In a study reported in the Journal of Clinical Oncology, Morita et al found that clearance of somatic mutations at complete remission—particularly those in nonpreleukemic genes—was associated with improved outcomes in previously untreated patients with acute myeloid leukemia (AML).
The study involved 235 patients who received idarubicin plus cytarabine-based front-line intensive induction therapy in 3 phase II studies conducted between 2010 and 2015 at The University of Texas MD Anderson Cancer Center. Among these patients, 180 (77%) achieved morphologic complete remission at approximately day 30; of these, 131 (73%) had both pretreatment and complete remission bone marrow samples available for analysis.
Pretreatment and complete remission marrow were analyzed by targeted capture DNA sequencing. The study assessed the association between mutation clearance on the basis of variant allele frequency at complete remission (MC2.5 = variant allele frequency of residual mutations < 2.5%; MC1.0 = variant allele frequency <1%; and complete mutation clearance = no detectable residual mutations), event-free survival, overall survival, and cumulative incidence of relapse.
Mutation Clearance and Outcomes
Two-year overall survival was better with MC1.0 vs non-MC1.0 (75% vs 61%, P = .0465) and with complete mutation clearance vs non–complete mutation clearance (77% vs 60%, P = .0303). Similarly, 2-year cumulative incidence of relapse was better with MC1.0 vs non-MC1.0 (26% vs 46%, P = .0349) and with complete mutation clearance vs non–complete mutation clearance (24% vs 46%, P = .03). No significant difference in these outcomes was observed for MC2.5 vs non-MC2.5 status.
In multivariate analysis adjusting for age, cytogenetic risk, allogeneic stem cell transplantation, and flow cytometry–based minimal residual disease, patients with complete mutation clearance had significantly better event-free survival (hazard ratio [HR] = 0.43, P = .0083), overall survival (HR = 0.47, P = .04), and cumulative incidence of relapse (HR = 0.27, P < .001) vs patients without complete mutation clearance. These prognostic associations for complete mutation clearance were stronger when potentially preleukemic mutations (eg, in CHIP [clonal hematopoiesis of indeterminate potential]-related genes), such as DNMT3A, TET2, and ASXL1, were removed from the analysis—ie, hazard ratios of 0.38 (P = .0016) for event-free survival, 0.33 (P = .0022) for overall survival, and 0.29 (P < .001) for cumulative incidence of relapse.
The investigators concluded, “Clearance of somatic mutations at [complete remission], particularly in nonpreleukemic genes, was associated with significantly better survival and less risk of relapse. Somatic mutations in nonpreleukemic genes may function as a molecular minimal residual disease marker in AML.”
The study was supported in part by the Cancer Prevention Research Institute of Texas, Welch Foundation, University of Texas System STARS Award, Khalifa Scholar Award, Charif Souki Cancer Research Fund, National Institutes of Health, Japan Society for the Promotion of Science for Young Scientists, and philanthropic contributions to MD Anderson’s Moon Shot Program.
Koichi Takahashi, MD, of the Department of Leukemia and Genomic Medicine, The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
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