Combination of Minimal Residual Disease By Flow Cytometry before and after Hematopoietic Stem Cell Transplantation Predicts Survival in Patients with Acute Myeloid Leukemia
Authors: Nuñez-Torron stock Claudia , Jiménez Carlos , Martín Moro Fernando , Marquet Juan , Piris-Villaespesa Miguel , Lopez Hernandez Clara , Luna Alejandro , García Gutiérrez Valentín , Chinea Anabelle , Moreno Jimenez Maria Gemma , López Javier , Herrera Puente Pilar 
Published: December 2024

Introduction: the measurement of the disease burden in patients with acute myeloid leukemia (AML) is one of the most important predictors of posttransplant (HSCT) survival. Patients with positive minimal residual disease (MRD) by multiparametric flow cytometry (MFC) or active disease (AD) before HSCT have dismal outcomes, but also the measurement in early postHSCT is a powerful tool to predict survival and the combination of both measurements can provide us with complementary information to identify high-risk patients.

Aim: to analyse the influence of burden disease before HSCT (MRD negative, MRD positive or AD), the MRD in early postHSCT and the relation between both in terms of survival.

Material and methods: we performed a retrospective analysis of 173 patients who received an allogeneic HSCT in the same centre between 2008 and 2023. All patients had an assessable bone marrow before HSCT (including patients in complete remission (CR) with valuable MRD by MFC or patients with AD) and/or at least one available MRD measurement among days +30 and +115 after HSCT. For MRD we use a cut-off of ≥0.1% to define MRD+. Overall survival (OS) and event-free survival (EFS) analysis were performed through Kaplan-Meier method. Cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) were estimated using cumulative incidence method and differences were estimated using Gray´s method, considering each risk as a competing risk. P&lt;0.05 was defined as statistically significant difference.

Results: The median age of the cohort was 54 (range 45-61) years, and 58.4% were males. 31.2% of patients had secondary AML and 18.0% had favourable, 54.1% intermediate and 27.9% adverse risk by ELN2017 classification at diagnosis. Most patients (68.2%) were transplanted in first CR. The donor was sibling donor in 36.4%, haploidentical in 37% and unrelated in 26.6%. The conditioning intensity was myeloablative in 52.6%, 42.8% reduce intensity and 4.6% sequential conditioning.

According to pre-HSCT disease, 160 patients had assessable bone marrow: 100 patients in CR with MRD-, 37 in CR with MRD+, and 23 with AD. The 3y-EFS was 58.5% in MRD- vs 31.5% in MRD+ vs 9.0% in AD patients (MRD- vs MRD+ p = 0.007; MRD- vs AD+ &lt;0.001; MRD+ vs AD p = 0.012). The 3y-OS were 61.5% vs 47.0% vs 13.5% (MRD- vs MRD+ p = 0.048; MRD- vs AD p &lt; 0.001; MRD+ vs AD p = 0.002). The 3y-CIR was 17.0% vs 49.0% vs 69.0% (p &lt; 0.001). According to postHSCT, 151 patients had at least one assessable bone marrow aspiration with valuable MRD (posMRD) and without cytologic relapse, of those 136 had posMRD- and 15 posMRD+. The 3y-EFS was 52.0% vs 26.5% (p = 0.006) and 3y-OS 58.0% vs 28.0% (p = 0.015). The 3y-CIR was 30% in posMRD- and 60% in posMRD- (p = 0.003). Finally we evaluated patients with a valuable pretransplant aspirate and at least one aspirate after HSCT without haematological relapse and we divide patients among different groups: 1) patients with MRD-/MRD- (n=83), 2) patients with MRD+/MRD- (n=27), 3) patients with AD/MRD- (n=15) and finally 4) patients with MRD+ after HSCT regardless of the preHSCT status (posMRD+) (n=13). The 3y-EFS was 66.0% vs 40.5% vs 13.5% vs 23.0% comparing the four groups respectively (MRD-/MRD- vs MRD+/MRD- p = 0.014; MRD-/MRD- vs AD/MRD- p &lt; 0.001; MRD-/MRD- vs posMRD+ p &lt;0.001; MRD+/MRD- vs AD/MRD- p = 0.035; MRD+/MRD- vs posMRD+ p = 0.063; AD/MRD- vs pos MRD+ p = 0.957). The 3y-OS was 68.0% vs 56.0% vs 22.0% vs 23.0% (MRD-/MRD- vs MRD+/MRD- p = 0.08; MRD-/MRD- vs AD/MRD- p &lt; 0.001; MRD-/MRD- vs posMRD+ p = 0.001; MRD+/MRD- vs AD/MRD- p = 0.013; MRD+/MRD- vs posMRD+ p = 0.041 and AD/MRD- vs pos MRD+ p = 0.803). The 3y-CIR was 17.0% in MRD-/MRD- vs 44.0% in MRD+/MRD- vs 65.0% in AD and 61.5% in posMRD+ respectively (p &lt;0.001)

Conclusions: preHSCT disease burden or early postHSCT MRD measurements are both prognostic factors of postHSCT survival, but the combination of both are more informative in our series. Patients with MRD+ and especially those with AD before HSCT, have adverse outcomes regardless they achieve early posMRD-. The prognosis of patients with posMRD+ was also dismal. Patients with posMRD+ in early HSCT and those with any residual disease before HSCT are high-risk patients for relapse in whom we must implement therapeutic strategies.