Impact of NCCN Risk Stratification and Minimal Residual Disease on Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia

Introduction: Cytogenetic abnormality is considered to be an independent prognostic factor in newly diagnosed acute myeloid leukemia (AML). However, recent studies have demonstrated that acquired gene mutations also play an important role in the pathogenesis and prognosis of AML. It has been well known that minimal residual disease (MRD) pre-conditioning has remarkable impact on disease-free survival (DFS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute lymphoblastic leukemia, but the effect of MRD pre-transplant on allo-HSCT in AML is still unclear. Objective: In present study, the effect of NCCN risk stratification which has integrated gene mutations into cytogenetics as well as MRD pre-transplant on DFS after allo-HSCT in AML was studied in order to learn whether risk-directed conditioning and prevention of relapse are needed. Methods: Between April 2012 and March 2015, consecutive 258 patients with AML in complete remission (CR) (186 cases in CR1 and 72 cases in CR2) who underwent allo-HSCT in our hospital were analyzed retrospectively. The median age was 25 (1.8-64) years. Male (M) to female (F) was 147:111. The median disease course was 6 (1-51) months. According to 2015-NCCN risk stratification, 63 (24.4%) cases were in low risk, 112 (43.4%) cases in intermediated risk, and 83 (32.2%) cases in high risk. MRD in bone marrow pre-conditioning was detected by eight-color flow cytometry. Results: With the median follow up 18 (5-41) months, overall 2-year DFS was78.0%. No significant difference in DFS was found among low-risk (78.6%), intermediated-risk (76.0%) and high-risk (80.3%) patients (P=0.886). 205 (79.5%) cases were MRD- and 53 (20.5%) cases were MRD+ before conditioning. DFS after transplant in MRD+ patients was significant lower than that in MRD- patients(65.0% vs. 81.4%, P=0.003). Univariate analysis showed that DFS was not associated with patient age (≤14years vs.>14years, P=0.292), disease course before HSCT (≤6 months vs.>6months, P=0.532), WBC counts at diagnosis (≤50×10⁹/L vs.>50×10⁹/L, P=0.120), CBC recovery pre-HSCT (yes vs. no, P=0.664), disease status (CR1 vs. CR2, P=0.201), extramedullary leukemia before transplant (yes vs. no, P=0.532), conditioning regimen (BUCy/Flu-based vs. TBICy/Flu-based, P=0.753), donor type (identical sibling vs. unrelated vs. haploidentical, P=0.743), donor-recipient gender (M-M vs. M-F vs. F-M vs. F-F, P=0.245), donor-recipient blood type (compatibility vs. major incompatibility vs. minor incompatibility vs. major and minor incompatibility, P=0.402), mononuclear cells infused (≤8×10⁸/kg vs.>8×10⁸/kg, P=0.583), CD34⁺ cells infused (≤4×10⁶/kg vs.>4×10⁶/kg, P=0.946), and CD3⁺ cells infused (≤1.6×10⁸/kg vs.>1.6×10⁸/kg, P=0.143). DFS was significant lower in the patients with secondary AML (79.4% in primary AML vs. 53.5% in secondary AML, P=0.006) and MRD+ cases before transplant (81.4% in MRD- vs. 65.0% in MRD+, P=0.003). Accumulative non-relapse mortality (NRM) was significant higher in secondary AML (11.7% in primary AML vs. 33.3% in secondary AML, P=0.004) and MRD+ patients (10.5% in MRD- vs. 21.9% in MRD+, P=0.010). Accumulative relapse rate was significant higher in CR2 cases (8.0% in CR1 vs. 17.5% in CR2, P=0.046). Multivariate analysis showed that MRD pre-HSCT was the only impact factor on DFS and NRM with higher DFS (P=0.020) and lower NRM (P=0.045) in MRD- cases. Conclusions: Allo-HSCT has attenuated the influence of cytogenetics and gene mutations on DFS in AML. Secondary AML has lower DFS and higher NRM. Although disease status (CR1 vs. CR2) has no significant influence on DFS, relapse rate in CR2 is higher than that in CR1. MRD pre-conditioning was a key impact factor on DFS after allo-HSCT in AML but not conditioning regimen and donor type.