Next-generation sequencing–based posttransplant monitoring of acute myeloid leukemia identifies patients at high risk of relapse

Abstract

Key Points Higher allelic burden at day 21 of post-HCT is associated with higher risk of relapse and mortality. Longitudinal tracking of AML patients receiving HCT is feasible and provides clinically relevant information.

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

“…The prognostic relevance of these post‐treatment persisting preleukemic mutations has been a controversial question, with some studies suggesting that persisting preleukemic mutations (particularly in the DNMT3A gene) impart no (or minimally) significant prognostic utility . In contrast, our study, as well as several others, has shown that the post‐treatment persistence of any leukemia‐associated mutation, including preleukemic mutations, is associated with an inferior outcome . Some of these studies had large enough cohorts to be able to specifically modify their definition of “MRD‐positive” to either include or exclude persisting pre‐leukemic (mostly DNMT3A) mutations.…”

“…Our study, for example, used an MRD time point prior to HSCT (median 3.6 months after diagnosis) that was later in the treatment cycle (after more cumulative chemotherapy), than all of the MRD studies that found preleukemic persisting mutations to be non‐prognostic, when assessed at an earlier post‐induction or first‐remission time point . The standard initial induction chemotherapy used to achieve a first remission often fails to effectively clear preleukemic mutations . The subsequent intense conditioning regimen used prior to stem cell transplantation, has been shown to be preferentially most effective in clearing those clones that are the most resistant to the prior induction chemotherapy .…”

“…The standard initial induction chemotherapy used to achieve a first remission often fails to effectively clear preleukemic mutations . The subsequent intense conditioning regimen used prior to stem cell transplantation, has been shown to be preferentially most effective in clearing those clones that are the most resistant to the prior induction chemotherapy . The confirmed MRD prognostic utility of any persisting mutation (without excluding preleukemic mutations) in patients with subsequent HSCT (our study and), vs the apparent lack of prognostic utility for persisting preleukemic mutations in those who did not get transplanted may then be partly attributable to the more intense treatment given before transplantation.…”

“…Our findings suggest that serial NGS‐based MRD monitoring of AML patients can provide practical prognostic information at a key decision‐making pre‐transplant time point. Other post‐treatment MRD time points have been shown to provide analogous risk stratification information . The translation of this prognostic information into practical therapeutic actions is the next obvious target for intense investigation.…”

“…Morphologic assessment of the percentage of bone marrow myeloblasts has long been the traditional laboratory method for monitoring the response to AML therapy, and “complete remission” (CR), defined as <5% bone marrow myeloblasts, is a consensus therapeutic goal. More recent studies, however, have shown that a variety of other laboratory methods for more sensitively measuring submicroscopic MRD can be utilized as consistent, independent prognostic factors for AML relapse and survival . These more sensitive MRD techniques include multicolor flow cytometry (MFC), RT‐PCR for overexpressed genes, single‐gene PCR for commonly mutated genes, fluorescent in situ hybridization (FISH), and next‐generation sequencing (NGS) .…”