Dissecting the AML Patients with FLT3-ITD into High-Risk and Low-Risk Relapsed Ones Based on Pre-Transplantation Minimal Residual Disease Determined By Multiparameter Flow Cytometry

Acute myeloid leukemia (AML) with fms-related tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) often have a poor clinical prognosis. Though several previous studies had demonstrated that allogeneic hematopoietic stem cell transplantation (allo-HSCT) could improve its outcomes, there were a number of studies indicated that FLT3 mutational status was still an independent risk factor for adverse outcomes after allo-HSCT in AML. The minimal residual disease prior to transplantation (pre-MRD) has been proved to be able to predict leukemia relapse after allo-HSCT. However, due to limitation of detecting techniques, FLT3-ITD is not a very suitable marker of MRD. Thus, in this study we attempted to investigate that impact of pre-MRD determined by multiparameter flow cytometry (MFC) on the transplant outcomes of AML patients with FLT3-ITD mutation. Total 20 patients who received human leukocyte-antigen (HLA)-matched sibling donor transplantation (MSDT) and 63 patients who received unmanipulated haploidentical HSCT (haplo-HSCT) were enrolled in this study. Pre-MRD was determined using MFC. The results showed that all patients acquired stable neutrophil engraftment. Patients who received haplo-HSCT with positive pre-MRD had a longer period of time to neutrophil engraftment compared to those with negative pre-MRD (median: 15 days vs. 13 days, P=0.033). Patients undergoing MSDT or haplo-HSCT were classified into four groups based on the status of pre-MRD: group 1, with positive pre-MRD before MSDT; group 2, with negative pre-MRD before MSDT; group 3, with positive pre-MRD before haplo-HSCT; group 4, with negative pre-MRD before haplo-HSCT. The cumulative incidence of grade II-IV° acute graft-versus-host disease (aGVHD) and chronic GVHD were comparable between group 1 and 2 as well as group 3 and group 4 (P>0.05). Through Kaplan-Meier analysis, it showed that patients of group1 had the worst clinical outcomes. They had the highest cumulative incidence of relapse (2-year CIR, 75.0%), the lowest leukemia-free survival (2-year LFS, 25.0%) and the overall survival (2-year OS, 25.0%) among all four groups. The other three groups of patients had the comparable CIR (2-year CIR: group 2 vs. group 3 vs. group 4, 12.5% vs.30.3% vs. 20.9%, P>0.05) and LFS (2-year LFS: group 2 vs. group 3 vs. group 4, 87.5% vs. 62.5% vs. 66.5%, P>0.05). Multivariate analysis indicated that disease status (>CR1) and pre-MRD were associated with a higher CIR and a lower LFS when patients were classified into above four groups determined by MFC and transplant type. These results indicated that the AML patients with FLT3-ITD were able to be dissected into high-risk and low-risk relapsed groups based on pre-transplantation MRD determined by MFC. In addition, haplo-HSCT might overcome the negative impact of pre-MRD on patient outcomes compared to MSDT.