DNA Sequencing to Detect Residual Disease in Adults with Acute Myeloid Leukemia Prior to Hematopoietic Cell Transplant

Laura W. Dillon, Gege Gui, Kristin M. Page, Niveditha Ravindra, Zoë C. Wong, Georgia Andrew, Devdeep Mukherjee, Scott L. Zeger, Firas El Chaer, Stephen Spellman, Alan Howard, Karen Chen, Jeffery Auletta, Steven M. Devine, Antonio Martin Jimenez Jimenez, Marcos J.G. De Lima, Mark R. Litzow, Partow Kebriaei, Wael Saber, Daniel J. WeisdorfChristopher S. Hourigan

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Importance: Preventing relapse for adults with acute myeloid leukemia (AML) in first remission is the most common indication for allogeneic hematopoietic cell transplant. The presence of AML measurable residual disease (MRD) has been associated with higher relapse rates, but testing is not standardized. Objective: To determine whether DNA sequencing to identify residual variants in the blood of adults with AML in first remission before allogeneic hematopoietic cell transplant identifies patients at increased risk of relapse and poorer overall survival compared with those without these DNA variants. Design, Setting, and Participants: In this retrospective observational study, DNA sequencing was performed on pretransplant blood from patients aged 18 years or older who had undergone their first allogeneic hematopoietic cell transplant during first remission for AML associated with variants in FLT3, NPM1, IDH1, IDH2, or KIT at 1 of 111 treatment sites from 2013 through 2019. Clinical data were collected, through May 2022, by the Center for International Blood and Marrow Transplant Research. Exposure: Centralized DNA sequencing of banked pretransplant remission blood samples. Main Outcomes and Measures: The primary outcomes were overall survival and relapse. Day of transplant was considered day 0. Hazard ratios were reported using Cox proportional hazards regression models. Results: Of 1075 patients tested, 822 had FLT3 internal tandem duplication (FLT3-ITD) and/or NPM1 mutated AML (median age, 57.1 years, 54% female). Among 371 patients in the discovery cohort, the persistence of NPM1 and/or FLT3-ITD variants in the blood of 64 patients (17.3%) in remission before undergoing transplant was associated with worse outcomes after transplant (2013-2017). Similarly, of the 451 patients in the validation cohort who had undergone transplant in 2018-2019, 78 patients (17.3%) with residual NPM1 and/or FLT3-ITD variants had higher rates of relapse at 3 years (68% vs 21%; difference, 47% [95% CI, 26% to 69%]; HR, 4.32 [95% CI, 2.98 to 6.26]; P <.001) and decreased survival at 3 years (39% vs 63%; difference, -24% [2-sided 95% CI, -39% to -9%]; HR, 2.43 [95% CI, 1.71 to 3.45]; P <.001). Conclusions and Relevance: Among patients with acute myeloid leukemia in first remission prior to allogeneic hematopoietic cell transplant, the persistence of FLT3 internal tandem duplication or NPM1 variants in the blood at an allele fraction of 0.01% or higher was associated with increased relapse and worse survival compared with those without these variants. Further study is needed to determine whether routine DNA-sequencing testing for residual variants can improve outcomes for patients with acute myeloid leukemia..

Original languageEnglish (US)
Pages (from-to)745-755
Number of pages11
JournalJAMA
Volume329
Issue number9
DOIs
StatePublished - Mar 7 2023

Bibliographical note

Funding Information:
Funding/Support: This work was supported by the Intramural Research Program of the NHLBI and by the National Institutes of Health Director’s Challenge Innovation Award . Sequencing was performed in the NHLBI Intramural DNA Sequencing and Genomics Core . Digital droplet polymerase chain reaction (PCR) was performed in the National Cancer Institute (NCI) Intramural CCR Genomics Core . The Center for International Blood and Marrow Transplant Research (CIBMTR) is supported primarily by Public Health Servic e grant U24CA076518 from the NCI, NHLBI, and the National Institute of Allergy and Infectious Diseases (NIAID); grants U24HL138660 and U24HL157560 from the NHLBI and NCI ; grant U24CA233032 from the NCI; grant OT3HL147741 and U01HL128568 from the NHLBI ; grants HHSH250201700005C, HHSH250201700006C, and HHSH250201700007C from the Health Resources and Services Administration (HRSA); and grants N00014-20-1-2832 and N00014-21-1-2954 from the Office of Naval Research .

Publisher Copyright:
© 2023 by the Author(s).

PubMed: MeSH publication types

  • Journal Article
  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

Fingerprint

Dive into the research topics of 'DNA Sequencing to Detect Residual Disease in Adults with Acute Myeloid Leukemia Prior to Hematopoietic Cell Transplant'. Together they form a unique fingerprint.

Cite this