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2020-09-10T10:10:49.000Z

Residual circulating tumor DNA as a prognostic biomarker in patients with AML/MDS

Sep 10, 2020
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In the retrospective setting, residual circulating tumor DNA (ctDNA) can be useful as a prognostic biomarker to identify patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) at high risk of relapse after allogeneic stem cell transplantation (allo-SCT).1

To assess the prognostic value of ctDNA status after allo-SCT in such patients in the prospective setting, Miho Ogawa and colleagues2 examined the utility of this approach in a Japanese multicenter, prospective, observational study (KSGCT1702). The interim results of this study were reported during the Virtual 46th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT).

Methods2

The study included patients with AML and MDS planning to undergo allo-SCT after a myeloablative conditioning regimen.

Tumor samples plus control (buccal swab) and matched serum samples were collected at diagnosis, and serum samples were also collected pretransplant and at Day 30, 60, 90, and 120 post allo-SCT. Tumor DNA (bone marrow or peripheral blood) and buccal swab DNA were analyzed by next-generation sequencing (NGS) to identify candidate driver mutations.

One or two allele-specific droplet digital PCR (ddPCR) assays, indicating driver mutation/structural variants for each patient, were designed to monitor characteristic driver mutations in ctDNA. The primary objective of the study was to evaluate the 1-year cumulative incidence of relapse rate (CIR) post allo-SCT, according to residual ctDNA status.

Results2

The study enrolled 60 patients, and 46 underwent allo-SCT. The baseline patient characteristics are reported in Table 1.

Table 1. Patient characteristics2

allo-SCT, allogeneic stem cell transplantation; AML, acute myeloid leukemia; BM, bone marrow; BPDCN, blastic plasmacytoid dendritic cell neoplasm; MDS, myelodysplastic syndromes; NOS, not otherwise specified; PB, peripheral blood.

 

Characteristic

Patients

(n = 46)

Age, years (range)

54 (2565)

Diagnosis, n (%)

 

AML with recurrent genetic abnormalities

16 (34.8)

AML with myelodysplasia-related changes

9 (19.6)

Therapy-related myeloid neoplasms

2 (4.3)

AML NOS

11 (23.9)

BPDCN

1 (2.9)

MDS

7 (15.2)

Disease status at allo-SCT, n (%)

 

Complete remission

16 (34.8)

Relapse or refractory

12 (26.1)

Untreated

4 (8.7)

Cytogenetics, n (%)

 

Normal karyotype

14 (30.4)

Aberrant karyotype

14 (30.4)

Complex karyotype, monosomal karyotype

4 (8.7)

The median follow-up period was 123 days (25─360); out of 46 patients who underwent allo-SCT, five died without relapse and eight relapsed before Day 360.

Mutations detected by NGS included single nucleotide variants DNMT3A, CEBPA, NRAS, TET2, PTPN11, NPM1, IDH2, TP53, SMC3, RUNX1, JAK2, ASXL2, GATA2, STAG2, IDH1, DDX41, CBL, ASXL1, SETBP1, SF3B1, and FLT3, and structural variants CBFB/MYH11, KMT2A/MLLT3, and KMT2A/AFDN. Patient-specific driver mutations were used to design specific ddPCR assays.

A strong correlation was observed between diagnostic ctDNA and matched tumor DNA from BM with regard to variant allele frequency.

Fourteen patients were available for ctDNA status 3 months post allo-SCT, four with positive and ten with negative ctDNA status. Patients with positive ctDNA status at 3 months post allo-SCT had higher CIR at 10 months: 100% in patients with positive ctDNA status versus 0% in patients with negative ctDNA status.

Conclusion

Different methods, summarized in Table 2, are available to assess measurable residual disease. ctDNA monitoring is a non-invasive method that could predict relapse in patients with AML and MDS who underwent allo-SCT. However, because of the limitations of this study, such as the small sample size and the short observation period, additional studies are needed to confirm the results.

Table 2. Advantages and disadvantages of methods for MRD assessment2

FISH, fluorescence in situ hybridization; NGS, next-generation sequencing; PCR, polymerase chain reaction; qPCR, quantitative PCR.

MRD method

Markers

Advantage

Disadvantage

Chimerism (PCR)

Short tandem repeat regions

Standardized method; high applicability

Low sensitivity, etc.

Chimerism (FISH)

Sex chromosome

Standardized method

Low applicability (50%); low sensitivity

Flow cytometry

Aberrant antigen, etc.

Rapid; standardized method

Low sensitivity

qPCR

Fusion mRNA, etc.

Standardized method; high sensitivity (< 0.1%)

Low applicability (< 20─30%)

Personalized digital PCR (used in this study)

Driver mutations/structural variants

High applicability; low limit of detection (0.04%)

Need NGS and intensive labor before assay construction

  1. Nakamura S, Yokoyama K, Shimizu E, et al. Prognostic impact of circulating tumor DNA status post-allogeneic hematopoietic stem cell transplantation in AML and MDS. Blood. 2019;133(25):2682-2695. DOI: 10.1182/blood-2018-10-880690
  2. Ogawa M, Yokoyama K, Ishii H, et al. Impact of residual circulating tumor DNA status post allogeneic SCT in patients with acute myeloid leukemia and myelodysplastic syndromes: Interim results of a prospective study. ePoster #B241. 46th Annual Meeting of the EBMT; Aug 29, 2020; Virtual.

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