Combination of disease burden before allogeneic transplantation and early post-transplant minimal residual disease predicts survival in patients with acute myeloid leukemia

Abstract

The burden disease before allogeneic transplantation (HSCT) or the early post-transplant minimal residual disease (MRD) are both predictive parameters for relapse and post-HSCT survival in acute myeloid leukemia (AML). Nonetheless, the combination of both can provide more accurate information to identify high risk patients. To analyze the impact of pre-HSCT disease burden (MRD- vs. MRD + vs. active disease (AD), the early post-transplant MRD (posMRD + vs. posMRD-), and the combination of both pre- and post-HSCT disease status of the post-HSCT outcomes in AML patients. We retrospectively analyzed 173 patients with AML who underwent HSCT in a single institution, patients were classified according to pre-HSCT disease status, and post-HSCT MRD. MRD was measured by multiparameter flow cytometry using a cut-off of 0.1% for MRD+. The post-HSCT outcomes were analyzed based on the pre-transplant status, post-transplant status, and by combining both parameters. Patients with AD and MRD + before HSCT had worse 3y-event free (EFS) and overall survival (OS) than MRD- patients, due to a higher cumulative incidence of relapse (CIR). Also, patients with posMRD + had worse outcomes than posMRD- group. In the combined analysis, patient with MRD-/posMRD- had the best EFS and OS (3y-EFS 66.5%, 3y-OS 70.0%). Patients with MRD+/posMRD- have worse prognosis (3y-EFS 39.0%, 3y-OS 54.0%) and specially the group with AD/MRD- (3y-EFS 13.5%, 3y-OS 22.0%) and posMRD + regardless pre-HSCT disease status(3y-EFS 26.5%, 3y-OS 28.0%) had dismal OS and EFS. The combination of pre-HSCT disease burden and post-HSCT MRD measurements help us for identifying high-risk subgroups. Any level of pre-transplant disease (MRD+, and especially patients with active AD) is a risk factor, even when MRD- was achieved post-transplant. Patients with post-transplant MRD + also had an adverse prognosis. These should be target groups for implementing tailored pre- and post-transplant strategies to improve outcomes.

Keywords: Acute myeloid leukemia; Allogeneic transplantation; Minimal residual disease; Pretrasplantation disease burden; multiparameter flow cytometry.

Fig. 1

Sankey diagram of patients with LMA included in the study. On the left of the diagram patients are classified according to the pre-HSCT disease status, while on the right patients are classified according to early post-HSCT MRD. HSCT, haematopoietic stem cell transplantation; MRD, minimal residual disease

Fig. 2

Event-free survival (1 A) and overall survival (1B) according to pre-HSCT disease burden. Estimates of (left) EFS and (right) OS after HSCT for patients with AML according to pre-HSCT, shown individually for MRD- (n = 100), MRD+ (n = 37) and AD (n = 23) respectively. Patients with MRD + and especially those with AD have significantly worse EFS and OS than patients with MRD- (3y-EFS 58.5% in MRD- vs. 31.5% in MRD + vs. 9.0% in AD patients; 3y-OS 61.5% vs. 47.0% vs. 13.5%). AD, active disease; EFS, event-free survival; HSCT, haematopoietic stem cell transplantation; MRD, minimal residual disease; OS, overall survival

Fig. 3

Event-free survival (2 A) and overall survival (2B) according to post-HSCT disease burden. Estimates of (left) EFS and (right) OS after HSCT for patients with AML according to post-HSCT, shown individually for posMRD- (n = 136) and posMRD+ (n = 15) respectively. Patients with posMRD + have significantly worse EFS and OS than patients with posMRD- (3y-EFS 52.0% in posMRD- vs. 26.5%% in MRD+; 3y-OS 58.0% vs. 28.0%). EFS, event-free survival; HSCT, haematopoietic stem cell transplantation; MRD, minimal residual disease; OS, overall survival

Fig. 4

Event-free survival (2 A) and overall survival (2B) according to combined pre- and post-HSCT disease burden. Estimates of (left) EFS and (right) OS after HSCT for patients with AML according to combined pre-HSCT and post-HSCT, shown individually for MRD-/posMRD- (n = 82), MRD+/posMRD- (n = 28), AD/posMRD- (n = 15) and posMRD+ (n = 15) respectively. While patients with MRD-/posMRD- have the best prognosis, patients with MRD+/posMRD- have an intermediate prognosis and patients with AD/MRD- and posMRD + have the worst EFS and OS (3y-EFS was 66.5% in MRD-/posMRD- vs. 39.0% in MRD+/posMRD- vs. 13.5% in AD/MRD- vs. 26.5% posMRD+; 3y-OS was 70.0% vs. 54.0% vs. 22.0% vs. 28.0%). AD, active disease; EFS, event-free survival; HSCT, haematopoietic stem cell transplantation; MRD, minimal residual disease; OS, overall survival

Fig. 5

Cumulative incidence of relapse according to pre-HSCT status (4 A), post-HSCT MRD (4B) and combined pre- and post-HSCT disease burden (4 C). Estimates of CIR after HSCT for patients with AML according to pre-HSCT (up-left), shown individually for MRD- (n = 100), MRD+ (n = 37) and AD (n = 23) respectively. Estimates of CIR after HSCT for patients with AML according to post-HSCT (up-right) and combined pre and posHSCT disease burden (down-left), shown individually for posMRD- (n = 136) and posMRD+ (n = 15) respectively. Estimates of CIR after HSCT for patients with AML according to pre- and post-HSCT disease burden (down-left), according to combined pre-HSCT and post-HSCT, shown individually for MRD-/posMRD- (n = 82), MRD+/posMRD- (n = 28), AD/posMRD- (n = 15) and posMRD+ (n = 15) respectively. Patients with MRD + and especially those with AD have significantly worse CIR than patients with MRD- (3y-CIR 17.0% in MRD- vs. 49.0% in MRD + vs. 69.0% in AD patients). Also, patients with posMRD + have worse CIR than posMRD- (3y-CIR 30% in posMRD- vs. 60.0% in posMRD+). In combined group, patients with posMRD + and AD/MRD- have the higher CIR, while patients with MRD+/posMRD- have an intermediate prognosis and the MRD-/posMRD- have the best prognosis (3y-CIR 16.0% in MRD-/MRD- vs. 46.0% in MRD+/MRD- vs. 65.0% in AD/MRD- and 60.0% in posMRD + respectively). AD, active disease; CIR, cumulative incidence of relapse; HSCT, haematopoietic stem cell transplantation; MRD, minimal residual disease