Dynamic Changes of Genetic Mutations in AML Patients from Diagnosis to Complete Remission and Relapse

Background

Acute myeloid leukemia(AML)is an aggressive hematopoietic malignancy and accumulation of genetic alterations is a common mechanism in the clonal evolution of AML. Some mutations(DNMT3A, ASXL1, TET2)often persist during remission and disease progression, while relapse can either be driven by the acquisition of mutations in the founder clone or by the selection of resistant subclones (Blood,2021,137:3093-3104). However, the relationship between complete remission(CR)/relapse and the critical dynamic changes in genetic mutations is still not well covered. This study aimed to explore the dynamic changes of genetic mutations in AML patients from diagnosis to CR and relapse.

Methods

A total of ninety-seven AML patients with sequential serial samples were sequenced by our reported targeted exome-seq for human leukemia driver genes (Blood Cancer J,2022;12:145) from 28 May, 2019 to 7 June, 2024. Sixty-six Patients were sequenced at diagnosis and CR, twenty-four patients were sequenced at diagnosis, CR and relapse, while seven patients were sequenced at diagnosis and relapse.

Results

Ninety-three de novo AML patients and four secondary AML patients were analyzed with a median age of 60(15~86) years, including 53 males and 44 females. The median interval time between diagnosis to CR was 2(1~5) months, the median interval time from CR to relapse was 5(1~16) months, as well as the interval time from diagnosis to relapse was 8(2~28) months.

The median number of mutations detected at CR was significantly less than the mutations detected at diagnosis( 1 vs. 3, P<0.001), moreover, 40 patients(44.5%)lost all of the mutations detected at diagnosis and had no mutations at CR. Although the other patients still had mutations detected at diagnosis, the variant allele frequency of these mutations significantly decreased. Furthermore, we found that patients who still had mutations detected at diagnosis had worse relapse-free survival than patients who lost all of the mutations detected at diagnosis (5 vs 11 months, P =0.042 ).

Then, to explore the critical mutations that may promote relapse in AML patients, we found the median number of mutations detected at relapse had no difference than at the diagnosis(3 vs. 3, P= 0.401 ). However, most (20/31,64.5%)patients had newly acquired mutations at relapse, the median number of newly acquired mutations at relapse was 1(0~5).The most frequent newly acquired mutations were RAS(NRAS,KRAS,PTPN11,CBL,NF1)pathway(n=5 ,16.1 %),NPM1(n=4,12.9%) and FLT3(n= 3,9.7%) mutations.

Conclusion

The study clarified the dynamic changes of genetic mutation in AML patients from diagnosis to CR and relapse. Sweeping away and decreasing the genetic mutations detected at diagnosis promotes patients to CR. Newly acquired mutations and Reappeared mutations detected at the diagnosis lead to relapse. Newly acquired RAS pathway, NPM1 and FLT3 mutations may promote patients to relapse and should be targeted as potential intervention points.

No relevant conflicts of interest to declare.