Potential biomarker linked to better outcomes in acute myeloid leukemia

Somatic mutations in certain genes may function as a molecular minimal residual disease marker for acute myeloid leukemia (AML), according to a study led by Koichi Takahashi, M.D., assistant professor of Leukemia at MD Anderson. The study showed that clearance of somatic mutation at complete response, particularly in non-preleukemic genes, is associated with significantly better overall survival (OS) and cumulative incidence of relapse (CIR).

An early understanding of which patients are likely to relapse is crucial given that, although 70 percent of AML patients achieve complete remission (CR) with intensive induction chemotherapy (ICC), approximately half of the patients will relapse.

“Our goal was to determine whether the degree of mutation clearance at remission predicts the risk of relapse in AML,” said Takahashi. “To address this question, we performed DNA sequencing on prospectively collected samples from 131 AML patients treated with frontline ICC in three Phase II clinical trials, and studied bone marrow samples from 39 patients who had been treated with reduced-intensity chemotherapy induction.”

Takahashi and fellow researchers defined three levels of mutation clearance (MC) based on the variant allele frequency (VAF) of residual mutations at CR. These included MC2.5 if at least one mutation persisted with a VAF of less than 2.5 percent, MC1.0 if less than 1 percent, and complete mutation clearance (CMC) if there were no persistent mutations.

“In our study, MC1.0 and CMC had prognostic significance, whereas MC2.5 did not have a significant prognostic impact,” said Takahashi. “The results of this trial may help characterizing the role of MC as a decision-guiding tool, such as whether to transplant or not.”

Multivariate analysis considering age, cytogenetic risk, allogeneic stem cell transplant, MRD detection by flow cytometry, and MC revealed that patients with CMC had significantly better event-free survival (EFS), OS and CIR, and the prognostic associations were stronger when pre-leukemic mutations such as DNMT32, TET2, and ASXL1 were removed from the analysis.

OS was calculated from the date of CR to the date of death from any cause and censored on the date of last follow-up. EFS was calculated from the date of CR to the date of relapse, or death for those without relapse, and censored on the date of last follow-up without relapse. CIR was measured from the date of CR to the date of relapse, considering death without relapse as a competing event.

The study confirmed that clearance of somatic mutations at day 30, particularly in non-preleukemic genes with a VAF of less than 1 percent, was associated with significantly better survival and lower risk of relapse in AML patients treated with ICC.