| Background and purposeSo far,allogeneic hematopoietic stem cell transplantation(allo-HSCT)is a crucial treatment for the majorities of malignant hematologic diseases,and even the only curative therapy for some hematologic malignancies,such as high-risk acute myeloid leukemia(AML)and refractory acute leukemia.Allo-HSCT has been proved to be the best post-remission therapy in patients with high-risk AML.For them,undergoing allo-HSCT after first complete remission(CR1),is urgently needed.Meanwhile,allo-HSCT remains the most effective way to cure refractory acute leukemia.Currently,donor sources of adult allogeneic hematopoietic stem cell transplantation mainly include matched related donors(MSDs),haploidentical donors(HIDs),matched unrelated donors(MUDs)and unrelated cord blood(UCB).MSDs are still the first choice for allo-HSCT because of their relatively low risk of graft-versus-host disease(GVHD)and infections,and comparatively low cost.However,due to the limitation of donor sources,only about 30%of the patients can find a MSD.HSCT from MUD offers a valid alternative option,and a growing number of studies have demonstrated that MUD transplant can achieve similar outcomes with MSD transplant.But MUDs can still satisfy a minority of patients because of several shortcomings.For example,it’s less likely to find a suitable MUD due to restriction from geographical,ethnic and other factors.Meanwhile,it usually takes three-six months to find a MUD,which is too long for a patient who need to be transplanted immediately.Although unrelated cord blood transplant has its own advantages of ready availability,easy access,no risk to donors and low incidence of acute GVHD,the cord blood bank scale is small and the number of cord blood cells is low.As a result,graft failure is a prominent problem for adult patients.So UCB transplantation may be less suitable for adult patients.With the development of transplantation technology and rich experience in the treatment of transplant related complications,haploidentical donors have been widely used in recent years.Haploidentical transplantation has the following advantages:1.Almost all patients can find donors,and most patients have multiple donors to choose from,and finally they can choose the best one for transplantation;2.For patients who need transplantation urgently,such as relapsed and refractory leukemia,Haploidentical donors provide better accessibility;3.With the rich experience in transplantation technology and treatment of transplantation complications,a large number of studies have shown that Haploidentical transplantation can achieve comparable outcomes with matched unrelated and matched related transplantation,regardless of ATG-based protocol or post-CTX protocol.In addition,studies have shown that for high-risk patients,the curative effect of haploidentical transplantation is even better than that of MSD or MUD transplantation,which is attributed to the fact that haploidentical transplantation can significantly reduce relapse rate in these patients,but it does not show higher non-relapse death,and finally obtains the advantage of survival.However,these studies are mainly retrospective,subgroup-analysis and heterogenous in term of study population with relatively small sample size.Whether haploidentical transplantation has stronger graft anti-leukemia effect(GVL)than matched related transplantation,thus reducing recurrence and improving survival remains controversial.To further explore this matter,in the first part,we designed a multicenter prospective study to compare the clinical efficacy of haploidentical transplantation and MSD transplantation in genetic high-risk AML in CR1.In the second part,the data of relapsed/refractory acute leukemia patients in two prospective studies were analyzed,and the clinical efficacy of haploidentical transplantation and MSD transplantation was compared.The evaluation points include minimal residual disease(MRD),cumulative incidence of relapse(CIR),treatment related mortality(TRM),disease free survival(DFS),overall survival(OS),infection,GVHD and hematopoietic reconstitution after transplantation.The objective of this study is to provide more potent clinical evidence for the matter of GVL between haploidentical transplant and MSD transplant,and the donor selection of allo-HSCT for high-risk AML and relapsed/refractory acute leukemia.Additionally,for HID-SCT,there are two main transplant protocols,including ATG-based protocol and post-CTX protocol.In China,ATG-based protocol plays a dominant role.Nevertheless,infections,especially viral infections,remain an important drawback of this strategy.To date,the optimal dose of ATG that has sufficient efficacy for GVHD prophylaxis and minimizes the risk of infection is unknown for haplo-HSCT.Several studies have demonstrated that the risk of infection depends on the dose of ATG.In our previous single-center study,6 mg/kg rabbit ATG was associated with a lower incidence of Epstein-Barr virus(EBV)infection but higher risks of severe acute GVHD(aGVHD)and chronic GVHD(cGVHD)in haplo-HSCT than 10 mg/kg rabbit ATG.As the decreased mortality from non-GVHD complications in the 6 mg/kg ATG group was offset by an increased incidence of severe GVHD,the optimal dose was left undetermined.A middle dose of 7.5 mg/kg ATG,which is the common dose used for unrelated HSCT,needs to be evaluated in HID-SCT.Here,we designed a multicenter randomized study to evaluate the effect of 7.5 mg/kg and 10.0 mg/kg rabbit ATG aiming at reducing the incidence of viral infections without increasing the incidence of GVHD in HID-SCT.Methods1.This was a multicentre,prospective cohort study performed from June 2013 to January 2016 at four medical centers in China including Nanfang Hospital,Peking University People’s Hospital,Xiangya Hospital,and Fujian Medical University Union Hospital.Patients were assigned to groups transplanted with HID or MSD based on donor availability(biological randomization).The modified BuCy regimen was used in all patients.HID patients were transplanted with a combination of bone marrow(BM)and peripheral blood stem cell(PBSC)grafts,whereas MSD patients received PBSC grafts.Ciclosporin A(CsA),methotrexate(MTX)and mycophenolate(MMF)were administered to patients undergoing MSD transplant for GVHD prophylaxis.CsA+ MTX+ MMF+ATG were administered to patients undergoing HID transplant for GVHD prophylaxis.Infection prophylaxis was performed routinely.MRD in bone marrow samples were analyzed pre-transplantation and post-transplantation.Multiparameter flow cytometry(MFC)and real-time quantitative PCR(qPCR)were used to monitor MRD.Subjects were defined as post-MRD+if they had two consecutive positive results using MFC or qPCR,or were both positive in a single sample.For preventing relapse,immunosuppressant withdrawal or discontinuation as well as preemptive G-CSF mobilized donor lymphocyte infusion(DLI)was administered in patients with post-MRD+when donor lymphocytes were available if patients had no active GVHD.Besides,Sorafenib was preemptively administered to patients with FLT3/ITD mutation.For the patients with post-MRD+who were undergoing GVHD treatment,Decitabine was administered for preemptive treatment.The primary endpoint was the incidence of post-MRD+.Secondary endpoints included CIR,engraftment,GVHD,viral infections,TRM,OS,DFS,and GVHD-free,relapse-free survival(GRFS).The SPSS statistics 19.0(SPSS,Chicago,IL)and R version 3.4.3(R Development Core Team,Vienna,Austria)were used for all data analysis.2.This study population came from two prospective multicenter trials(NCT01883180,NCT02673008).Patients undergoing allo-HSCT between June 2013 and December 2017 were enrolled in this study if they met the following criteria:(1)refractory acute leukemia in non-remission pre-transplant;(2)using HID or MSD as donors;(3)first allo-HSCT.The sequential intensified conditioning regimen was used in all patients.The prevention of leukemic relapse included early tapering of immunosuppressant,prophylactic and preemptive therapies.The primary endpoint included CIR and OS.Secondary endpoints included engraftment,disease response,GVHD,infections,TRM,DFS,and GRFS.The Stata SE 12.0(StataCorp,LP)and R version 3.4.3(R Development Core Team,Vienna,Austria)were used for all data analysis.3.This multicenter,open-label,randomized study was performed in four hospitals in China including Nanfang Hospital,Peking University People’s Hospital,Fujian Medical University Union Hospital and Xiangya Hospital from June 2013 to January 2016.Patients with acute leukemia who were scheduled to receive HID-SCT were eligible for the study if they were 14 to 65 years old.Patients were randomly assigned to a 7.5 mg/kg or a 10.0 mg/kg ATG group in a 1:1 ratio.The patients in complete remission(CR)received the mBuCy regimen,while those in non-CR received the sequential intensified regimen.Ciclosporin A+methotrexate+mycophenolate+antithymocyte globulin were administered to patients undergoing HID transplant for GVHD prophylaxis.the EBV-and CMV-DNA loads in the blood were measured regularly by real-time quantitative polymerase chain reaction(RQ-PCR).Pre-emptive therapy was given to the patients who developed viremia.Generally,immune reconstitution post-transplantation was assessed.The primary endpoint was EBV DNAemia within 1 year post-transplantation.The secondary endpoints included GVHD,CMV DNAemia,EBV-and CMV-associated diseases,engraftment,leukemia relapse,TRM,OS,DFS and tolerability.The SPSS statistics 19.0(SPSS,Chicago,IL)and R version 3.4.3(R Development Core Team,Vienna,Austria)were used for all data analysis.Results1.There were 189 patients enrolled in this comparative cohort study between June 2013 and January 2016,including 83 in HID group and 106 cases in MSD group.Until the last follow-up,MRD+ was observed in 59 patients after transplantation,including 15 cases in HID and 44 in MSD groups.The cumulative incidences of post-MRD+were 18%(95%CI,11-27)and 42%(95%CI,32-51;p<0.001)in HID and MSD groups,respectively.Multivariate analysis showed that HID was a beneficial factor for post-MRD+(p=0.001,HR=0.349).According to the criteria mentioned above,preemptive DLI was administered to 52 patients with post-MRD+,including 13 in HID and 39 cases in MSD groups(p=0.001).The overall cumulative incidences of grade Ⅱ-Ⅳ aGVHD were 40%(95%CI,29-50)and 46%(95%CI,36-55;p=0.848),and Ⅲ-Ⅳ aGVHD were 11%(95%CI,5-19)and 11%(95%CI,6-18;p=0.948)in HID and MSD groups,respectively.The overall cumulative incidences of cGVHD were 39%(95%CI,28-49)and 51%(95%CI,41-60;p=0.152),and extensive cGHVD were 12%(95%CI,6-20)and 18%(95%CI,11-26;p=0.274)in HID and MSD groups,respectively.The 3-year cumulative incidence of relapse post-transplants were 14%(95%CI,7-22)and 24%(95%CI,17-33;p=0.101).Multivariate analysis showed that cGVHD was a protective factor for relapse(p=0.030,HR=0.464).The 3-year cumulative incidence of TRM were 15%(95%CI,8-23)and 10%(95%CI,5-17;p=0.368)in HID and MSD groups,respectively.The 3-year OS were 72%(95%CI,67-77)and 68%(95%CI,63-72;p=0.687),and DFS were 71%(95%CI,67-76)and 66%(95%CI,61-71;p=0.579)in two groups,respectively.The 3-year GRFS were 63%(95%CI,57-68)and 43%(95%CI,39-48;p=0.035)in two groups,respectively.Multivariate analysis showed that pre-and post-MRD+were risk factors for DFS(p=0.006,HR=2.119;p=0.019,HR=2.029,respectively)and OS(p=0.007,HR=2.135;p=0.028,HR=1.981,respectively).2.There were 251 patients enrolled in this study,including 119 in HID group and 132 in MSD group.On day 30 post-transplantation,94%of the patients achieved CR and 6%NR,and there was no difference in CR rate between two groups(94%vs 93%;p=0.802).According to the DLI strategy mentioned above,a total of 199 patients received DLI for preventing relapse,including 91(76%)cases in HID group and 108(82%)cases in MSD group(p=0.350).Until the last follow-up,114 episodes of post-MRD+were recorded in 92 patients including 60 cases before DLI and 12 after DLI.The 1-year cumulative incidences of grades Ⅱ-Ⅳ aGVHD were 62%(95%CI,58-67)and 54%(95%CI,50-58;p=0.025),and Ⅲ-Ⅳ aGVHD post-transplants were 16%(95%CI,13-19)and 11%(95%CI,8-13;p=0.180)in HID and MSD groups,respectively.The 3-year cumulative incidences of cGVHD were 55%(95%CI,50-59)and 55%(95%CI,51-60;p=0.789),and extensive cGHVD were 21%(95%CI,17-25)and 19%(95%CI,16-22;p=0.830)in HID and MSD groups,respectively.The 5-year cumulative incidence of relapse post-transplant for all patients was 32%(95%CI,23-41),with 26%(95%CI,18-35)in HID group and 38%(95%CI,29-47:p=0.034)in MSD group,respectively.In multivariate analysis,the percentage of BM blasts≥ 3%on day 0 and post-MRD+was an adverse factor for relapse(p=0.037,HR=1.652;p=0.003,HR=2.019,respectively).HID,DLI,and cGVHD were protective factors for relapse(p=0.047,HR=0.615;p=0.034,HR=0.561;p=0.023,HR=0.580,respectively).Within the first 100 days’ post-transplant,there was higher infection-related mortality in HID than MSD(8%vs 2%,p=.049).At a median follow-up of 20.3(range,0.2-72.7)months post-transplantation,the 5-year cumulative incidence of TRM was 31%(95%CI,22-40)and 23%(95%CI,16-30;p=0.114).in HID and MSD groups,respectively.The 5-year OS was 46%(95%CI,42-51)and 42%(95%CI,37-46;p=0.832),DFS was 43%(95%CI,38-48)and 39%(95%CI,35-44;p=0.665),and GRFS was 28%(95%CI,24-33)and 26%(95%CI,22-30;p=0.795)in HID and MSD groups,respectively.Multivariate analysis showed that DLI was a protective factor for OS and DFS(p<0.001,HR=0.423;p<0.001,HR=0.402,respectively),and cGVHD was associated with better DFS(p=0.016,HR=0.659).The percentage of BM blasts≥ 3%on day 0 and post-MRD+was an adverse factor for OS(p=0.011,HR=1.573;p=0.027,HR=1.490,respectively)and DFS(p=0.005,HR=1.630;p=0.003,HR=1.668,respectively).3.A total of 412 consecutive patients were enrolled in this study.408 cases completed the study and were analyzed,including 203 patients in the 7.5 mg/kg group and 205 in the 10.0 mg/kg group.The 1-year cumulative incidence of EBV DNAemia was 20.7%[95%CI,15.4-26.5%]and 40.0%(33.3-46.6%)in the 7.5 mg/kg and 10.0 mg/kg groups,respectively(p<0.001).The 1-year cumulative incidence of CMV DNAemia was 73.4%(67.2-79.4%)and 83.4%(77.5-87.9%)in the 7.5 mg/kg and 10.0 mg/kg groups,respectively(p=0.038).The 2-year cumulative incidence of EBV-associated diseases post-transplantation was 3.0%(1.2-6.0%)and 7.3%(4.3-11.4%)in the 7.5 mg/kg and 10.0 mg/kg groups,respectively(p=0.048).The 2-year incidence of CMV-associated diseases was 1.5%(0.4-4.0%)and 5.9%(3.2-9.7%)in the 7.5 mg/kg and 10.0 mg/kg groups,respectively(p=0.019).The 100-day cumulative incidence of grade Ⅱ to Ⅳ aGVHD was 27.1%(21.1-33.4%)and 25.4%(19.6-31.5%)in the 7.5 mg/kg and 10.0 mg/kg ATG groups,respectively(p=0.548).The 100-day cumulative incidence of grade Ⅲ to Ⅳ aGVHD was 7.9%(4.7-12.2%)and 5.4%(2.8-9.1%)in the 7.5 mg/kg and 10.0 mg/kg groups,respectively(p=0.299).The 2-year cumulative overall incidence of cGVHD was 34.6%(27.8-41.4%)and 36.2%(29.1-43.2%)in the 7.5 mg and 10.0 mg groups,respectively(p=0.814).The 2-year cumulative incidences extensive cGVHD were 12.8%(8.5-18.0%)and 10.2%(6.3-15.2%),respectively(p=0.417).The 3-year cumulative incidence of TRM was 20.2%(15.0-26.0%)and 24,4%(18.7-30.4%)in the 7.5 mg/kg and 10.0 mg/kg groups,respectively(p=0.289,).The 3-year incidence of relapse post-transplantation was similar between the two groups[17.6%(12.4-23.6%)vs 15.3%(10.2-21.5%);p=0.442].The 3-year OS was 69.5%(63.2-75.8%)and 63.5%(56.2-70.8%)in the 7.5 mg/kg and 10 mg/kg groups,respectively,and the DFS was 62.2%(55.3-69.1%)and 60.3%(53.0-67.6%)in the 7.5 mg/kg and 10.0 mg/kg groups,respectively(OS:p=0.308;DFS:p=0.660).Conclusions1.HID transplantation had lower incidence of post-MRD+than MSD transplantation,suggesting that HID might exert a stronger GVL than MSD.A lower proportion of patients in HID group received DLI than that of MSD group,HID transplant showed superior GRFS compared with MSD transplant.So HID transplant should be recommended as one of the optimal choices for patients with high-risk AML in CR1.2.For patients with refractory acute leukemia in NR pre-transplantation,HID transplantation had lower incidence of relapse,but had higher infection related mortality within 100 days post-transplant than MSD transplantation.Eventually,there were comparable survival rates between HID and MSD transplant.For those patients,allo-HSCT remains the optimal curative treatment,HIDs can be valid alternatives in absence of MSDs.3.Preemptive and prophylactic DLI are effective means to prevent relapse post-transplantation.For patients with refractory acute leukemia in NR pre-transplantation,sequential conditioning may lower relapse and improve transplant outcomes.4.Compared with 10.0 mg/kg,7.5 mg/kg ATG for GVHD prophylaxis was associated with reduced EBV and CMV infections without increased incidence of GVHD in HID-SCT. |
PDF Full Text Request