Measurable residual disease monitoring for patients with acute myeloid leukemia following hematopoietic cell transplantation using error corrected hybrid capture next generation sequencing


Autoři: Vidya Balagopal aff001;  Andrew Hantel aff002;  Sabah Kadri aff001;  George Steinhardt aff001;  Chao Jie Zhen aff001;  Wenjun Kang aff003;  Pankhuri Wanjari aff001;  Lauren L. Ritterhouse aff001;  Wendy Stock aff002;  Jeremy P. Segal aff001
Působiště autorů: Department of Pathology, Division of Genomic and Molecular Pathology, The University of Chicago, Chicago, Illinois, United States of America aff001;  Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois, United States of America aff002;  Center for Research Informatics, The University of Chicago, Chicago, Illinois, United States of America aff003
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224097

Souhrn

Improved systems for detection of measurable residual disease (MRD) in acute myeloid leukemia (AML) are urgently needed, however attempts to utilize broad-scale next-generation sequencing (NGS) panels to perform multi-gene surveillance in AML post-induction have been stymied by persistent premalignant mutation-bearing clones. We hypothesized that this technology may be more suitable for evaluation of fully engrafted patients following hematopoietic cell transplantation (HCT). To address this question, we developed a hybrid-capture NGS panel utilizing unique molecular identifiers (UMIs) to detect variants at 0.1% VAF or below across 22 genes frequently mutated in myeloid disorders and applied it to a retrospective sample set of blood and bone marrow DNA samples previously evaluated as negative for disease via standard-of-care short tandem repeat (STR)-based engraftment testing and hematopathology analysis in our laboratory. Of 30 patients who demonstrated trackable mutations in the 22 genes at eventual relapse by standard NGS analysis, we were able to definitively detect relapse-associated mutations in 18/30 (60%) at previously disease-negative timepoints collected 20–100 days prior to relapse date. MRD was detected in both bone marrow (15/28, 53.6%) and peripheral blood samples (9/18, 50%), while showing excellent technical specificity in our sample set. We also confirmed the disappearance of all MRD signal with increasing time prior to relapse (>100 days), indicating true clinical specificity, even using genes commonly associated with clonal hematopoiesis of indeterminate potential (CHIP). This study highlights the efficacy of a highly sensitive, NGS panel-based approach to early detection of relapse in AML and supports the clinical validity of extending MRD analysis across many genes in the post-transplant setting.

Klíčová slova:

Acute myeloid leukemia – Bone marrow – Disease surveillance – Flow cytometry – Mutation detection – Next-generation sequencing – Point mutation – Polymerase chain reaction


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Článek vyšel v časopise

PLOS One


2019 Číslo 10