Minimal Residual Disease by Flow Cytometry Pre-Conditioning has Significant Impact on Disease-Free Survival after Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia

Abstract

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 (HSCT) for patients with acute lymphoblastic leukemia, but the effect of MRD before transplant on the outcomes of allogeneic HSCT in acute myeloid leukemia (AML) is still unclear. In present study, the effect of MRD by flow cytometry (FCM) pre-conditioning on DFS after allogeneic HSCT in AML was investigated. Between April 2012 and December 2014, consecutive 168 patients with AML in CR1 who underwent allogeneic HSCT in our hospital were analyzed retrospectively. The median age was 23 (1.8 to 64) years old. Children (≤14 years) were 51 (30.4%) and adults (>14 years) were 117 (69.6%) cases. The median disease course was 8 (2-37) months. Cytogenetics in good-, intermediate-, high-risk were 40 (23.8%), 89 (53.0%), and 39 (23.2%) cases. Donor sources were identical sibling (IS) in 44 (26.2%), unrelated (UR) in 23 (13.7%), and haploidentical (HI) in 101 (60.1%) cases. Myeloablative conditioning regimens were administered with either busulfan (Bu) plus cyclophosphamide (Cy)/fludarabine (Flu)-based in 150 (89.3%) or TBI plus Cy/Flu-based in 18 (10.7%) patients. ATG was used in UR and HI transplant. Unmanipulated bone marrow (BM) and peripheral blood stem cells (PBSC) for IS and HI HSCT, and PBSC for UR transplant. Cyclosporine, short-term methotrexate, and mycophenolate mofetil were employed for GVHD prophylaxis. MRD in BM before conditioning was detected by FCM. MRD was 0% in 140 (83.3%), 0.01% to 0.1% in 3 (1.8%), 0.1% to 1% in 17 (10.1%), and 1% to 3% in 8 (4.8%) patients. With the median follow up 16 (6-39) months, two-year DFS was 81.6%. Two-year DFS after transplant for patients with AML was 52.9% vs 87.0% with or without MRD (p<0.0001). The levels of MRD has remarkable influence on DFS post-HSCT in AML (87.0% for MRD 0%, 66.6% for MRD 0.01% to 0.1%, 57.1% for MRD 0.1% to 1%, 28.5% for MRD1% to 3%, respectively (p<0.0001). Univariate analysis showed that DFS after HSCT in AML was not associated with patient age (children vs. adults, 86.3% vs. 80.0%, p=0.53), cytogenetics (good- vs. intermediate- vs. high-risk, 86.5% vs. 82.4% vs. 73.8%, p=0.62), donor source (IS vs. UD vs. HI, 87.0% vs. 84.8%vs. 77.8%, p=0.51), and conditioning regimen (Bu-based vs. TBI-based, 82.1% vs. 78.7%, p=0.92). Multivariate analysis indicated that MRD pre-HSCT was the only impact factor on DFS after transplant in AML (p=0.000). We have demonstrated that MRD pre-conditioning for patients with AML has significant impact on DFS after allogeneic HSCT but not patient age, cytogenetics, donor source and conditioning regimen. Allogeneic HSCT has attenuated the influence of cytogenetics on DFS in AML.