Pre-Transplant Minimal Residual Disease Determined By Multiparameter Flow Cytometry Is Better Than RQ-PCR to Predict the Outcomes of Ph+ALL Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation

Acute lymphoblastic leukemia with the Philadelphia (Ph) chromosome (Ph+ALL) occurs in about 25-30% adult patient ALL. Though the appearance of tyrosine kinase inhibitors (TKIs) greatly improved the outcomes of this kind of leukemia, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still a radical approach for this kind of leukemia. Several previous studies had demonstrated that minimal residual disease prior to transplantation (pre-MRD) could predict the transplant outcomes, especially leukemia relapse. For Ph+ALL, multiparameter flow cytometry (MFC) and real-time quantitative polymerase chain reaction (RQ-PCR) were used to monitor MRD. In this study, we compared the impact of pre-MRD determined by MFC and BCR/ABL expression on the outcomes of Ph+ALL who underwent allo-HSCT. Total 155 patients who received HLA-matched sibling donor transplantation (MSDT, n=49) and unmanipulated haploidentical HSCT (haplo-HSCT, n=106) were enrolled. Pre-MRD was determined using MFC (pre-MFC) and RQ-PCR-based BCR/ABL expression (pre-BCR/ABL). The results showed that patients received MSDT and haplo-HSCT could have the comparable clinical outcomes. When pre-MRD was evaluated by RQ-PCR, the patients with or without BCR/ABL expression in both MSDT and haplo-HSCT groups didn't show any significant difference in cumulative incidence of relapse (CIR), transplantation related mortality (TRM), leukemia-free survival (LFS) and overall survival (OS). In addition, we also divided patients into 5 groups based on pre-BCR/ABL level: group 1, BCR/ABL=0; group 2, 0<BCR/ABL<0.1%; group 3, 0.1%<BCR/ABL<1%; group 4, 1%<BCR/ABL<10%; group 5, BCR/ABL>10%. Through kaplan-meier analysis, it showed that only patients of group 5 would show the extremely higher CIR (75.0%) while there was no significant difference among the other four groups (group 1 vs. 2 vs. 3 vs. 4, 14.5% vs. 10.2% vs. 20.6% vs. 10.0%, P>0.05). However, when pre-MRD was determined by MFC, patients with negative pre-MFC had a lower 2-year CIR and a slight higher 2-year leukemia-free survival (LFS) than those with positive pre-MFC in whole crowd (CIR: 7.5% vs. 40.0%, P<0.001; LFS: 74.4% vs. 61.2%,P=0.119). For those pre-BCR/ABL positive patients, they were further stratified by pre-MFC in both MSDT and haplo-HSCT groups. Patients with pre-MFC prior to MSDT showed a higher 2-year CIR and lower 2-year LFS compared to those with negative MRD (CIR: 44.4% vs. 6.6%, P=0.002; LFS: 44.4% vs. 85.7%, P=0.019). In patients undergoing haplo-HSCT, the 2-year CIR in pre-MFC positive group was higher than that of pre-MFC negative group (32.4% vs. 5.9%, P=0.014), while the 2-year LFS was comparable between above two groups (62.9% vs. 73.8%, P=0.513). Multivariate analysis indicated that prolonged neutrophil engraftment (HR, 1.243; 95% CI, 1.073-1.440, P=0.004) and positive pre-MFC (HR, 5.492; 95% CI, 1.574-19.161; P=0.008) was associated with a higher CIR. The results indicated that, pre-transplant MRD determined by MFC was better than RQ-PCR-based BCR/ABL expression in predicting outcomes of Ph+ALL patients receiving allo-HSCT.