MRD predictive outcomes AML serve surrogate endpoint new ClinicalTrials

Measurable (formerly minimal) residual disease, or MRD, refers to low levels of leukemia that cannot be detected by morphologic assessment alone. While not a new concept in the management of patients with leukemias, MRD testing in the management of acute myeloid leukemia (AML) has recently gained increased attention among disease-state experts. In a large-cohort meta-analysis conducted by Nicholas J. Short, MD, et al, and published in JAMA Oncology, achievement of MRD negativity was associated with superior disease-free survival (DFS) and overall survival (OS) in patients with AML.

Dr Short and colleagues evaluated the role of MRD through various methods and reported significant differences in DFS and OS on the basis of MRD positivity vs negativity. Their analysis showed that estimated 5-year DFS was 64% for MRD-negative and 25% for MRD-positive patients; estimated OS was 68% for MRD-negative and 34% for MRD-positive patients. The difference in 5-year restricted mean survival time for MRD-negative and MRD-positive groups was 15.37 months for OS and 19.61 months for DFS. The association between MRD and survival was observed across ages, disease subtypes, time of assessment, specimen source, and most MRD detection methods. (The MRD association using cytogenetics/fluorescence in situ hybridization [FISH] was not significant, but the authors suggested this may be explained in part by the fact that only 2 studies using that method were included in the analysis. Also, cytogenetics/FISH has the lowest sensitivity among the methods considered.)

In an Invited Commentary to the JAMA Oncology publication, Dr Deepa Jeyakumar and Dr Susan O’Brien also discussed the growing role of MRD, pointing out that the current “3+7” approach to AML treatment has not changed in over 40 years, even though it cures only a minority of patients. Therefore, more-rapid development of therapies for AML is needed. In both articles, the authors concluded that MRD testing may be beneficial as a surrogate endpoint for clinical trials in AML to allow for more-rapid evaluation of the efficacy of novel therapies. However, Dr Short and colleagues also suggested that accelerated approval of a new therapeutic on the basis of an intermediate endpoint such as MRD would require eventual confirmation using traditional endpoints such as OS.

High level
The magnitude of benefit of MRD negativity in DFS and OS was substantial. Therefore, achievement of MRD negativity is an important endpoint across clinical contexts, including the most relevant MRD detection methods currently used in clinical practice and research. Frequently used methods to assess MRD include multicolor flow cytometry, which is the most commonly used method in the US, as well as next-generation sequencing and polymerase chain reaction. These methods vary in their sensitivity and applicability to different patient populations, so the optimal MRD assay and timing of assessment should be guided by each specific clinical scenario.

The poor outcomes associated with MRD positivity emphasize the need for novel therapeutic approaches for these patients. Evidence suggests that MRD negativity may be an effective measure of treatment efficacy in AML in clinical trials to facilitate drug development and accelerated drug approval. Surrogate endpoints help to get effective therapies to patients in a timely manner while still confirming the benefit of those agents with an assessment of survival. As new agents are approved on the basis of this endpoint, there will be an increased need for incorporation of MRD testing into protocols for AML management.

Ground level
In the original article, Dr Short and colleagues found that timing of MRD negativity is a consistent predictor of outcomes. These findings emphasize the need for incorporation of MRD analysis into AML patient care and provide additional, quantitative support for consensus guidelines to establish complete remission without MRD as the optimal response in AML. With regard to specimen source, Dr Short and colleagues reported that peripheral blood assessment of MRD better distinguished MRD-positive and MRD-negative groups compared with bone marrow assessment of MRD.

The results also underscore the need for new approaches to AML treatment, such as the use of hypomethylating agents for MRD-positive patients and novel therapies in patients unable to achieve MRD negativity with standard care.