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Blood. 2019 Apr 1. pii: blood-2018-10-880690. doi: 10.1182/blood-2018-10-880690. [Epub ahead of print]

Prognostic impact of circulating tumor DNA status post-allogeneic hematopoietic stem cell transplantation in AML and MDS.

Author information

1
Division of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
2
Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
3
Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
4
Department of Applied Genomics, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
5
Health Intelligence Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
6
Department of Cell Processing and Transfusion, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
7
Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; a-tojo@ims.u-tokyo.ac.jp.

Abstract

This study was performed to assess the utility of tumor-derived fragmentary DNA, or circulating tumor DNA (ctDNA), for identifying high-risk patients for relapse of acute myeloid leukemia and myelodysplastic syndrome (AML/MDS) after undergoing myeloablative allogeneic stem cell transplantation (alloSCT). We retrospectively collected tumor and available matched serum samples at diagnosis and 1 and 3 months post-alloSCT from 53 patients with AML/MDS. After identifying driver mutations in 51 patients using next-generation sequencing, we designed at least one personalized digital-PCR assay per case. Diagnostic ctDNA and matched tumor DNA exhibited excellent correlations with variant allele frequencies. Sixteen patients relapsed after a median of 7 months post-alloSCT. Both mutation-persistence (MP) in bone marrow at 1 and 3 months post-alloSCT and corresponding ctDNA-persistence (CP) in the matched serum (MP1 and MP3; CP1 and CP3, respectively) were comparably associated with higher 3-year cumulative incidence of relapse rates [MP1 vs. non-MP1: 72.9% vs. 13.8% (P = 0.0012); CP1 vs. non-CP1: 65.6% vs. 9.0% (P = 0.0002); MP3 vs. non-MP3; 80% vs. 11.6% (P = 0.0002); CP3 vs. non-CP3: 71.4% vs. 8.4% (P < 0.0001)]. We subsequently evaluated whether subset analysis of patients with three genes associated with clonal hematopoiesis, DNMT3A, TET2, and ASXL1 (DTA), could also be helpful in relapse prediction. As a result, CP based on DTA gene mutations also had the prognostic effect on CIR. These results, for the first time, support the utility of ctDNA as a non-invasive prognostic biomarker in patients with AML/MDS, undergoing alloSCT.

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