NEW YORK (GenomeWeb) – The presence or absence of tumor DNA after treatment appears to be an independent prognostic marker for individuals with a common acute myeloid leukemia subtype, according to a study published online yesterday in the New England Journal of Medicine.
Members of the UK National Cancer Research Institute's AML Working Group used a PCR-based approach to search for NPM1 gene mutations — a marker for minimal residual disease (MRD) in the standard-risk AML cases considered — in bone marrow or blood samples from 346 individuals who had received at least two rounds of chemotherapy. They also profiled mutation patterns in a subset of the diagnostic and relapse tumor samples using a 51-gene panel.
The mutation-focused analysis unearthed too much tumor molecular heterogeneity for a prognostic analysis, the team reported, identifying more than 150 molecular sub-groups for 223 cases. But the presence of MRD after treatment appeared to be significantly tied to risk of both relapse and death within three years — findings the group verified in 91 more AML cases.
"[O]ur study involving a large cohort of intensively treated patients showed that the presence of minimal residual disease predicted relapse and was superior to the baseline diagnostic molecular genetic markers that are currently used to guide decisions with respect to stem-cell transplantation," the authors wrote.
The current results didn't see a survival benefit for individuals with post-treatment MRD who had received more intensive transplantation treatment, though the researchers noted that only a handful of the available cases fit the bill for that analysis.
As part of the NCRI AM17 trail, the researchers did digital RT-qPCR-based on 902 bone marrow samples and 1,667 peripheral blood samples collected from 364 AML cases classified as standard-risk based on the presence of NPM1 mutations.
The team assessed a median of six samples per individual, ranging from samples collected at diagnosis to those taken after treatment and at relapse, if applicable.
For individuals with detectable tumor DNA after treatment, the team saw that the risk of AML recurrence was significantly higher, with 82 percent of patients experiencing relapse. In contrast, relapse risk in the MRD-free group appeared to be around 30 percent.
And while the three-year survival rate was 75 percent for AML patients with no detectable MRD after treatment, less than one-quarter of those with post-treatment MRD survived for three years or more.
In samples analyzed sequentially from individuals who developed disease again after treatment, the researchers noted that levels of mutated NPM1 crept up in blood or bone marrow samples in the time leading up to relapse.
Although the presence of NPM1 mutations served as a marker for relapse risk in both the discovery and validation group, the team did not see the same pattern for all of the mutations. For example, the results pointed to pre-leukemic mutation persistence in some individuals with lasting remission after treatment.
In a related NEJM editorial, Medical College of Wisconsin and Children's Hospital of Wisconsin pediatric hematology and oncology researcher Michael Burke discussed the results in the context of other leukemia types affecting adults and children.
He noted that "with the ability to reclassify standard-risk or low-risk patients as high-risk on the basis of the persistent expression of mutant NPM1 transcripts, it may be possible that stem-cell transplantation is a better approach in patients who otherwise would be treated with chemotherapy alone and that transplantation may be avoidable in high-risk patients who have no evidence of minimal residual disease."
While he cautioned that additional research is needed to test that possibility, Burke noted that MRD-based risk stratification has already gained traction as a prognostic marker in other types of leukemia, including acute lymphoblastic leukemia and childhood AML.