Can DNA Sequencing of Blood From Patients With AML in Remission Prior to HCT Identify Those At-Risk For Poor Outcomes?

In a retrospective observational study, researchers found that the detection of residual FLT3 internal tandem duplication (FLT3-ITD) or NPM1 variant mutations in the blood of adult patients with acute myeloid leukemia (AML) in remission prior to allogeneic hematopoietic cell transplant (HCT) was associated with increased rates of relapse and decreased rates of survival compared with those testing negative for traces of those variants.

Prior studies have suggested that for those with AML, the presence of measurable residual disease prior to first HCT was associated with higher relapse rates and worse overall survival, but there has been a lack standardized testing for certain variant mutations.

Enter Dillon and colleagues who performed DNA sequencing on the pre-transplant blood of adults who had undergone their first HCT during first remission for AML from 2013 through 2019 (N = 1075).

The researchers split the participants into two cohorts: those who had undergone HCT between March 1, 2013 and December 31, 2017 were considered the discovery cohort (n = 454) and those who had undergone transplant between January 1, 2018, and February 14, 2019 were considered the validation cohort (n = 621). Dillon and colleagues collected their clinical data using the Center for International Blood and Marrow Transplant Research through May 2022. The primary outcomes were overall survival and relapse. 

Of the 1075 patients tested, 822 had FLT3-ITD and/or NPM1 variant mutations: 371 patients in the discovery cohort and 451 patients in the validation cohort.

The results indicated that DNA-sequencing of persistent FLT3-ITD or NPM1 variants in the pre-transplant blood of adult patients with AML in remission was associated with increased rates of relapse and decreased survival compared with those without such variants.

Of the 371 patients in the discovery cohort, 64 (17.3%) had persistent NPM1 and/or FLT3-ITD variants detected in pre-transplant remission blood. This group had higher post-transplant relapse rates at 3 years than those without such variants (59% vs 24%; difference = 35% [two-sided 95% CI, 22% to 48%]; HR = 3.71 [95% CI, 2.55 to 5.41]; p < .001) and lower overall survival at 3 years (34% vs 66% difference = −32% [2-sided 95% CI, −45% to −19%]; HR = 2.60 [95% CI, 1.85 to 3.65]; p  < .001).

Of the 451 patients in the validation cohort, 78 patients (17.3%) had persistent NPM1 and/or FLT3-ITD variants, and this group had a higher post-transplant relapse rates at 3 years (68% vs 21%; difference = 47% [two-sided 95% CI, 26% to 69%]; HR = 4.32 [95% CI, 2.98 to 6.26]; p  < .001) and lower overall survival at 3 years compared with those without such variants (39% vs 63%; difference= −24% [two-sided 95% CI, −39% to −9%]; HR = 2.43 [95% CI, 1.71 to 3.45]; p < .001).

This study includes limitations, most notably that the authors did not investigate whether the results of DNA sequencing would be different if it was tested on bone marrow instead of blood. The authors also noted that additional study on this topic is still needed.

“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 above was associated with increased relapse and worse survival compared with those without these variants,” the authors concluded. “Further study is needed to determine whether routine DNA-sequencing testing for residual variants can improve outcomes for patients with AML.”

Reference:
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;329:745-755. doi:10.1001/jama.2023.1363.