Among patients with acute myeloid leukaemia (AML) in first remission prior to allogeneic haematopoietic cell transplant (HCT), the persistence of FLT3 internal tandem duplication (FLT3-ITD) 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 variants detected.
In discovery set of 371 patients with AML in first complete remission who received a transplant from 1 March 2013 through 31 December and validation set of 451 patients who received a transplant from 1 January 2018 through 14 February 2019, the presence of residual FLT3-ITD and/or NPM1 DNA variants before transplant were associated with significantly increased rates of relapse and significantly worse survival at 3 years, compared with those without these variants. Findings from DNA sequencing of blood in adults with AML are published by Laura W. Dillon of the US National Institutes of Health in Bethesda, MD, US, and colleagues on 7 March 2023 in JAMA.
The authors wrote in the background that preventing relapse for adults with AML in first remission is the most common indication for allogeneic HCT. The presence of AML measurable residual disease has been associated with higher relapse rates, but testing is not standardised. The aim of this study was to determine whether DNA sequencing can detect residual variants in the blood of adults with AML in first remission before allogeneic HCT that identify patients at increased risk of subsequent relapse and death.
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 HCT during first remission for AML associated with variants in FLT3, NPM1, IDH1, IDH2, or KIT at 111 treatment sites from 2013 through 2019. Clinical data were collected, through May 2022, by the Center for International Blood and Marrow Transplant Research in Minneapolis, MN, US. The primary outcomes were overall survival and relapse. Day of transplant was considered day 0. Hazard ratios (HRs) were reported using Cox proportional hazards regression models.
Of 1075 patients tested, 822 had FLT3-ITD and/or NPM1 mutated AML. Median age was 57.1 years and 54% of patients were 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 in 2013-2017 period was associated with worse outcomes after transplant. 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% versus 21% (HR 4.32, 95% confidence interval [CI] 2.98 to 6.26; p < 0.001) and decreased survival at 3 years, 39% versus 63% (HR 2.43, 95% CI 1.71 to 3.45; p < 0.001).
The authors concluded that among patients with AML in first remission prior to allogeneic HCT, the persistence of FLT3-ITD 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. They commented that further study is needed to determine whether routine DNA sequencing testing for residual variants can improve outcomes for patients with AML.
Dillon LW, Gui G, Page KM, et al. DNA Sequencing to Detect Residual Disease in Adults With Acute Myeloid Leukemia Prior to Hematopoietic Cell Transplant. JAMA 2023;329(9):745-755. doi:10.1001/jama.2023.1363