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International Journal of Hematology

, Volume 108, Issue 4, pp 402–410 | Cite as

Circulating tumor DNA dynamically predicts response and/or relapse in patients with hematological malignancies

  • Sousuke Nakamura
  • Kazuaki Yokoyama
  • Nozomi Yusa
  • Miho Ogawa
  • Tomomi Takei
  • Asako Kobayashi
  • Mika Ito
  • Eigo Shimizu
  • Rika Kasajima
  • Yuka Wada
  • Rui Yamaguchi
  • Seiya Imoto
  • Tokiko Nagamura-Inoue
  • Satoru Miyano
  • Arinobu Tojo
Original Article

Abstract

A growing body of evidence suggests that tumor-derived fragmentary DNA, known as circulating tumor DNA (ctDNA), has the potential to serve as a non-invasive biomarker for disease monitoring. However, in the setting of hematological malignancy, few published studies support the utility of ctDNA. We retrospectively investigated ctDNA levels of 17 patients with various hematological malignancies who had achieved remission after first-line therapy. We identified somatic driver mutations by next-generation sequencing, and designed droplet digital PCR assays for each mutation to measure ctDNA. Variant allele frequencies of ctDNA changed in association with clinical response in all patients. Eight patients clinically relapsed after a median of 297 days post-first-line therapy (termed, “relapsed group”); the remaining nine patients remained disease-free for a median of 332 days (termed, “remission group”). Among patients in the relapsed group, ctDNA levels increased more than twofold at paired serial time points. In marked contrast, ctDNA levels of all patients in the remission group remained undetectable or stable during clinical remission. Notably, ctDNA-based molecular relapse demonstrated a median 30-day lead time over clinical relapse. In summary, ctDNA monitoring may help identify hematologic cancer patients at risk for relapse in advance of established clinical parameters.

Keywords

Circulating tumor DNA Liquid biopsy Mutation tracking MRD Hematological malignancy 

Notes

Acknowledgements

We are grateful to all patients for their cooperation and participation in the study.

Author contributions

SN, KY, and AT, wrote the manuscript. SN, NY, MO, TT, AK, and MI performed experiments. SN and KY analyzed the data with ES, RK, RY, SI, and SM providing assistance in informatics analysis. TIN and YW provided vital samples. KY and AT designed and supervised the study.

Compliance with ethical standards

Conflict of interest

Arinobu Tojo has received research funding from Chugai Pharma. All other authors have no disclosures.

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Copyright information

© The Japanese Society of Hematology 2018

Authors and Affiliations

  • Sousuke Nakamura
    • 1
  • Kazuaki Yokoyama
    • 1
    • 2
  • Nozomi Yusa
    • 3
  • Miho Ogawa
    • 1
  • Tomomi Takei
    • 1
  • Asako Kobayashi
    • 1
  • Mika Ito
    • 1
  • Eigo Shimizu
    • 4
  • Rika Kasajima
    • 5
  • Yuka Wada
    • 6
  • Rui Yamaguchi
    • 4
  • Seiya Imoto
    • 5
  • Tokiko Nagamura-Inoue
    • 6
  • Satoru Miyano
    • 4
    • 5
  • Arinobu Tojo
    • 1
    • 2
  1. 1.Division of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical ScienceThe University of TokyoTokyoJapan
  2. 2.Department of Hematology/Oncology, Research Hospital, The Institute of Medical ScienceThe University of TokyoTokyoJapan
  3. 3.Department of Applied Genomics, Research Hospital, The Institute of Medical ScienceThe University of TokyoTokyoJapan
  4. 4.Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical ScienceThe University of TokyoTokyoJapan
  5. 5.Health Intelligence Center, The Institute of Medical ScienceThe University of TokyoTokyoJapan
  6. 6.Department of Cell Processing and Transfusion, Research Hospital, The Institute of Medical ScienceThe University of TokyoTokyoJapan

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