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Clinical Trial
. 2021 Jun 4;11(6):109.
doi: 10.1038/s41408-021-00500-9.

Prognostic value of measurable residual disease monitoring by next-generation sequencing before and after allogeneic hematopoietic cell transplantation in acute myeloid leukemia

Hee-Je Kim #  1   2 , Yonggoo Kim #  3   4 , Dain Kang  3 , Hoon Seok Kim  3   4 , Jong-Mi Lee  3   4 , Myungshin Kim  5   6 , Byung-Sik Cho  7   8
Affiliations
Clinical Trial

Prognostic value of measurable residual disease monitoring by next-generation sequencing before and after allogeneic hematopoietic cell transplantation in acute myeloid leukemia

Hee-Je Kim et al. Blood Cancer J. .

Abstract

Given limited studies on next-generation sequencing-based measurable residual disease (NGS-MRD) in acute myeloid leukemia (AML) patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT), we longitudinally collected samples before and after allo-HSCT from two independent prospective cohorts (n = 132) and investigated the prognostic impact of amplicon-based NGS assessment. Persistent mutations were detected pre-HSCT (43%) and 1 month after HSCT (post-HSCT-1m, 20%). All persistent mutations at both pre-HSCT and post-HSCT-1m were significantly associated with post-transplant relapse and worse overall survival. Changes in MRD status from pre-HSCT to post-HSCT-1m indicated a higher risk for relapse and death. Isolated detectable mutations in genes associated with clonal hematopoiesis were also significant predictors of post-transplant relapse. The optimal time point of NGS-MRD assessment depended on the conditioning intensity (pre-HSCT for myeloablative conditioning and post-HSCT-1m for reduced-intensity conditioning). Serial NGS-MRD monitoring revealed that most residual clones at both pre-HSCT and post-HSCT-1m in patients who never relapsed disappeared after allo-HSCT. Reappearance of mutant clones before overt relapse was detected by the NGS-MRD assay. Taken together, NGS-MRD detection has a prognostic value at both pre-HSCT and post-HSCT-1m, regardless of the mutation type, depending on the conditioning intensity. Serial NGS-MRD monitoring was feasible to compensate for the limited performance of the NGS-MRD assay.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Mutational dynamics of the 132 AML patients.
a Bar plot showing the mutational status of genes at initial diagnosis (red bar), before transplantation (pre-HSCT, blue bar), and 1 month after transplantation (post-HSCT-1m, green bar). b Clonal dynamics of mutations from initial diagnosis to pre-HSCT to post-HSCT-1m. Each symbol represents the mean VAF. c Changes in the mean VAF in patients with NGS-MRD positivity without relapse. Many mutations showed late clearance at post-HSCT-3m. Other1 shows the mean VAF of genes including CBL, IDH, NPM1, SETBP1, SF3B1, and TP53. Other2 shows the mean VAF of genes including BCOR, BRAF, DDX41, FBXW7, GATA2, NRAS, and SETD2. d–g Variant allele frequency dynamics with mutational clearance and evolution at initial diagnosis and during follow-up. d–g Fish plots showing the appearance of mutations before overt relapse. d Selective clearance of the CEBPA mutation. e Evolution of new NRAS and FLT3 mutations at relapse. f Later clearance of DNMT3A and IDH2 mutations, and reappearance of BCOR and IDH2 mutations before overt relapse. g A donor organ-originated DNMT3A mutation detected post-HSCT-1m that diminished at relapse, with evolving NRAS, PTPN11, and FLT3 mutations at relapse.
Fig. 2
Fig. 2. Prognostic roles of NGS-MRD at pre-HSCT and post-HSCT.
a Cumulative incidence of relapse and overall survival according to NGS-MRD status at pre-HSCT and post-HSCT-1m. b–d Prognostic effect of changes in NGS-MRD status between pre-HSCT and post-HSCT-1m. b NGS-MRD status at pre-HSCT and post-HSCT-1m. c Outcomes in the three groups classified by changes in NGS-MRD status between pre-HSCT and post-HSCT-1m. d Survival outcomes in the three groups classified by changes in NGS-MRD status between pre-HSCT and post-HSCT-1m.
Fig. 3
Fig. 3. Prognostic impact of persistent DTA or CHIP mutations.
Cumulative incidence of relapse according to detectable DTA (a, b) or CHIP (c, d) mutations at pre-HSCT (a, c) and post-HSCT-1m (b, d).
Fig. 4
Fig. 4. Effects of conditioning intensity on the prognostic value of NGS-MRD detection.
Cumulative incidence of relapse (a, c) and non-relapse mortality (b, d) by NGS-MRD status at pre-HSCT and post-HSCT-1m according to conditioning intensity (myeloablative (MAC) and reduced-intensity conditioning (RIC)).
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