Minimal Residual Disease Detected By Multiparameter Flow Cytometry and Complex Karyotype Are the Major Prognostic Factors for Relapse after HCT

Allogeneic hematopoietic cell transplantation (HCT) is considered definitive consolidation therapy for many patients with acute myeloid leukemia (AML) once complete remission (CR) is achieved. Nevertheless, relapse remains a major cause of treatment failure post-HCT. Increasing evidence suggests that the presence of minimal residual disease (MRD) at the time of HCT identifies a subset of patients that is at high risk of relapse.

In the present analyses, we sought to determine the impact of MRD detected by 8-color flow cytometry (FC) at HCT on 1-year relapse incidence (RI) in patients transplanted in first CR (CR1).

Between 2010 and 2012, 159 AML CR1 patients with a median age of 53 years were transplanted with matched sibling donor (MSD, n=42), matched unrelated donor (MUD, n=78) or mismatched donor (MMD (n=39). Of 159 patients, 50 had MRD by 10-color FC at HCT (MRDpos). Compared with patients without MRD (MRDneg), MRDpos were older (median age 60 vs. 53, p=0.0003), required more than 1 line of induction chemotherapy to achieve CR1 (40% vs. 17%, p=0.001), had more incomplete recovery of counts (CRi/p) at HCT (58% vs. 9%, p<0.001) and had more complex karyotype (CK) as diagnostic abnormality (25% vs. 13%, p=0.08). The distribution of conditioning intensity and donor type were similar between groups.

The median follow-up of 105 survivors was 368 days. MRDpos patients had a higher 1-year RI (HR=3.2, p=0.003) compared with MRDneg,. Patients with CK was another group with higher 1-year RI compared with patients without CK (HR=3.2, p=0.003). Multivariate regressions showed that MRDnegCKneg patients represented the best prognostic group with the lowest 1-year RI while MRDposCKpos was the worst prognostic group (HR=6.8, p=0.002). Patients with either MRDpos or CKpos represented an intermediate risk group (HR=3.2, p=0.03) for 1-year RI after HCT (Figure 1a). The 1-year RI adjusted by age, line of induction regimen to achieve CR, intensity and donor type was 8% for MRDnegCKneg, 30% for MRDposCKneg and 47% for MRDposCKpos patients.

Similarly, 1-year relapse-free survival (RFS) was lower for patients who were MRDpos (HR=1.9, p=0.01) compared with patients who were MRDneg. Among other variables, CRi/p (HR=2.0, p=0.01) and CK (HR=2.2, p=0.009) also decreased 1-year RFS. Multivariate regressions showed that patients with MRDnegCKneg with complete count recovery at HCT had the best 1-year RFS and CKpos patients with either MRDpos or CRi/p had the worst outcomes (HR=5.2, p<0.001). Patients with only CKpos (HR=2.4, p=0.048) and CKneg but either MRDpos or CRi/p (HR=2.7, p=0.002) represented an intermediate risk group for 1-year RFS(Figure 1b).

Our study shows that MRD by FC at HCT is associated with other high risk disease features and its prognostic impact on 1-year RI is not independent of the cytogenetic risk profile. Patients without CK enjoy a lower incidence of relapse with better RFS even if they are MRDpos at HSCT. We believe that this group of patients with CKpos and MRDpos or CRi/p should be a target of innovative transplant and post-transplant strategies to further improve their outcomes.

Table: Demographic by MRD

	MRDneg	MRDpos	P
Median age	53	60	<0.001
AML-t	18 (17%)	11 (22%)	0.4
CRi/p	10 (9%)	29 (58%)	0.1
Complex karyotype	14 (13%)	12 (25%)	0.08
≥2 lines of induction to achieve CR1	18 (17%)	20 (40%)	0.001
Myeloablative conditioning	66 (61%)	26 (52%)	0.3
MUD/MMD	53/26 (49%/24%))	25/13 (50%/26%)	0.8