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

National Heart, Lung, And Blood Institute

Investigators

Linked publications, trials & patents

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 clinical trials of novel biomarker and immunotherapy approaches, and the development of molecular and genomic laboratory methods (Measurable Residual Disease, MRD) to predict development or recurrence of myeloid malignancy. 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 (using ultra-deep DNA-sequencing) into groups with either high or low leukemic relapse rates, based on a pre-transplant peripheral blood sample, prior to allogeneic hematopoietic cell transplantation (alloHCT). We have also shown that therapy intensification may mitigate the negative prognostic impact of detectable residual AML. Our work on AML MRD has continued (1-5) including the development of novel genomic tools that may be used in assessment of AML MRD (6,7). 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. While the focus on the laboratory is currently laboratory-based translational research, in the past year we have reported on our previously conducted clinical trial (NCT02996474, PD-AML) testing the first-in-human combination of pembrolizumab and decitabine (J Immunother Cancer, 2022, Ref 8). In a single-arm open-label 10-subject pilot feasibility study, in adult patients with refractory or relapsed AML, we found this novel combination was clinically feasible. Translational correlative work demonstrated that immunological changes (identified using T cell receptor sequencing as well as single-cell immunophenotypic and RNA expression analyses) following PD-1 blockade were observed in patients experiencing immune-related adverse events but no such distinctive immune changes were detectable in those experiencing a measurable antileukemic response during treatment. An extramural collaboration on AML therapeutic discovery also resulted in publication this year (9). We have also continued to collaborate with intramural colleagues at the NIH Clinical Center who treat patients with non-malignant hematological conditions of whom a subset may develop myeloid malignancy (10) and with extramural colleagues on alloHCT for acute leukemia (11-17) and AML more generally (18). 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.