft-versus-host disease after transplantation had a significantly lower survival rate and thalassemia-free survival than patients who did not develop graft-versus-host disease(OS: 86.79% VS 94.62%,P = 0.023;TFS: 83.09% VS 94.62%,P = 0.002);patients sufferend from the cytomegalovirus infection after transplantation was significantly lower in the survival rate and thalassemia-free survival rate than those without cytomegalovirus infection(OS: 83.80% VS 95.15%,P = 0.004;TFS: 82.44% VS 94.03%,P = 0.00).The transplantation-related mortality rate of patients with risk grades Ⅰ and Ⅱ was significantly lower than that of grade Ⅲ,respectively,0,7.85%,16.67%(P=0.033);The transplantation-related mortality rate of patients who developed cytomegalovirus infection was significantly higher than those without cytomegalovirus infection(16.40% VS 4.91%,P= 0.004);The incidence of transplant-related mortality was significantly higher in patients suffered from occlusive bronchiolitis than those without occlusive bronchiolitis(36.51% VS 6.29% P <0.0001);The incidence of transplant-related mortality was significantly higher in patients with acute graft-versus-host after transplantation than in patients without graft-versus-host(13.71% VS 5.38,P = 0.017).The rate of graft rejection was significantly higher in patients who developed acute graft-versus-host after transplantation than those who did not develop acute graft-versus-host(3.92% VS 0,P =0.011).Patients suffered from bronchitis obliterans after transplantation had a higher rejection rate than those without bronchitis obliterans(14.77% VS 0.41%,P <0.0001).Cox regression analysis revealed that risk classification of patient(P =0.027,HR:3.002,95%CI:1.134-7.944),bronchiolitis obliterans(P =0.008,HR:3.983,95%CI:1.432-11.079),cytomegalovirus infection(P =0.008,HR:3.339,95%CI:1.361-8.190)were independent risk factors that affects overall survival after transplantation.At the same time,acute graft-versus-host disease(P =0.019,HR:2.754,95%CI:1.178-6.438),bronchiolitis obliterans(P =0.000,HR:6.396,95%CI:2.616-15.634),cytomegalovirus infection(P =0.054,HR:2.264,95%CI:0.987-5.193)were the independent risk factors that affects the thalassemia-free survival after transplantation.Risk classification of patient(P =0.033,HR:2.875,95%CI:1.089-7.591),bronchiolitis obliterans(P =0.004,HR:4.554,95%CI:1.633-12.701),cytomegalovirus infection(P=0.008,HR : 3.362,95%CI :1.371-8.243)were independent risk factors that affects transplant-related mortality after transplantation.Cytomegalovirus infection(P =0.011,HR:23.196,95%CI:2.079-258.145)was an independent risk factor affecting graft rejection.ConclusionHuman leukocyte antigen(HLA)fully-matched donor transplantation is still the first choice in hematopoietic stem cell transplantation(HSCT)for severe thalassemia.HLA mismatched donors can achieve similar therapeutic effects as HLA fully-matched donors based on the our conditioning regimenCytomegalovirus infection was also found to be an independent risk factor affecting OS、TFS、TRM,which mostly occur early after transplantation(within 100 days).Early identification and treatment of cytomegalovirus infection can effectively improve survival after transplantation.a GVHD is also an independent risk factor that affects the TFS、GR.,which can be prevented by adjusting the dose of ATG.Prognosis is inferior in risk class Ⅲ patients.Improving the status of patient before transplantation and transplanting as soon as possible can ameliorate the living standards.Bronchiolitis obliterans significantly affecting OS、TFS、TRM、GR.Controlling infection may avoid induced immune disorders.