| Background and purposeCurrently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative therapy for a majority of malignant hematologic diseases, especially acute leukemia. A number of factors affect the efficacy of allo-HSCT, including donor sources, conditioning regimens, graft versus host disease (GVHD) and so on. All these factors are constraint condition for allo-HSCT. For patients who are suitable to undergo allo-HSCT, the key is to find a optimal donor.HSCT from HLA-matched sibling donor (MSD) offers the best results for these diseases, but lack of this donor resource has restricted its wide application. The probability of having a MSD was about 30%. HSCT from unrelated donor (MUD) provides another option, and many studies demonstrated that MUD transplantation achieved comparable outcomes compared to MSD transplantation. But MUDs still cannot satisfy all patients due to unsuccessful donor searches, it’s less likely to find a suitable MUD due to restriction from geographical, ethnic and other factors. Data from International bone marrow transplant group registry displayed that the probability of finding a MUD was about 50%, in China 20%. Unrelated cord blood (UCB) transplantation has its own particular advantages such as ready availability, easiness to obtain and low incidences of graft versus host disease (GVHD), and it is safe for donors. But the cord blood bank scale is small and the number of cord blood cells is low. Consequently, graft failure is a prominent problem for adult patients, the probability of which in reduced intensity conditioning is about 10%, but reaches up to 20% in myeloablative conditioning. So UCB transplantation is not suitable for adult patients.Almost all patients have an available related donor with whom they share a single HLA haplotype (ie, haploidentical related donor), and it owns the advantage of immediate availability, especially for those who urgently need transplantation. What’s more, the results of HLA-haploidentical HSCT (HRD-HSCT) have improved significantly over the past few years owing to the development of highly immunosuppressive conditioning, graft manipulation, and prophylaxis of GVHD. And similar outcomes were observed in patients undergoing HRD-HSCT by using T-cell-replete grafts combined with T-cell depletion in vivo compared with those undergoing MUD-HSCT or MRD-HSCT. A novel protocol to HRD-HSCT was developed by Huang et al at Peking university, which uses G-CSF primed T-cell-replete peripheral blood stem cells and bone marrow mixed grafts in combination with ATG to deplete T lymphocytes in vivo. The underwent a long-term follow-up of 756 cases who received HRD transplantation in their center and reported favorable outcomes. In addition, they reported HRD transplantation achieved similar efficacy to MUD and MSD transplantation, for high risk patients, the efficacy of HRD transplantation was better than MSD transplantation. But it remains controversial whether HRD transplantation can achieve identical outcomes to transplantation from HLA-matched donors. Moreover, the results from such haploidentical transplantation have not formally been compared with those of transplantation in patients contemporaneously using MSDs and MUDs for adult acute leukemia. Here we retrospectively compared outcomes of consecutive patients with acute leukemia undergoing such haploidentical transplantation performed at our single institute with those undergoing MSDs and MUDs from April 2008 to April 2014. The objective of this study is to provide more potent clinical evidence for the selection of donor in allo-HSCT.MethodsThree hundred and fifty-five patients with acute leukemia, who underwent allo-HSCT from April 2008 to April 2014 at Nanfang hospital, Southern Medical University, were enrolled in this analysis. The clinical efficacy of HRD-HSCT, MSD-HSCT and MUD-HSCT in these patients were compared. All patients received myeloablative conditioning regimens. Cyclosporin A (CsA) and methotrexate (MTX) were administered in patients undergoing MSD transplants for GVHD prophylaxis. CsA+ MTX+antithymocyte globulin (ATG) used in patients undergoing MUD transplants and CsA+MTX+ATG+mycophenolate in patients undergoing HRD transplants. All patients in the HRD grouptransplanted with the combination of G-CSF primed PBSC and BM, while patients in the MSD and MUD groups all received PBSC grafts.. A number of factors affected the efficacy of allo-HSCT, including age, sex, genetics, disease state, conditioning regimens, cell source, graft versus host disease (GVHD), therapy post-transplant (donor lymphocyte infusion) and so on. The hematopoietic reconstruction, GVHD, recurrence and death, long-term survival, etc. were analyzed among three different donors. Statistical analysis:SPSS 13.0 statistical package was used for processing, the data were showed as mean ± standard deviation(x±s). The data before and after mobilization, between two independent groups were compared with independent sample or paired sample t test. The ranked data were compared with Chi-square test. Differences between characteristics were assessed by Kruskal-Wallis test. The survival and univariate analysis were described according to the Kaplan-Meier method. Differences between survival curves were assessed by the log rank test. Cox regression model was used for multivariate analysis. Statistical significance was defined at the P less than or equal to 0.05 level.Results1.General characteristics:Of the 355 patients with acute leukemia from April 2008 to April 2014,96 patients received HRDs,153 received MSDs and 106 received MUDs transplantation.229 cases were male and 126 female, the median age was 28(range, from 12 to 61). There were significant differences among the three groups in the category of patient age (p=0.031), donor age (p<0.001), median time from diagnosis to transplantation (p=0.002), risk classification (p=0.005) and disease status at transplantation (p=0.016).2.Risk classification:257 cases achieved CR pre-transplantation and 98 cases NR. 206 cases were classified into high risk and 149 cases were standard risk.3.Engraftment:Analyses of chimerism indicated that all patients achieved full donor chimerism by day +30 posttransplantation, except for two patients who died of bacterial septicemia on day 7, and one of primary graft failure after transplantation (all in HRD transplantation). Neutropbil reconstruction was faster in the MSD than in the HRD and MUD groups (p<0.001; p=0.030, respectively). Platelet engraftment was significantly faster in the MSD and MUD cohorts than in the HRD cohort (p=0.001;p=0.019, respectively).4.Viral infections:Compared with MSD-HSCT, the incidences of EBV viremia and EBV associated diseases were higher in HRD-HSCT and MUD-HSCT(p<0.001;p=0.001, respectively). Compared with MSD-HSCT, the rates of CMV viremia were significantly higher in HRD-HSCT, and less significantly higher in MUD-HSCT (p<0.001 for MSD vs HRD,p=0.019 for MSD vs MUD and p=0.013 for MUD vs HRD). However, the incidences of CMV associated diseases didn’t differ significantly among three cohorts (p=0.475).5.GVHD:73 cases received prophylactic DLI:including 27 (28.1%),34 (22.2%) and 19 (17.9%) in HRD-HSCT, MSD-HSCT and MUD-HSCT (p=0.221). The cumulative incidence of grade II-IV by day+100 post-transplantation were 40.6%±5.0%,23.5%±3.4% and 34.0%±4.6% in HRD-, MRD- and MUD-HSCT, respectively (p=0.008) The cumulative incidences of grade III to IV aGVHD were 11.4%±3.6%,7.8%±2.3% and 10.5%±3.1% in HRD, MSD and MUD-HSCT groups (p=0.565). One hundred and forty-five of 330 cases surviving more than 100 days developed cGVHD including 50 after DLI. The 2-year cumulative incidences of cGVHD and extensive cGHVD were 47.9%±5.1% and 19.1%±4.8%,41.2%±4.0% and 16.8%±3.3%,39.6%±4.8% and 15.4%±4.0%, respectively, in HRDs, MSDs and MUDs groups (p=0.499;p=0.888; respectively).6.Relapse and survival:The 5-year cumulative incidences of relapse were 18.9%±4.8% in HRD-HSCT,27.6%±4.0% in MSD-HSCT and 29.3±5.1% in MUD-HSCT (p=0.268). For patients in NR, relapse rates were significantly lower in HRD-HSCT compared with those in MSD-HSCT (27.0% vs 55.3%,p=0.030), and in MUD-HSCT (27.0% vs 60.8%,p=0.043). In multivariate analysis of relapse, HRD transplantation (p=0.017, RR= 0.460) was a beneficial factor. The 5-year cumulative incidences of TRM were 25.2%±5.5% in HRD-HSCT,18.6%±4.7% in MSD-HSCT and 23.5±4.4% in MUD-HSCT (p=0.131). In the multivariate analysis, TRM was not significantly affected by three different donors. With a median follow up of 22.1 (range,0.1 to 83.1) months post-transplantation,229 patients survived and 126 died. The 5-year DFS rates after transplantation were 59.6%±5.9%,58.8%±4.8% and 54.9%±5.0% in HRD, MSD and MUD cohorts, respectively (p=0.423). The 5-year cumulative incidences of OS post-transplantation were 62.7%±5.6%,63.4%±4.7% and 57.5%±5.0% for patients undergoing HRD, MSD and MUD transplantation, respectively (p=0.297). Furthermore, we found that OS was superior in HRD-HSCT compared to that in MUD-HSCT for patients in NR (54.7% vs 26.8%; p=0.037), but multivariate analysis didn’t show that HRD-HSCT was a protective factor. In multivariate analysis for survival, NR disease status at transplantation, non-myelogenous leukemia, the incidence of grade II-IV aGVHD and patients age older than 28 were independently risk factors. On the other hand, the incidence of cGVHD were beneficial factors.Conclusion1 Our study suggests that HRD transplantation is safe and effective for patients with acute leukemia. Outcomes after HRD transplantation are identical to those after MUD and MSD transplantation. HRD is superior to MUD because donor source is unlimited and choice of treatment could be made promptly according to disease status.2 A lower relapse rate was achieved in HRD-HSCT compared to results in MUD-HSCT and MSD-HSCT for acute leukemia patients in NR, suggesting a stronger GVL in HRD-HSCT. |
PDF Full Text Request