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

Sousuke Nakamura, Kazuaki Yokoyama, Eigo Shimizu, Nozomi Yusa, Kanya Kondoh, Miho Ogawa, Tomomi Takei, Asako Kobayashi, Mika Ito, Masamichi Isobe, Takaaki Konuma, Seiko Kato, Rika Kasajima, Yuka Wada, Tokiko Nagamura-Inoue, Rui Yamaguchi, Satoshi Takahashi, Seiya Imoto, Satoru Miyano and Arinobu Tojo

Key points

  • Non-invasive testing of serum circulating tumor DNA (ctDNA) persistence post allogeneic transplant could predict relapse in AML and MDS.

  • Predictive utility of testing ctDNA, including DNMT3A, TET2, and ASXL1, was comparable to that of mutation persistence in matched BM.

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.

  • Submitted October 16, 2018.
  • Accepted March 7, 2019.