Detection, prevention and treatment of acute myeloid leukemia (AML) relapse.

National Heart, Lung, And Blood Institute

Investigators

Linked publications & trials

Abstract

The fundamental interest of the Laboratory of Myeloid Malignancies is the detection, prevention, and treatment of acute myeloid leukemia (AML) relapse. Our work has focused on the development of molecular and genomic laboratory methods (Measurable Residual Disease, MRD) to predict development or recurrence of myeloid malignancy and, at times, clinical trials of novel biomarker and immunotherapy approaches. Foundational to our objective has been the development of high sensitivity biomarkers for residual AML in those patients who have been treated to apparent remission but remain at risk of clinical relapse. Previously we have demonstrated the ability to risk stratify AML patients into groups with either high or low leukemic relapse rates, using DNA-sequencing of a remission blood sample from immediately prior to allogeneic hematopoietic cell transplantation (alloHCT). We have also shown that therapy intensification may mitigate the negative prognostic impact of detectable residual AML. The work of the past year focused largely on a large nationwide project, Pre-MEASURE, evaluating standard clinical flow cytometry performed locally at 111 transplant centers compared with our centralized DNA-sequencing approach in 1075 patients with AML in first remission who received a first alloHCT between 2013-2019 (1,2). Prevention of relapse in adults with AML in first remission is the most common indication for alloHCT in the United States. The Pre-MEASURE study demonstrated that pre-transplant blood testing by DNA-sequencing could identify approximately 1 in 6 patients, with the most common AML mutations FLT3-ITD and/or NPM1, who are at a very high risk of relapse and death when treated according to the current clinical standard of care. Specifically, persistence of NPM1 mutations at a variant allele fraction (VAF) of 0.01% or higher were found in the blood of 15.3% of adult patients in first remission before first allogeneic transplant and were associated with significantly higher relapse (MVA, HR: 4.9 (3.5 to 7), p:<0.001) and death (MVA, HR: 2.9 (2.2 to 4.0), p:<0.001) post-transplant. Persistence of FLT3-ITD in blood at VAF 0.01% or higher were found in 14% of adult patients in first remission before first allogeneic transplant and were associated with significantly higher relapse (MVA, HR: 4.2 (3.1 to 5.7), p:<0.001) and death (MVA, HR: 2.6 (2.0 to 3.6), p:<0.001). Overall, the continued persistence of mutated NPM1 and/or FLT3-ITD in remission was detected in the pre-transplant blood of 142 of 822 (17.3%) patients with those mutations at initial diagnosis and was associated with increased relapse (62% vs. 23%, p:<0.001) and worse survival (36% vs. 66%, p: <0.001) at three years compared with those testing negative. Furthermore, it was shown that currently used clinical testing using flow cytometry was suboptimal in identifying such patients and added no prognostic information to the results of centralized DNA-sequencing based AML MRD testing. Work is now ongoing to validate and implement DNA-based AML MRD testing nationwide. Our focus on AML MRD has also continued in other domains, including the demonstration of the clinical utility of duplex error-suppression methodology to track kinetics of somatic mutation clearance in adults with newly diagnosed AML undergoing intensive induction chemotherapy (3), development of single-cell sequencing approaches (4), and other clinical informing work in AML MRD (5-8). While detection of high-risk residual disease in patients with AML in an apparent clinical remission remains the primary objective, a longer-term aspiration of our group is the development of more effective therapy for those with AML who are refractory to standard approaches (9). More broadly we have also continued to work on the genomics of myeloid malignancy risk (10-12), particularly in the context of allogeneic transplantation (13,14) as well as the biology and treatment of myelodysplastic syndrome (15,16) and AML (17-20) more generally. In summary, the primary interest of the Myeloid Malignancies Section remains the detection, prevention, and treatment of AML relapse, in particular the development of molecular and genomic laboratory methods to predict development or recurrence of myeloid malignancy. Going forward we will continue to integrate genomic and immunophenotypic approaches on carefully annotated clinical samples to better understand myeloid malignancy and will also expand the evidence for clinical utility of AML MRD testing using molecular testing of large informative patient cohorts.