Precision and prognostic value of clone-specific minimal residual disease in acute myeloid leukemia

Abstract

The genetic landscape of adult acute myeloid leukemias (AML) has been recently unraveled. However, due to their genetic heterogeneity, only a handful of markers are currently used for the evaluation of minimal residual disease (MRD). Recent studies using multi-target strategies indicate that detection of residual mutations in less than 5% of cells in complete remission is associated with a better survival. Here, in a series of 69 AMLs with known clonal architecture, we design a clone-specific strategy based on fluorescent in situ hybridization and high-sensitivity next generation sequencing to detect chromosomal aberrations and mutations, respectively, in follow-up samples. The combination of these techniques allows tracking chromosomal and genomic lesions down to 0.5–0.4% of the cell population in remission samples. By testing all lesions in follow-up samples from 65 of 69 evaluable patients, we find that initiating events often persist and appear to be, on their own, inappropriate markers to predict short-term relapse. In contrast, the persistence of two or more lesions in more than 0.4% of the cells from remission samples is strongly associated with lower leukemia-free and overall survivals in univariate and multivariate analyses. Although larger prospective studies are needed to extend these results, our data show that a personalized, clone-specific, MRD follow up strategy is feasible in the vast majority of AML cases.

Next‐generation sequencing‐defined minimal residual disease before stem cell transplantation predicts acute myeloid leukemia relapse

“…Several recent AML studies have shown that the persistence of leukemia‐associated mutations after the initial course of standard induction chemotherapy imparts a significantly increased risk of subsequent leukemic relapse and death . For those patients undergoing HSCT, we have extended these conclusions by also assessing NGS‐defined MRD at the subsequent pre‐transplant time point (within 30 days of HSCT), and showing that a persisting leukemia‐associated mutation was a sensitive (but not specific), strong (hazard ratio ~8), and independent predictor of leukemic relapse.…”

Clonal evolution of acute myeloid leukemia from diagnosis to relapse

“…Thus, mutation clearance is directly correlated to the risk of AML relapse and its dynamics. [69][70][71][72] On the other hand, as the subclonal diversity of AML at diagnosis is commonly high, individual cells capable of giving rise to relapse may already exist at diagnosis. 73,74 If a particular mutation that provides resistance is already present in a single cell, this cell has the strongest fitness of all cells under the new selective pressure of chemotherapy.…”

Single-cell mutational profiling enhances the clinical evaluation of AML MRD

“…This finding is similar to previously published work using bulk NGS assays with a sensitivity of 0.2% that showed that persistence of $2 lesions was associated with significantly reduced leukemia-free survival and OS. 19 This finding raises the possibility that identification of complex or multiple clones during remission increases the risk of resistant disease and future relapse. Multiple groups are exploring personalized digital droplet PCR assays for MRD tracking to leverage this finding.…”