Value of Pretransplantation Minimal Residual Disease in Acute Myeloid Leukemia and Myeloablative Hematopoietic Cell Transplantation.
Authors: Bento Leyre , Kwon Mi , Buno Ismael , Martinez-Laperche Carolina , Anguita Javier , Pérez-Corral Ana M , Pascual Cristina , Balsalobre Pascual , Serrano David , Gayoso Jorge , Diez-Martin Jose Luis 
Published: October 2019

Abstract
Abstract 2510
Relapse remains the main cause of treatment failure in patients with acute myeloid leukemia (AML) in first remission (CR1) after allogeneic hematopoietic stem cell transplantation (SCT). The detection of minimal residual disease (MRD) in AML has improved in the past years with multiparametric flow cytometry (MFC) and molecular analysis (RT-PCR). However the prognostic impact of pre-transplantation MRD and the outcome after SCT has not been well studied. The aim of this study was to evaluate pre-transplantation MRD in patients in first remission undergoing myeloablative allogeneic SCT.
We retrospectively studied 35 consecutive patients receiving myeloablative SCT for AML in first cytologic remission after intensive chemotherapy with available MRD determination before transplant. MRD was studied by 4-color MFC on bone marrow aspirates, and quantitative RT-PCR (NPM1, WT1, MLL) on bone marrow and/or peripheral blood samples obtained within thirty days before transplant.
Thirty-five patients consecutively transplanted in our institution between 1999 and 2012, and for which pre-transplant MRD data was available were analyzed (Table 1). Eighteen showed negative MRD pre-transplant whereas 17 showed positive values. Characteristics of patients were homogeneous between both groups, including number of chemotherapy cycles received before transplantation (Table 1).
Within the MRD-negative group, 17 patients showed negative MRD by MFC (12 of them showed negative values also by PCR) and 1 patient showed negative MRD by PCR (MFC not available). Within the MRD-positive group, 9/17 (52%) patients showed MRD-positive values by MFC: in 5 cases MRD was also detected by PCR, only 1 showed negative PCR and in the remaining 3 cases, PCR was not available. On the other hand, in 8/17 (47%) patients MRD was not detected by MFC, however, PCR detected MRD in all of the cases in bone marrow (2), peripheral blood (4) or both samples (2).
With a median follow-up of the whole series of 23 months, 2-years estimates of overall survival were 82% (95% CI, 97–55) and 30% (95% CI, 3–71) for MRD-negative and MRD-positive patients (p=0.045), respectively. Cumulative incidence of relapse were 21% (95% CI, 5–48) and 56% (95% CI 10–73) for MRD-negative and MRD-positive patients (p=0.11).
In the MRD-negative group, cause of death was toxicity in 11% of the cases and relapse in 11%, while in the MRD-positive group, 17% of patients died due to toxicity and 23% due to relapse.
Conclusions: Our data shows that the presence of MRD before allogeneic SCT in patients with AML in CR1 is associated with a significant worse OS rate compared to patients with negative MRD, as well as a tendency towards a higher risk of relapse. The detection of MRD by MFC correlates with the detection by PCR in most of the cases. However, in a significant group of patients, MRD was detected only by PCR. This could be related to differences in sensitivity between both methods. Further studies including larger series are needed to confirm these observations.
Table 1 Patient and Disease Characteristics by MRD status Pre-transplant MRD MRD-negative MRD-positive N=35 18 17 Age at transplant (median, R) 36 (19-62) 42 (19-68) Gender (male/female) 8/10 12/5 Cytogenetics and molecular markers     Normal/Intermediate risk 77% 83%     FLT3+ 28% 27%     NPM1+/FLT3- 6% 7%     FLT3-/NPM1- 28% 40%     High-risk 22% 17% Secondary AML 16% 6% Cycles pre-transplantation (median, R) 3 (2-5) 3 (2-5) MRD detection     MFC only 27% 18%     RT-PCR only 5% 0%     Both 68% 82% Donor*     HLA-identical sibling 50% 35%     HLA-matched unrelated 22% 29%     SCU-dual 22% 24%     HLA-haploidentical related 6% 12% acute GVHD II-IV (n°/patients at risk) 44% (8/18) 24% (4/17) chronic GVHD lim/ext (n°/patients at risk) 53% (8/15) 57% (8/14) MRD: minimal residual disease, MFC: multiparametric flow cytometry, RT-PCR: real time PCR, GVHD: graft vs host disease,

SCU-dual: single cord blood with co-infusion of selected CD34+ cells from a third party HLA-mismatched donor.
*The MRD negative group includes 2 MAC SCU-dual cases with primary graft failure rescued immediatly by a second graft (1 Dual and 1 Haplo) using a RIC regimen. The MRD positive group includes 1 MAC SCU-dual case rescued immediatly by a second graft (1 Haplo).

Disclosures:
No relevant conflicts of interest to declare.