Effects of pre‐ and post‐transplantation minimal residual disease on outcomes in pediatric patients with acute myeloid leukemia receiving human leukocyte antigen‐matched or mismatched related donor allografts
Authors: Ying‐Jun Chang, Xiao‐Su Zhao, Yu Wang, Yan‐Rong Liu, Lan‐Ping Xu, Xiao‐Hui Zhang, Huan Chen, Yu‐Hong Chen, Wei‐ Han, Yu‐Qian Sun, Chen‐Hua Yan, Xiao‐Dong Mo, Kai‐Yan Liu, Xiao‐Jun Huang
Journal: American Journal of Hematology (2017)

Allogeneic stem cell transplantation (allo-SCT) is a powerful therapeutic modality for patients with acute myeloid leukemia (AML).1 However, relapse after transplantation remains a primary cause of mortality. Many studies suggest that the presence of minimal residual disease (MRD) determined by multiparameter flow cytometry (MFC) before and after allo-SCT can identify a subgroup of patients at high risk of recurrence.2, 3 However, these studies primarily focused on adult AML patients who received HLA-matched sibling donor transplantation (MSDT) or unrelated donor transplantation. Little information exists about the impact of MRD on the transplant outcomes of pediatric AML patients, particularly in the haploidentical SCT (haplo-SCT) setting. To explore the effects of pre- and post-transplantation MRD, as determined by MFC, on outcomes in pediatric AML patients, 161 cases who underwent MDST (n = 12) or haplo-SCT (n = 64) with provided written informed consent were retrospectively enrolled (Supporting Information Table S1). Eight-color MFC was employed to evaluate MRD prior to SCT as well as between 30 to 180 days after transplantation. The study was conducted according to the Declaration of Helsinki and was approved by the Institutional Review Board of Peking University. Total patients were classified as being in either the negative pre-MRD group (n = 121) or the positive pre-MRD group (n = 40). Patients negative for pre-MRD had a significantly lower cumulative incidence of relapse (CIR) than those in the positive pre-MRD group (17% vs. 38%, P = .007), but the two groups had comparable incidences of nonrelapse mortality (NRM) (7% vs. 3%, P = .262) and similar probabilities of leukemia-free survival (LFS) (75% vs. 60%, P = .084) and overall survival (OS) (78% vs. 67%, P = .165). Multivariate analysis showed no association between positive pre-MRD status and relapse, NRM, LFS, or OS (Supporting Information Table S2). Compared to patients who received MSDT, patients who received haplo-SCT experienced a significantly lower incidence of relapse (60% vs. 21%, P < .0001) and superior LFS (40% vs. 74%, P = .001; Supporting Information Table S3). Subsequently, all patients were further classified into four groups (Supporting Information Table S3 and Figure 1, group A, n = 6; group B, n = 6; group C, n = 115; group D, n = 34). The CIR of group A, group C, and group D were comparable (17% vs. 17% vs. 27%, P > .05), and all of these values were significantly lower than the CIR of group B (100%, P < .01 for all). The cumulative incidence of NRM was comparable among groups A, B, C and D (0% vs. 0% vs. 8% vs. 3%, respectively, P > .05). The LFS probabilities of group A, group C, and group D were comparable (83% vs. 75% vs. 70%, P > .05), and all of these values were significantly higher than that of group B (0%, P < .01 for all). The OS probabilities for group A, group C, and group D were comparable (100% vs. 77% vs. 74%, P > .05), and all of these values were significantly higher than that of group B (25%, P < .01 for all). Multivariate analysis showed that positive pre-MRD status with Haplo-SCT was associated with a lower cumulative incidence of relapse, along with superior LFS and OS than in those who underwent MSDT (Supporting Information Table S4). Transplant outcomes of pediatric AML patients who underwent allo-SCT classified by pre-transplantation MRD and transplantation modality (n = 161). Estimates of the (A) cumulative incidence of relapse (CIR), (B) cumulative incidence of nonrelapse mortality (NRM), (C) leukemia-free survival (LFS), and overall survival (OS). P values between the four groups: CIR: A vs. B, P = .008; A vs. C, P = .916; A vs. D, P = .790; B vs. C, P = .000; B vs. D, P = .000; C vs. D, P = .324. TRM: A vs. C, P = .480; A vs. D, P = .660; B vs. C, P = .223; B vs. D, P = .756; C vs. D, P = .334. LFS: A vs. B, P = .008; A vs. C, P = .760; A vs. D, P = .703; B vs. C, P = .000; B vs. D, P = .000; C vs. D, P = .745. OS: A vs. B, P = .013; A vs. C, P = .242; A vs. D, P = .210; B vs. C, P = .001; B vs. D, P = .005; C vs. D, P = .758. MRDneg = negative MRD status; MRDpos = positive MRD status. Group A, with negative pre-MRD status who received MSDT; Group B, with positive pre-MRD status who received MSDT; Group C, with negative pre-MRD status who received HBMT; Group D, with positive pre-MRD status who received HBMT [Color figure can be viewed at wileyonlinelibrary.com] Total patients were further classified into a negative post-MRD status group (n = 141) and a positive post-MRD status group (n = 20). Patients with negative post-MRD status had lower CIR than those with positive post-MRD status (14% vs. 78%, P < .001) similar incidences of NRM (7% vs. 0%, P = .266) and higher probabilities of LFS (79% vs. 22%, P < .001) and OS (81% vs. 34%, P < .001) (Supporting Information Figure S1 and Table S3). Multivariate analysis showed that positive post-MRD status was associated with high risk of relapse, inferior LFS and OS (Supporting Information Table S2). Multivariate analysis also showed that post-MRD status was associated with high risk of relapse, inferior LFS and OS in the haplo-SCT subgroup (data not shown). Finally, all patients were also divided into three groups based on peri-transplantation MRD kinetics (Supporting Information Table S3). The CIR of group G was significantly higher than those of group E and group F (Supporting Information Figure S2). Multivariate analysis showed that peri-transplantation MRD kinetics were associated with leukemia relapse, LFS, and OS (Supporting Information Table S5). The association of peri-transplantation MRD kinetics with transplant outcomes in the haplo-SCT subgroup was also observed (data not shown). In the current study, we confirmed the association between positive pre-MRD status and a high risk of relapse as well as poorer survival rates in patients who received MSDT as previously reported by others, but not in those who received haplo-SCT.2-6 These findings together with our previous study5, 6 suggested that, compared to MSDT, haplo-SCT may have a strong graft-versus-leukemia (GVL) effect for pre-MRD positive AML patients in both adult and pediatric populations. Several researchers reported the negative effects of positive post-MRD status on the outcomes of AML patients after allo-SCT. Here, we provide compelling evidence that positive post-MRD status had negative effects on pediatric AML relapses. These data indicate that interference strategies should be given to post-MRD positive cases to avoid developing a frank hematological relapse. As far as the peritransplantation MRD dynamics is concerned,2 which could allow for the identification of a subgroup of patients (12/161, 7.4%) with increasing MRD levels. Their outcomes were worse than that of those with negative pre-MRD and negative post-MRD status, and decreasing MRD levels. In this study, we failed to demonstrate the negative effects of FLT3-ITD and adverse cytogenetics on outcomes, although these two factors have been identified by univariate analysis as outcome predictive variables. These results suggest that, as a dynamic biomarker, MRD may be more important than FLT3-ITD and adverse cytogenetics in outcome prediction. This study had several limitations. First, this is a retrospective, single center study with a small sample of pediatric patients receiving MSDT. Second, MFC based MRD detection does not have a uniform sensitivity across all cases. In summary, our results indicate that for pre-MRD positive cases, haplo-SCT should be chosen, and prophylaxis donor lymphocyte infusion (DLI) should be performed if MSDT is used. Our results, together with the available literature, suggest that monitoring MRD during the peri-transplantation period, in combination with MRD-directed prophylaxis or preemptive therapies, could reduce the incidence of morphologic relapse and improve survival. This work was supported (in part) by the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (Grant No. 81621001), the National Natural Science Foundation of China (Grant No. 81470342), and the Key Program of the National Natural Science Foundation of China (Grant No. 81230013). We thank all the faculty members who participated in these studies. We would also like to thank American Journal Experts (https://www.aje.cn/) for assistance in editing this manuscript. The authors declare no conflict of interest. X.-J.H. designed the study; Y.-J.C., X.-S.Z., Y. W. and Y.-R. L. collected the data; Y.-J.C., X.-S.Z., Y. W., Y.-R. L., and X.-J.H. analyzed the data and drafted the manuscript; all authors contributed to the data interpretation, manuscript preparation, and approval of the final version. Additional Supporting Information may be found online in the supporting information tab for this article. Supporting Information Figure 1A Supporting Information Figure 1B Supporting Information Figure 1C Supporting Information Figure 1D Supporting Information Figure 2A Supporting Information Figure 2B Supporting Information Figure 2C Supporting Information Figure 2D Supporting Information Figures Supporting Information Table 1 Supporting Information Table 2 Supporting Information Table 3 Supporting Information Table 4 Supporting Information Table 5 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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