The data presented in this retrospective analysis support three major conclusions. First, patients with AML who are in first CR without flow cytometric evidence of MRD and who underwent myeloablative allogeneic HCT had favorable outcomes, with 2-year DFS and OS rates that approximate 75% and a 2-year cumulative incidence of relapse of less than 20%. Second, relative to MRD-negative patients, MRD-positive patients had significantly worse outcomes, with a 2-year cumulative incidence of relapse that exceeded 60%, which resulted in poor DFS and high mortality. And lastly, although MRD-positive and MRD-negative patients differed in many factors that predict poor outcome in AML, our multivariate models suggested that pre-HCT MRD is an adverse risk factor for HCT outcome, even after adjusting for these other factors.
Determination of MRD levels during aplasia, either early after induction and/or after consolidation chemotherapy, has proven useful to predict relapse and poor outcome after autologous HCT and may help in identifying patients with AML who require allogeneic HCT for treatment intensification.19–28
Similarly, MRD levels early after transplantation are predictive for outcome and may help as a tool for decision making after allogeneic HCT.29
Our data now indicate that detection of MRD at the time of HCT defines a population of patients with AML that is at higher risk for relapse, reduced OS and DFS, and even increased NRM compared with MRD-negative patients. With only 24 MRD-positive patients, 10 of whom had an MRD level ≤ 0.1%, it is difficult to draw any firm conclusions regarding the association between level of MRD and outcome (ie, whether patients with higher MRD levels have a worse outcome than those with lower levels). On the basis of our limited data, however, the risk of relapse among MRD-positive patients who had a level ≤ 0.1% did not appear to be lower than that among MRD-positive patients whose level was greater than 0.1% (HRs relative to MRD-negative patients, 10.26 and 7.20, respectively).
Of note, MRD was somewhat correlated with other adverse risk factors in our study population. In fact, patients according to the MRD status differed both with respect to disease-specific and treatment-specific factors. Specifically, besides being slightly older, MRD-positive patients more often had secondary disease and tended to more often have AML with poor-risk cytogenetics. The presence of secondary AML is an adverse predictor for outcome after myeloablative allogeneic HCT for patients with AML in first CR, as we found in a recent analysis of a larger cohort of patients with AML (data not shown). The cytogenetic risk at initial disease presentation is predictive for outcome after myeloablative allogeneic HCT for patients with AML in first CR30
; this study revealed a similar finding (according to multivariate analysis; ), although the smaller numbers of patients limited the power to detect a statistically significant effect. It is certainly not surprising that MRD-positive patients more often had poor-risk features, as such diseases are intuitively more likely to persist with MRD after induction and consolidation therapy than more favorable AML. Moreover, MRD-positive patients also received less consolidation therapy and, in particular, less HIDAC-containing consolidation therapy before HCT and had a shorter duration of remission before HCT. Given the retrospective nature of this analysis and that our center serves as a referral center for HCT, we can only speculate about the reasons for this difference. Previous studies did not find a benefit of postremission chemotherapy before allogeneic HCT for patients with AML in first CR.31–33
Of note, however, these studies did not include analyses of MRD status, and it is unknown whether this lack of benefit extends equally to MRD-negative and MRD-positive patients. An important, testable question for future studies is whether additional pre-HCT consolidation chemotherapy could revert an MRD-positive state into an MRD-negative state and whether achievement of MRD negativity before HCT improves the outcome in these patients.
MRD-negative and MRD-positive patients differed additionally with regard to other pre-HCT characteristics. Relative to MRD-negative patients, MRD-positive patients more frequently had abnormal findings from routine karyotype analyses at the time of HCT, whereas the proportion of patients presenting with incomplete blood count recovery was comparable. Our analyses show that the presence of an abnormal karyotype in routine cytogenetic studies before HCT is a strong predictor for adverse outcome after HCT in our patient cohort, both in univariate and multivariate models. The presence of incomplete blood count recovery was similarly associated with an increased hazard of relapse and death, although the relatively small number of patients (and hence, events) limited the power to detect a statistically significant impact.
As expected, our data support the notion that the factors discussed in this paper are not independent from each other. Despite an imbalance in these adverse factors between MRD-positive and MRD-negative patients, our multivariate models suggest that evidence of MRD before HCT remains a significant risk factor for post-transplantation relapse and death. This negative impact on outcome extended, somewhat surprisingly, also to NRM in our patient cohort (unless the analysis is restricted to patients with recovered blood counts and normal cytogenetic analysis at the time of HCT), and additional studies will be necessary to fully understand this observation.
Together, our findings suggest that detection of any MRD by MFC at the time of HCT defines a population of patients with AML who are at higher risk for adverse outcome, even after adjusting for other factors that influence post-HCT outcome. Although these findings should be confirmed in a larger patient cohort, they support the routine use of pre-HCT MRD assessment for risk stratification of post-HCT outcome. Furthermore, they provide the rationale for future studies to test whether the outcome of MRD-positive patients could be improved through MRD-stratified interventions, for example additional pretransplantation chemotherapy, modified HCT conditioning, or additional pre-emptive treatment after HCT.