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

Abstract

In acute myeloid leukemia (AML), the assessment of post‐treatment minimal residual disease (MRD) may inform a more effective management approach. We investigated the prognostic utility of next‐generation sequencing (NGS)‐based MRD detection undertaken before hematopoietic stem cell transplantation (HSCT). Forty‐two AML subjects underwent serial disease monitoring both by standard methods, and a targeted 42‐gene NGS assay, able to detect leukemia‐specific mutant alleles (with >0.5% VAF) (mean 5.1 samples per subject). The prognostic relevance of any persisting diagnostic mutation before transplant (≤27 days) was assessed during 22.1 months (median) of post‐transplant follow‐up. The sensitivity of the NGS assay (27 MRD‐positive subjects) exceeded that of the non‐molecular methods (morphology, FISH, and flow cytometry) (11 positive subjects). Only one of the 13 subjects who relapsed after HSCT was NGS MRD‐negative (92% assay sensitivity). The cumulative incidence of post‐transplant leukemic relapse was significantly higher in the pre‐transplant NGS MRD‐positive (vs MRD‐negative) subjects (P = .014). After adjusting for TP53 mutation and transplant conditioning regimen, NGS MRD‐positivity retained independent prognostic significance for leukemic relapse (subdistribution hazard ratio = 7.3; P = .05). The pre‐transplant NGS MRD‐positive subjects also had significantly shortened progression‐free survival (P = .038), and marginally shortened overall survival (P = .068). In patients with AML undergoing HSCT, the pre‐transplant persistence of NGS‐defined MRD imparts a significant, sensitive, strong, and independent increased risk for subsequent leukemic relapse and death. Given that NGS can simultaneously detect multiple leukemia‐associated mutations, it can be used in the majority of AML patients to monitor disease burdens and inform treatment decisions.

Measurable residual disease (MRD) testing for acute leukemia in EBMT transplant centers: a survey on behalf of the ALWP of the EBMT

“…This technique is applicable to virtually all AML patients but the interpretation of the results requires complex bioinformatics approaches. The sensitivity of this approach is generally lower than what can be achieved with qPCR or MFC but this technique also allows the identification of leukemic sub clones [33]. As a first step aimed at including pre-and posttransplant MRD status as routine registry capture parameters, we conducted a survey among EBMT-affiliated centers focused on MRD assessment pre-and post-allo-HCT for patients with either AML or ALL.…”

Next‐generation sequencing for measurable residual disease detection in acute myeloid leukaemia

“…Recent studies utilizing NGS for the detection of MRD in AML vary greatly in their design and technical aspects. Cohorts studied have included AML patients undergoing allogeneic haematopoietic cell transplantation (alloHCT) (Getta et al , ; Kim et al , ; Thol et al , ; Zhou et al , ; Press et al , ), receiving standard induction chemotherapy (Klco et al , ; Gaksch et al , ; Jongen‐Lavrencic et al , ; Morita et al , ; Onecha et al , ; Rothenberg‐Thurley et al , ; Thol et al , ; Wong et al , ), receiving novel therapies in clinical trials (Levis et al , ), or having only specific mutations (Thol et al , ; Kohlmann et al , ; Salipante et al , ; Levis et al , ; Patkar et al , ; Zhou et al , ; Patel et al , ). Also, since most studies to date have had access to diagnostic samples, de novo leukaemia‐associated mutation discovery using remission samples alone remains an important unmet challenge.…”

Impact of detectable measurable residual disease on umbilical cord blood transplantation

“…[13][14][15][16][17][18] During the last decade, several reports have highlighted the negative impact of detectable measurable residual disease (MRD) at transplantation, on transplantation outcomes in patients transplanted from either HLA-matched related or unrelated donors, as well as in those given cells from HLA-haploidentical donors. [19][20][21][22][23][24][25] This remained true in patients in second complete remission (CR) at transplantation. 26 Interestingly, the negative impact of detectable MRD at transplantation holds true in large registry studies in which various techniques (depending on transplant center) were used for MRD detection.…”