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Comment & Response
March 25, 2021

The Role of Acute Myeloid Leukemia Minimal Residual Disease in Regulatory Decision-making—Reply

Author Affiliations
  • 1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston
  • 2Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania
JAMA Oncol. 2021;7(5):784-785. doi:10.1001/jamaoncol.2021.0128

In Reply We appreciate the thoughtful comments from Przepiorka and colleagues regarding the potential application of measurable residual disease (MRD) as a surrogate marker for drug development and approval. We agree with them that quantitation and standardization of MRD assays are important in establishing them as surrogate markers of outcome. As they suggest, the magnitude of benefit for achieving an MRD negative status is likely dependent on its quantitation and reproducibility across different institutions. However, the intent of our systematic review and meta-analysis1 was to demonstrate the powerful predictive ability of detection of residual leukemia across various assays used to date. We agree that even when using the same assay, different laboratories may arrive at different quantities of residual disease, but we would like to point out that in some studies, any level of MRD was associated with inferior outcomes compared with no MRD.2 Indeed, these thresholds are generally arbitrary with limited consensus among the experts on the best cutoff point for any of the assays. Studies with very valid and sensitive assays arrive at different thresholds for “MRD negativity”; this is particularly true for comparison across techniques, such as flow cytometry and molecular assays. Furthermore, the predictive ability of the currently available assays is by no means absolute, with many patients relapsing despite being MRD negative and some remaining in long-term disease-free survival despite having been MRD positive. However, as we have shown in our meta-analysis,1 we believe that using current technology, it is no longer a point of contention that achieving a response with no detectable MRD by any of the available assays (performed by a laboratory with adequate expertise) is superior to a response with persistent MRD. Przepiorka and colleagues also notably pointed out that various morphological response states may be associated with the magnitude of benefit of achieving negative MRD.3 In our report,1 although many of the studies included did not restrict their cohort to patients in “true” complete remission, the vast majority of patients were in complete remission at the time of MRD assessment (particularly in studies looking at postinduction time points).

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