From the Journals

Mutations may be detectable years before AML diagnosis



Individuals who develop acute myeloid leukemia (AML) may have somatic mutations detectable years before diagnosis, a newly published analysis shows.

Mutations in IDH1, IDH2, TP53, DNMT3A, TET2, and spliceosome genes at baseline assessment increased the odds of developing AML with a median follow-up of 9.6 years in the study, which was based on blood samples from participants in the Women’s Health Initiative (WHI).

The findings suggest a “premalignant landscape of mutations” that may precede overt AML by many years, according to Pinkal Desai, MD, assistant professor of medicine at Cornell University and oncologist at New York–Presbyterian/Weill Cornell Medical Center, New York, and her coauthors.

“The ability to detect and identify high-risk mutations suggests that monitoring strategies for patients, as well as clinical trials of potentially preventative or disease-intercepting interventions should be considered,” wrote Dr. Desai and her colleagues. The report was published in Nature Medicine.

Their analysis comprised 212 women who participated in the WHI who were healthy at the baseline evaluation but went on to develop AML during follow-up. They performed deep sequencing on peripheral blood DNA for these cases and for 212 age-matched controls.

Women who developed AML were more likely than were controls to have mutations in baseline assessment (odds ratio, 4.86; 95% confidence interval, 3.07-7.77), and had demonstrated greater clonal complexity versus controls (comutations in 46.8% and 5.5%, respectively; odds ratio, 9.01; 95% CI, 4.1-21.4), investigators found.

Illustration of DNA ©GunarsB/Thinkstock

All 21 patients with TP53 mutations went on to develop AML, as did all 15 with IDH1 or IDH2 mutations and all 3 with RUNX1 mutations. Multivariate analysis showed that TP53, IDH1 and IDH2, TET2, DNMT3A and several spliceosome genes were associated with significantly increased odds of AML versus controls.

Based on these results, Dr. Desai and colleagues proposed that patients at increased AML risk should be followed in long-term monitoring studies that incorporate next-generation sequencing.

“Data from these studies will provide a robust rationale for clinical trials of preventative intervention strategies in populations at high risk of developing AML,” they wrote.

In clinical practice, monitoring individuals for AML-associated mutations will become more feasible as costs decrease and new therapies with favorable toxicity profiles are introduced, they added.

“Molecularly targeted therapy is already available for IDH2 mutations and is under development for mutations in other candidate genes found in this study including IDH1, TP53 and spliceosome genes,” they wrote.

The authors reported having no relevant financial disclosures. The WHI program is funded by the National Institutes of Health.

SOURCE: Desai P et al. Nat Med. 2018;24:1015-23.

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