Posttransplantation MRD monitoring in patients with AML by next-generation sequencing using DTA and non-DTA mutations

Abstract

Next-generation sequencing (NGS)-based measurable residual disease (MRD) monitoring in patients with acute myeloid leukemia (AML) is widely applicable and prognostic prior to allogeneic hematopoietic cell transplantation (alloHCT). We evaluated the prognostic role of clonal hematopoiesis–associated DNMT3A, TET2, and ASXL1 (DTA) and non-DTA mutations for MRD monitoring post-alloHCT to refine MRD marker selection. Of 154 patients with AML, 138 (90%) had at least one mutation at diagnosis, which were retrospectively monitored by amplicon-based error-corrected NGS on day 90 and/or day 180 post-alloHCT. MRD was detected in 34 patients on day 90 and/or day 180 (25%). The rate of MRD positivity was similar when DTA and non-DTA mutations were considered separately (17.6% vs 19.8%). DTA mutations had no prognostic impact on cumulative incidence of relapse, relapse-free survival, or overall survival in our study and were removed from further analysis. In the remaining 131 patients with at least 1 non-DTA mutation, clinical and transplantation-associated characteristics were similarly distributed between MRD-positive and MRD-negative patients. In multivariate analysis, MRD positivity was an independent adverse predictor of cumulative incidence of relapse, relapse-free survival, and overall survival but not of nonrelapse mortality. The prognostic effect was independent of different cutoffs (above limit of detection, 0.1% and 1% variant allele frequency). MRD log-reduction between diagnosis and post-alloHCT assessment had no prognostic value. MRD status post-alloHCT had the strongest impact in patients who were MRD positive prior to alloHCT. In conclusion, non-DTA mutations are prognostic NGS-MRD markers post-alloHCT, whereas the prognostic role of DTA mutations in the posttransplant setting remains open.

Adding venetoclax to fludarabine/busulfan RIC transplant for high-risk MDS and AML is feasible, safe, and active

“…1,2 Persistent genomic evidence of measurable residual disease (MRD) is another determinant of disease relapse. [3][4][5][6] While myeloablative conditioning strategies may have the potential to overcome these obstacles, not all patients are candidates due to advanced age or medical co-morbidities and thus reduced intensity conditioning (RIC) approaches are required. 7 However, increasing the intensity of conditioning therapy is inadequate to overcome the negative impact of select high risk mutations especially TP53.…”

Measurable residual disease of canonical versus non-canonical DNMT3A, TET2, or ASXL1 mutations in AML at stem cell transplantation

“…Thus, the possibilities to define risk stratification prior to allogeneic HSCT in patients harboring DTA mutations have not yet been evaluated. One study analyzed the impact of detectable DTA mutations after HSCT but could not draw explicit conclusions [ 12 ], and none of the aforementioned studies analyzed canonical and non-canonical DTA mutations separately.…”

Prognostic and therapeutic implications of measurable residual disease in acute myeloid leukemia

“…These findings have been echoed by others, even with less sensitive NGS methods [ 79 ]. While its role after HSCT is less clear, NGS detection of MRD may also be of prognostic value, particularly when combined with MFC or when MRD is present prior to transplant [ 78 , 80 , 81 ].…”