The use of high sensitivity DNA sequencing tests to measure residual disease in AML could improve identification of patients at risk for relapse or death.
“In acute myeloid leukemia (AML), the association between measurable residual disease (MRD)—leukemic cells remaining in a patient during clinical remission but not detectable by standard clinical assessments—and increased risk for relapse and death has been known for years,” explains Laura W. Dillon, PhD, FACMG. “Despite this, it has been difficult for clinicians to translate this association into actionable knowledge. Although advances in DNA sequencing technology have allowed for the development of better tools for measuring residual disease, a need existed to conduct a definitive study using the same DNA sequencing assay to determine which mutations, and at what level of disease burden, are prognostic in a large cohort of patients.”
The study team, led by Christopher S. Hourigan, MD, DPhil, senior investigator and chief of the Laboratory of Myeloid Malignancies, hypothesized that the presence of residual AML mutations—as detected by DNA sequencing in the blood of patients with AML in first remission prior to allogenic hematopoietic cell transplant (allo-HCT)—would identify those patients at increased risk for relapse and death compared with those without these DNA variants.
“We chose to focus on the time of remission just prior to hematopoietic cell transplant, currently the only curative therapy for AML, as this is a critical clinical decision-making timepoint,” Dr. Dillon notes.
Measurable Residual Disease Is Key for Targeted Treatment
For a study published in JAMA, Dr. Dillon and colleagues utilized pre-transplant remission blood samples and clinical outcomes information collected by The Center for International Blood and Marrow Transplant (CIBMTR), which gathers clinical data for all patients undergoing allo-HCT in the United States. “Armed with data on 1,075 patients with AML undergoing allo-HCT across 111 sites during a 6-year period, we were able to assess the presence of residual AML mutations during remission using sensitive DNA sequencing techniques,” Dr. Dillon says. “Splitting the patients into discovery and validation cohorts allowed us to definitively determine which mutations were linked with increased risk for relapse and death.”
A key aspect of their findings was the impact of residual NPM1 and/or FLT3 internal tandem duplication (FLT3-ITD) mutations during remission on patient outcomes (Figure). “Those patients who achieve a complete remission are told they have, on average, approximately a 30% risk for relapse after transplant,” Dr. Dillon notes. “We observed that one out of every six of these patients has around a 70% risk for relapse while the remaining five have much lower risk, around 20%.”
The inclusion of MRD testing for these mutations would allow physicians to appropriately counsel patients and tailor treatment regimens, the study group points out.
The clinical characteristics of 454 patients with AML included in the discovery cohort matched those of the 621 patients with AML included in the validation cohort. “The power of this study, the largest of its kind, is that by utilizing two independent cohorts of patients treated at more than 100 transplant sites, we can definitively show that identifying residual NPM1 and/or FLT3-ITD mutations in the blood of patients with AML in first complete remission prior to first allo-HCT is linked with increased risk for relapse and death,” Dr. Dillon says.
A Need for Precision Medicine in AML and Other Cancers
The study team points out that current testing is not adequately assessing the risk for relapse and death in patients with AML. “The incorporation of highly sensitivity DNA sequencing tests for FLT3-ITD and NPM1 to measure MRD could improve identification of patients with AML in need of additional therapy or modified transplant conditioning regimens to decrease their risk for relapse and death,” Dr. Dillon says.
This research, she adds, highlights the need for precision medicine approaches in AML and other fatal cancers. “There are many unanswered questions in the field of AML MRD that can only be answered through large, coordinated efforts,” Dr. Dillon says. “CIBMTR and the National Marrow Donor Program have already started a follow-up prospective clinical protocol, MEASURE, which has begun to enroll patients across the United States. This will not only validate some of the findings of the pre-MEASURE study in a prospective manner, but will work to identify additional targets, testing strategies, and the utility of post-transplant MRD monitoring.”
Dr. Dillon and colleagues concur that their goal is to improve the performance of AML MRD testing and to establish a framework for future evidence-based, multicenter clinical trials within the MEASURE network that can test novel interventions based on MRD measurements to improve patient outcomes.
