MRD Negativity Indicative of Improved OS, DFS in AML, Study Says

October 15, 2020

Based on the findings, the researchers are arguing that minimal residual disease (MRD) should be considered as a clinical trial endpoint.

Minimal residual disease (MRD) is increasingly being recognized as an important prognostic marker in several cancers, including acute myeloid leukemia (AML). Now, new findings from a systematic review are indicating that MRD negativity is associated with improved long-term survival.1

Consisting of more than 11,000 patients, the systematic review of 81 studies demonstrated that patients who achieved MRD negativity had favorable both overall survival (OS) and disease-free survival (DFS), with MRD-negative patients having 5-year OS of 68% and MRD-positive patients having 34% 5-year OS.

Similarly, at 5 years, MRD-negative patients had an estimated DFS of 64% while MRD-positive patients had an estimated DFS of 25%.

“The magnitude of benefit associated with achieving MRD negativity was substantial, corresponding to a 64% reduction in the risk of death for MRD-negative patients,” wrote the researchers. “The results of this meta-analysis thus provide quantitative support for consensus guidelines that consider achievement of complete remission without MRD as the optimal response in AML.”

Based on these findings the researchers argue that the marker should be considered as a clinical trial endpoint, as it may allow for a quicker indication of the efficacy of novel therapies and lead to accelerated approval.

In an accompanying commentary2, researchers echoed the potential benefit of including MRD as a surrogate endpoint in clinical trials, writing that “Surrogate end point may aid in getting effective therapies to patients expeditiously while still confirming the benefit of these agents with an assessment of overall survival.”

However, the researchers of the systematic analysis cautioned that accelerated approvals based on intermediate endpoints, like MRD, are contingent on confirmatory trials using traditional efficacy endpoints, such as OS.

Looking further, the researchers found that improved long-term survival was prevalent for all subgroups they analyzed, with the exception of MRD determined by cytogenetics or fluorescent in situ hybridization. According to the researchers, this could be explained by the fact that just 2 studies using this method were included in the analysis and the method has the lowest sensitivity among those analyzed.

The prognostic marker was associated with improved OS and DFS regardless of age group (adult or pediatric), MRD assessment time point (induction, during consolidation, or after consolidation), AML subgroup (CBF or non-CBF), or specimen source (bone marrow or peripheral blood).

“Multivariate analysis further supported the benefit of MRD negativity across these subgroups,” noted the researchers, adding, “Nonetheless, the optimal MRD assay and timing of assessment should be guided by the specific clinical scenario. For example, while PCR for WTI expression provided useful MRD information in our analysis, consensus recommendations advise against PCR for WTI as a routine marker of MRD owing to its low sensitivity and specificity unless no other MRD test is available.”

References

1. Short N, Zhou S, Fu C, et al. Association of measurable residual disease with survival outcomes in patients with acute myeloid leukemia: a systematic review and meta-analysis. JAMA Onc. Published online October 8, 2020. doi: 10.1001/jamaoncol.2020.4600.

2. Jeyakumar D, O’Brien S. Minimal residual disease in acute myeloid leukemia. JAMA Onc. Published online October 8, 2020. doi: 10.1001/jamaoncol.2020.4599.