The MEASURE Genome Atlas: Acute Myeloid Leukemia at diagnosis and complete remission
Abstract
Abstract Introduction: Genetic profiling is essential for optimal management of patients with acute myeloid leukemia (AML). Whole genome sequencing (WGS) has been proposed as a replacement for the multiple testing modalities currently in use but has not yet been widely adopted. WGS may also reveal new or underappreciated biology with potential utility in diagnostics and drug discovery. We report here, from 18 major cancer centers in the USA, the largest cohort of WGS from AML diagnosis (Dx) and complete remission (CR) described to date. Methods: Adults with AML in CR screened for the prospective multicenter national protocol MEASURE (NCT05224661) were selected based on availability of stored Dx material. WGS data was generated (Illumina NovaSeq) centrally and interpreted independently to clinical molecular and cytogenetics reports. Dx-only and CR-only analysis used the DRAGEN 4.4 Heme WGS pipeline on Illumina Connected Analytics and was interpreted using Illumina Connected Insights 5.1. Paired Dx-CR analysis used DRAGEN MRD-Fingerprint and Somatic pipelines. Filters were established to identify variants in AML-related genes and cancer hotspots. Results: Of 255 patients (pts) included, 53% were male, median age was 59 years (range: 19-79y) and 70% were non-Hispanic White. Most (89.4%) were in first CR, and 26.7% had received induction less intensive than traditional cytotoxic chemotherapy. Considerable heterogeneity in clinical genetic profiling approaches between centers was observed. Median WGS depth was 117X (range: 59–300X) at Dx and 37X (range: 24–89X) at CR. Dx-only WGS was able to detect the prognostic and predictive genomic features reported by clinical testing (488/527, 93%) and resulted in identical ELN 2022 prognostic risk classifications in most pts (237/255, 93%). In 11 pts (4.3%) however classification would be refined due to additional information from WGS, including 3 pts downstaged to favorable risk. WGS frequently identified alterations commonly missed by standard clinical testing. KMT2A partial tandem duplication (KMT2A-PTD), reported as associated with adverse outcomes, was observed in 34 pts (13%). Tandem duplications were also identified in additional genes related to AML, including UBTF, RUNX1, EZH2, and CCDC26. Cytogenetically cryptic gene fusions were observed in 8 pts, involving NUP98 (5 pts), KMT2A (2 pts), and MECOM (1 pt). Copy-neutral loss of heterozygosity (CN-LOH) was observed in chromosome hotspots (eg: 2p, 11, 13q, 21q) in 43 pts (16.9%), overlapping with oncogenic variants in 30 of 43 pts (69.8%) including FLT3, RUNX1, DNMT3A, KMT2A, and WT1. Additional features were found, including microdeletions overlapping with AML driver genes, MYC amplification, deep intronic cryptic splice variants, and signatures of chromothripsis. In the subset of 109 pts with cytogenetically normal AML, defined by a successful clinical metaphase cytogenetics test yielding a normal result, WGS identified structural abnormalities in 51 pts (47%) including KMT2A-PTD (22 pts), CN-LOH (20 pts), microdeletions (7 pts), cryptic fusion genes (5 pts), chromosomal gains or losses (2 pts), and a translocation (1 pt). At CR, WGS profiling identified both persistent and emerging variants. A higher proportion of the less-intensively treated pts had at least one persistent mutation at CR (57.6% vs 33.3%; p<0.001) in genes recommended by ELN for testing at Dx. Oncogenic variants detected only in CR were seen in 30 pts, including PPM1D (7 pts), MPL (3 pts), U2AF1 (3 pts) and IDH1 and BRAF (1pt each). Finally, Dx-CR matched calling enabled the discovery of novel diagnostic features directly correlated with leukemic portion, including segregated variations from pre-leukemia clonal hematopoiesis and variations in regulatory regions not captured by standard clinical testing. Conclusions: WGS is a single assay for the comprehensive AML genomic profiling required for diagnostic, prognostic, and predictive purposes. In this multicenter study, WGS revealed many structural and copy number abnormalities missed by current standard of care clinical testing, including potential therapeutic targets. The rate of tandem duplications identified by deep WGS was higher than has been reported previously by other methodologies. WGS can provide novel insights into AML disease biology, prognostication, treatment effects, MRD targets, and potential therapeutic susceptibilities. The MEASURE Genome Atlas is a unique new resource for the AML community.
Article Details
Authors (64)
Kai Yu
Laura Dillon
1Fralin Biomedical Research Institute, Virginia Tech FBRI Cancer Research Center, Washington, United States
Jesse Tettero
1Amsterdam University Medical Center, Department of Hematology, Amsterdam, Netherlands
Gege Gui
1Fralin Biomedical Research Institute, Virginia Tech Fralin Biomedical Research Institute Cancer Research Center, Washington, DC
Rasha Al-Ali
1Fralin Biomedical Research Institute, Virginia Tech FBRI Cancer Research Center, Washington, United States
Michael Grunwald
4Division of Leukemia, Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NC
Elizabeth Krakow
3Fred Hutch Cancer Center, Seattle, United States
Elizabeth Griffiths
8Roswell Park Comprehensive Cancer Center, Buffalo, United States
Alexandra Gomez-Arteaga
7Weill Cornell Medicine, New York, NY
Rahul Vedula
1Dana-Farber Cancer Institute, Medical Oncology, Boston, United States
Melhem Solh
14Bone marrow Transplant Group of Georgia, Atlanta, United States
Amandeep Salhotra
2Division of Leukemia, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CA
Nelli Bejanyan
Moffitt Cancer Center, Tampa, Florida, United States
Lori Muffly
1Division of Blood and Marrow Transplantation & Cellular Therapy, Stanford University, Stanford, CA
Antonio Jimenez-Jimenez
11University of Miami, Sylvester Comprehensive Cancer Center, Miami, United States
Michael Drazer
1University of Chicago, Chicago, United States
Yi-Bin Chen
1Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
Aaron Logan
1University of California, San Francisco, Hematology, Blood and Marrow Transplantation, and Cellular Therapy Program, San Francisco, United States
Reena Jayani-Kosarzycki
1Vanderbilt University Medical Center, Department of Hematology/Oncology, Nashville, United States
Sophia Balderman
1Cleveland Clinic, Internal Medicine, Cleveland, United States
James Blachly
1The Ohio State University Comprehensive Cancer Center, Columbus, United States
Brian Shaffer
2Memorial Sloan Kettering Cancer Center, New York, United States
Marc Schwartz
Cecilia Yeung
Lawrence Druhan
1Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Charlotte, United States
Vanessa Kennedy
2Stanford University School of Medicine, Medicine, Division of Blood and Marrow Transplantation & Cellular Therapy, Stanford, United States
Sandeep Gurbuxani
3University of Chicago, Chicago, United States
Melissa Tjota
12University of Chicago, Chicago, United States
Max Smith
3Fred Hutch Cancer Center, Seattle, United States
Farah Sahoo
3Fred Hutch Cancer Center, Seattle, United States
Dylan Barfield
20Illumina Inc., San Diego, United States
Jim Guo
20Illumina Inc., San Diego, United States
James Han
20Illumina Inc., San Diego, United States
Jason Hu
Heejoon Jo
Vidya Kudlingar
20Illumina Inc., San Diego, United States
Wilfred Li
20Illumina Inc., San Diego, United States
Yutong Qiu
School of Chemistry, Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi’an Key Laboratory of Sustainable Energy Materials Chemistry
Pratheesh Sathyan
20Illumina Inc., San Diego, United States
Sean Truong
3Illumina Inc., San Diego, United States
Severine Catreux
3Illumina Inc., San Diego, United States
Sam Ng
20Illumina Inc., San Diego, United States
Khai Luong
20Illumina Inc., San Diego, United States
Yunjiao Zhu
20Illumina Inc., San Diego, United States
Reem Bahr
2Fralin Biomedical Research Institute, Virginia Tech Fralin Biomedical Research Institute, Cancer Research Center, Washington, DC
Jamie Diemer
21National Institutes of Health, Bethesda, United States
Jianqun Kou
2CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, United States
Stephanie Bo-Subait
2CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, United States
Jackie Bjerke
22National Marrow Donor Program (NMDP) and Center for International Blood and Marrow Transplant Research (CIBMTR), Minneapolis, United States
Steven Devine
24National Marrow Donor Program, Minneapolis, United States
Bergetta Dietel
22National Marrow Donor Program (NMDP) and Center for International Blood and Marrow Transplant Research (CIBMTR), Minneapolis, United States
Christina Ferrone
23National Cancer Institute, Bethesda, United States
Gabrielle Giammarino
22National Marrow Donor Program (NMDP) and Center for International Blood and Marrow Transplant Research (CIBMTR), Minneapolis, United States
Emily Heying
22National Marrow Donor Program (NMDP) and Center for International Blood and Marrow Transplant Research (CIBMTR), Minneapolis, United States
Emily Kolb
22National Marrow Donor Program (NMDP) and Center for International Blood and Marrow Transplant Research (CIBMTR), Minneapolis, United States
Danielle O'Donnell Vitali
22National Marrow Donor Program (NMDP) and Center for International Blood and Marrow Transplant Research (CIBMTR), Minneapolis, United States
Wael Saber
3CIBMTR® (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, United States
Stephen Spellman
10CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, United States
Brenna Tesch
22National Marrow Donor Program (NMDP) and Center for International Blood and Marrow Transplant Research (CIBMTR), Minneapolis, United States
Jenny Vogel
22National Marrow Donor Program (NMDP) and Center for International Blood and Marrow Transplant Research (CIBMTR), Minneapolis, United States
Stephanie Waldvogel
22National Marrow Donor Program (NMDP) and Center for International Blood and Marrow Transplant Research (CIBMTR), Minneapolis, United States
Syreeta Weatherspoon
22National Marrow Donor Program (NMDP) and Center for International Blood and Marrow Transplant Research (CIBMTR), Minneapolis, United States
Jeffery Auletta
2CIBMTR® (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, United States
Christopher Hourigan
13Fralin biomedical research institute, Virgina Tech University, Roanoke, United States