| BackgroundChildren's hematological diseases mainly include two kinds of diseases:malignant hematological diseases represented by acute leukemia(AL)and bone marrow failure syndromes(BMFs)represented by severe aplastic anemia(SAA),which are seriously harmful to children's health.Although the overall curative effect of combined chemotherapy for childhood acute leukemia is superior,about 30%-40%of children still relapse or suffer primary refractory.While the response rate of intensive immunosuppression therapy(IST)in the treatment of severe aplastic anemia is only about 50%-60%,and there is no effective radical treatment for congenital BMFs.At present,allogeneic hematopoietic stem cell transplantation(HCT)is the only cure for relapsed and refractory childhood hematologic diseases.However,now in our country,sibling matched donors and unrelated donors are far from meeting the clinical needs,and haploid donors are limited by their genetic background for congenital diseases.Umbilical cord blood transplantation(UCBT)has lots of advantages such as abundant storage,easy access,lower HLA matching requirements,lower graft versus host disease(GVHD),no injury to the donor and good long-term quality of life.Single cord blood can meet almost all the needs of children's stem cells'requirement,basically reaching "|everyone has a donor",so it is the most ideal alternative donor for children's transplantation.And it will be of great significance to optimize the conditioning regimen of umbilical cord blood transplantation,so that to improve the success rate of engraftment,accelerate hematopoietic reconstitution and reduce leukemia recurrence.ObjectiveTrying to optimize the conditioning regimen of allogeneic umbilical cord blood transplantation,in order to reduce the recurrence of childhood refractory/relapsed acute leukemia,improve the success rate of engraftment and accelerate hematopoietic reconstitution for bone marrow failure diseases.Trying to establish a basic standardized UCBT system suitable for children with hematological diseases,and evaluate its efficacy and safety.MethodsPart 1A total of 32 children with high-risk acute leukemia who received allogeneic umbilical cord blood stem cell transplantation in our center from December 2017 to November 2020 were enrolled One group was treated with fludarabine(Flu),busulfan(BU)and cyclophosphamide(CTX)as conditioning regimen(traditional group),and the other group(cladribine group)was treated with cladribine(cladribine),cytarabine(Ara-C),granulocyte colony-stimulating factor(G-CSF),busulfan and cyclophosphamide as pretreatment regimen.Retrospectively analyzed and compared the engraftment,GVHD incidence,survival and recurrence of the two groups.Part 2From September 2018 to Febrary 2021,12 children with bone marrow failure who received allogeneic umbilical cord blood stem cell transplantation in our center were enrolled in this study.Low dose total body irradiation(TBI),fludarabine(Flu)and cyclophosphamide(CTX)were used as conditioning regimen.Retrospectively analyzed and compared the engraftment,GVHD incidence and survival of these children.ResultsPart 1There were 25 cases in the traditional group and 7 cases in the cladribine group,with no significant differences in gender,age,donor-recipient gender match,donor-recipient blood type match,HLA mismatch,number of infused total nucleated cells(TNC)or CD34 positive cells between the two groups.The proportion of acute lymphoblastic leukemia(All)was higher in the traditional group,while acute myeloid leukemia(AML)was more common in the cladribine group(?2=9.796,P=0.007).Flow cytometry(FCM)was used to evaluate the minimal residual disease(MRD)of leukemia before transplantation.The FCM-MRD of cladribine group was higher than that of traditional group(1.39%vs 0.1%,P=0.011).Short tandem repeats(STRs)and polymerase chain reaction(PCR)were used to detect early chimerism at+7,+14,+21 days after transplantation,respectively.The chimerism of cladribine group was higher at+7 days after transplantation(74.16%vs 45.09%,P=0.002).The incidence of pre-engraftment syndrome(PES)was earlier(7.5 days vs 11.5 days,P=0.022)and higher(?2=10.279>P=0.001)in cladribine group,but there was no significant difference in neutrophil engraftment time,platelet engraftment time,relapse,transplant related mortality or GVHD cumulative incidence between the two groups.All patients were followed up to June 30,2021,with a median follow-up time of 17 months.In the traditional group;4 patients relapsed,including 3 patients died with bone marrow relapse,and 1 child achieved disease-free survival again after treatment with central nervous system relapse.In the cladribine group,there was no recurrence or death yet.The estimated 2-year overall survival(OS)and disease free survival[DFS)were 75.9%±9.8%vs 100%(P=0.241)and 73.3%±9.7%vs 100%(P=0.183),respectively.But the difference between the two groups was not statistically significant.Part 2There were 10 cases of severe aplastic anemia and 2 cases of inherited bone marrow failure in the whole cohort.The male to female ratio was 7:5,and the median age was 6.5(2-13)years old The median number of infused total nucleated cells and CD34 positive cells was 5.45(2.74-11.37)×107/kg,2.02(1.1-7.06)×105/kg,respectively.All patients achieved complete donor chimerism at+14 days after transplantation,and all patients achieved successful neutrophil and platelet engraftment by+100 days after transplantation.The median time of neutrophil engraftment was+19(12-30)days,and the median time of platelet engraftment was+30(18-61)days after transplantation.Among the 12 cases,6 cases developed grade?-? aGVHD(100-day cumulative incidence 50.0%±14.4%),two cases suffered grade?-? aGVHD(100-day cumulative incidence 16.7%±10.8%),while 2-year cumulative incidence of cGVHD was 25.9%±12.9%.All patients were disease-free alive by following up to June 30,2021,with a median follow-up of 21(4-33)months.ConclusionFor pediatric high-risk acute leukemia,the improved conditioning regimen based on cladribine can achieve faster donor chimerism and obtain superior disease-free survival.For bone marrow failure diseases,the conditioning regimen based on low-dose TBI not including ATG can obtain stable hematopoietic implantation,but does not significantly increase the incidence of GVHD.In general,the conditioning regimen system of allogeneic umbilical cord blood transplantation we explored has both efficacy and safety.Cord blood can be used as an ideal donor for children with hematologic diseases. |
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