DNA Sequencing Prior to HCT Identifies Patients at Risk of Poor AML Outcomes

In patients with acute myeloid leukemia (AML) in first remission, the persistence of certain DNA variants related to measurable residual disease (MRD) prior to allogeneic hematopoietic cell transplant (HCT) was associated with post-HCT relapse and worse survival outcomes in a recent study.

The findings, published in JAMA, suggest that the potential benefits of routine DNA testing for residual variants warrant further research in the context of AML. While allogeneic HCT is typically recommended for maintenance of initial AML remission, disease recurrence happens in approximately 30% of patients, the authors noted. Disease recurrence is the most common cause of death after HCT.

MRD has become a topic of interest, especially in hematological malignancies, with increasing evidence suggesting its value in predicting relapse and mortality in patients who are in cytomorphological complete remission. Despite the potential benefits, there is no standard method of MRD testing for patients with AML.

The current study aimed to determine whether the presence of specific residual AML-associated DNA variants in patients’ blood during remission but before allogeneic HCT would be associated with increased risk of relapse and mortality following HCT. Relapse-free survival and nonrelapse mortality were secondary outcomes of interest.

A total of 1075 patients from 110 US sites and 1 site in Europe were included in the retrospective, observational study. Of these patients, 454 in the discovery cohort underwent HCT between March 2013 and December 2017, and 621 in the validation cohort underwent HCT between January 2018 and February 2019.

Blood samples were collected a median of 9 days before transplant, and the discovery and validation cohorts had similar 3-year relapse rates and overall survival (OS) rates. In the discovery cohort, 131 patients (28.9%) had variants of interest, and 188 patients (30.3%) in the validation cohort showed variants in the genes of interest. Patients were tested for 5 genes of interest: NPM1, FLT3, IDH1, IDH2, and/or KIT.

In the overall cohort, 822 patients showed FLT3 internal tandem duplication (FLT3-ITD) and/or NPM1-mutated AML. Of these patients, 371 were in the discovery cohort and 451 were in the validation cohort.

In the discovery cohort, 64 patients with persistent of NPM1 and/or FLT3-ITD variants while in remission before undergoing transplant showed higher post-HCT relapse and worse OS compared with patients without persistent variants.

The validation cohort showed similar outcomes. The 78 patients who showed residual NPM1 and/or FLT3-ITD variants experienced higher rates of relapse and worse OS at 3 years. Those with persistent mutations relapsed in 68% of cases, compared with 21% of patients without persistent mutations. Three-year OS was 39% among those with persistent mutations and 63% among those without persistent variants.

The findings suggest that the persistence of FLT3-ITD or NPM1 variants in patients with AML during first remission but prior to HCT may be predictive of relapse and mortality, although further research is needed to determine whether DNA sequencing can help improve outcomes in this patient population.

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(9):745-755. doi:10.1001/jama.2023.1363