In patients with acute myeloid leukemia (AML) in first remission prior to undergoing allogeneic hematopoietic stem cell transplantation (HSCT), a study identified poorer outcomes in those who had residual FLT3-internal tandem duplication (ITD) or NPM1 genetic variants in blood at an allele fraction of ≥0.01%. Study findings were reported in JAMA.
This retrospective, observational study included data from a cohort of the Center for International Blood and Marrow Transplant Research. DNA sequencing was utilized for detection of measurable residual disease (MRD) from samples of pretransplant blood in adults with AML who later underwent an initial allogeneic HSCT while in first remission and whose AML had been associated with particular genetic alterations. The aim of the study was to determine if DNA sequencing results from blood from these patients were predictive of relapse and survival outcomes.
DNA analysis was focused on 5 genes, which included NPM1, FLT3, IDH1, IDH2, and KIT. MRD status was considered positive with a variant allele fraction of at least 0.01%. In this analysis, patients were divided into discovery and validation cohorts. In the discovery cohort, HSCT was performed from 2013 through 2017, while patients in the validation cohort underwent HSCT in 2018 or 2019.
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The population included 1075 patients for whom pretransplant next-generation sequencing for MRD was performed. A univariate analysis in the discovery cohort identified NPM1 variants and/or FLT3-ITD status as linked to higher relapse rates.
Among all patients, 822 had NPM1 altered or FLT3-ITD AML, including 371 patients in the discovery cohort and 451 in the validation cohort, and these patients were included in further analyses.
In the discovery cohort, worse posttransplant outcomes were observed for a subset of patients (17.3%) who showed persistent NPM1 and/or FLT3-ITD variants. In the validation cohort, 17.3% also demonstrated persistent NPM1 and/or FLT3-ITD variants, which were associated with worse outcomes.
In the validation cohort, persistence of these variants was associated with a higher 3-year posttransplant relapse rate (68%), compared with the lack of persistence of these variants (21%; hazard ratio [HR], 4.32; 95% CI, 2.98-6.26; P <.001). In this cohort, the 3-year survival rate was also lower with residual NPM1 or FLT3-ITD variants (39%) than without (63%; HR, 2.43; 95% CI, 1.71-3.45; P <.001). The discovery cohort also demonstrated significantly worse 3-year relapse and 3-year survival rates with residual NPM1 or FLT3-ITD variants.
Across the full study population, in 531 patients with NPM1-altered AML, the 3-year relapse rate was 28%. In 608 patients with FLT3-ITD AML, the 3-year relapse rate was 32%.
Based on the study’s findings, the investigators concluded that this patient population showed higher rates of relapse and poorer survival with persistent FLT3-ITD or NPM1 with a variant allele fraction of ≥0.01% in the blood. “Further study is needed to determine whether routine DNA-sequencing testing for residual variants can improve outcomes for patients with acute myeloid leukemia,” the investigators wrote in their report.
Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
Reference
Dillon LW, Gui G, Page K, 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
