Maintenance Therapy With Low-dose Decitabine Combined With Valproic Acid After Allogeneic Stem Cell Transplantation For Patients With Acute Leukemia/Myelodysplastic Syndrome

BackgroundThe main reasons of allogeneic hematopoietic stem cell(allo-HSCT)failure are post-transplant relapse and graft-versus-host disease(GVHD).As a methyltransferase inhibitor,decitabine could up-regulate the expression of cell surface tumor antigens by hypomethylating after transplantation,thereby enhancing the tumor-specific T cell response and exerting the graft-versus-leukemia(GVL)effect.At the same time,it could increase the number of regulatory T cells so as to reduce GVHD.Valproic acid(VPA)is a histone deacetylase inhibitor.Studies have reported that methyltransferase inhibitors and histone deacetylase inhibitors could synergistically inhibit tumor cells and restore the function of inactivated tumor suppressor genes.The combination of the two could synergistically induce apoptosis and anti-tumor immunity while overcoming drug resistance.Based on this,we hypothesized that maintain treatment with decitabine combined with VPA after transplantation can be used for patients to reduce relapse and decrease the incidence of GVHD to improve transplantation efficacy.ObjectiveTo observe the efficacy,scope and safety of maintenance therapy with low-dose decitabine combined with valproic acid after allo-HSCT in patients with acute leukemia/myelodysplastic syndrome(MDS).MethodsA total of 66 patients who underwent allo-HSCT in the Hematopoietic Stem Cell Transplantation Center of the First Affiliated Hospital of Zhengzhou University from April 1,2015 to June 30,2018 entered the study.Among them,33 patients entered the trial group,including 3 patients with MDS,14 patients with acute myeloid leukemia(AML),and 16 patients with acute lymphoblastic leukemia(ALL),which were treated with low-dose decitabine and VPA after transplantation.Thirty-three patients(3 patients with MDS,13 patients with AML,17 patients with ALL)who didn't receive any maintenance treatment after allo-HSCT were included in the control group.We analyzed the general clinical characteristics,the cumulative incidence of relapse rate(CIR),the incidence rate of GVHD,the disease-free rate(DFS)and long-term survival(OS)between the two groups and evaluated the safety of the protocol.Results1.There were no significant differences in age,gender,diagnosis,disease risk stratification,disease status at transplantation,HCI-CI score,EBMT risk score,donor type,transplantation method,ABO match,the number of infused CD34+ cells,the number of infused MNC cells and time of leukocyte and platelet engraftment between the two groups(P>0.1).2.The 1-year CIR in the trial group(n=33)and the control group(n=33)were 11.1% and 26.4%,respectively;the difference was not statistically significant(P=0.058).The 1-year DFS in the trial group and the control group were 83.9% and 62.2%,respectively;the difference was statistically significant(P=0.032).The 1-year OS of the trial group and the control group were 83.6% and 72.7%,respectively;the difference was not statistically significant(P=0.107).Subgroup analysis: for patients with ALL(n=33),the 1-year CIR in the trial group(n=16)and the control group(n=17) were 9.1% and 56.4%,respectively(P=0.015),and the 1-year DFS were 85.2% and 37.3%,respectively(P=0.021),and the difference was statistically significant;the 1-year OS rates in the trial group and the control group were 80.4% and 49.9%(P=0.206),respectively;and there was no statistically significant difference.For patients with AML(n=27),there was no significant difference in 1-year CIR,1-year OS rate and 1-year DFS rate between the trial group(n=14)and the control group(n=13)(P > 0.05).For median-risk patients(n=17),there was no significant difference in the CIR,OS and DFS between the trial group(n = 9)and the control group(n = 8)(P > 0.05).For highrisk patients(n = 49),there was no significant difference in the CIR,OS and DFS between the trial group(n = 24)and the control group(n = 25)(P > 0.05).3.Eleven patients developed acute GVHD in the trial group(2 with grade I,3 with grade II,3 with grade III,and 3 with grade IV)and 12 patients in the control group(7 with grade I,3 with grade II,1 with grade III,and 1 with grade IV)after transplantation(P=0.796).Fourteen patients experienced chronic GVHD(cGVHD)in the trial group(9 with mild cGVHD,3 with moderate cGVHD,and 2 with severe cGVHD)and 11 patients in the control group(5 with mild cGVHD,5 with moderate cGVHD,and 1 with severe cGVHD)after transplantation(P=0.447).4.In the trial group,only 4 cases(12.9%)of evaluabled patients developed grade 3-4 myelosuppression after treatment,and the remaining 27 cases(81.81%)developed grade 1-2 myelosuppression after treatment.5.Nine patients in the trial group developed unexplained thrombocytopenia after transplantation,and the cure rate was 87.5% after decitabine treatment.In the control group,7 patients developed unexplained thrombocytopenia after transplantation,and the cure rate was 14.2% after conventional treatment(P=0.041).Conclusion1.Maintenance therapy with low-dose decitabine and VPA after allo-HSCT could reduce the relapse rate of patients with ALL and prolong the disease-free survival time.2.Maintenance therapy with low-dose decitabine and VPA after transplantation has a low hematological toxicity without increasing the incidence of GVHD.3.Low-dose decitabine is effective in treating isolated thrombocytopenia after transplantation.