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Acute myeloid leukemia

Post-induction MRD by FCM and GATA1-PCR are significant prognostic factors for myeloid leukemia of Down syndrome

Leukemia volume 35, pages 2508–2516 (2021)Cite this article

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A Correction to this article was published on 01 September 2021

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Abstract

Myeloid leukemia of Down syndrome (ML-DS) is associated with good response to chemotherapy, resulting in favorable outcomes. However, no universal prognostic factors have been identified to date. To clarify a subgroup with high risk of relapse, the role of minimal residual disease (MRD) was explored in the AML-D11 trial by the Japanese Pediatric Leukemia/Lymphoma Study Group. MRD was prospectively evaluated at after induction therapy and at the end of all chemotherapy, using flow cytometry (FCM-MRD) and GATA1-targeted deep sequencing (GATA1-MRD). A total of 78 patients were eligible and 76 patients were stratified to the standard risk (SR) group by morphology. In SR patients, FCM-MRD and GATA1-MRD after induction were positive in 5/65 and 7/59 patients, respectively. Three-year event-free survival (EFS) and overall survival (OS) rates were 95.0% and 96.7% in the FCM-MRD-negative population, and 60.0% and 80.0% in the positive population. Three-year EFS and OS rates were both 98.1% in the GATA1-MRD-negative population, and 57.1% and 71.4% in the positive population. Adjusted hazard ratios for associations of FCM-MRD with EFS were 14.67 (p = 0.01). Detection of MRD by either FCM or GATA1 after initial induction therapy represents a significant prognostic factor for predicting ML-DS relapse.

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Fig. 1: Treatment outline of the AML-D11 study.
Fig. 2: Flow diagram of patients in the AML-D11 study.
Fig. 3: Survival curve of the patients with standard risk (n = 76).
Fig. 4: Event-free survival and overall survival of patients with standard risk according to FCM-MRD (n = 65) or GATA1-MRD (n = 59).

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Acknowledgements

The authors deeply appreciate the invaluable cooperation of the large number of physicians working at the institutions, central diagnostic laboratories, and the office and data center of the JPLSG. We also wish to thank Dario Campana and Elaine Coustan-Smith (National University of Singapore) for helpful discussions regarding FCM-MRD analysis. This work was supported by a Grant for Clinical Cancer Research and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour, and Welfare of Japan. This work was supported in part by the Project Promoting Clinical Trials for Development of New Drugs (JP19lk0201061t0004) and Practical Research for Innovative Cancer Control (JP19ck0106329) from the Japan Agency for Medical Research and Development (AMED) and by Grants-in-Aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (KAKENHI: 26253061, 18H04039).

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  1. These authors contributed equally: Takashi Taga, Shiro Tanaka, Daisuke Hasegawa

Authors and Affiliations

  1. Department of Pediatrics, Shiga University of Medical Science, Otsu, Japan

    Takashi Taga

  2. Department of Clinical Biostatistics, Graduate School of Medicine Kyoto University, Kyoto, Japan

    Shiro Tanaka

  3. Department of Pediatrics, St Luke’s International Hospital, Tokyo, Japan

    Daisuke Hasegawa

  4. Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

    Kiminori Terui, Tsutomu Toki & Etsuro Ito

  5. Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan

    Shotaro Iwamoto

  6. Department of Pediatrics, Graduate School of Medicine Kyoto University, Kyoto, Japan

    Hidefumi Hiramatsu

  7. Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan

    Takako Miyamura

  8. Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Suita, Japan

    Yoshiko Hashii

  9. Division of Pediatrics, Department of Reproductive and Developmental Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

    Hiroshi Moritake

  10. Department of Pediatrics, Kyushu Cancer Center, Fukuoka, Japan

    Hideki Nakayama

  11. Department of Pediatrics, Toho University, Tokyo, Japan

    Hiroyuki Takahashi

  12. Department of Pediatrics, Okayama University Graduate School of Medicine, Okayama, Japan

    Akira Shimada

  13. Laboratory of Clinical Hematology, Department of Medical Technology, Kyorin University Faculty of Health Sciences, Mitaka, Japan

    Tomohiko Taki

  14. Department of Hematology and Oncology, Children’s Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Asahito Hama

  15. Department of Pathology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Masafumi Ito

  16. Department of Hematology/Oncology, Saitama Children’s Medical Center, Saitama, Japan

    Katsuyoshi Koh

  17. Department of Hematology/Oncology, Hyogo Children’s Medical Center, Kobe, Japan

    Daiichiro Hasegawa

  18. Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Akiko M. Saito

  19. Human Health Science, Kyoto University, Kyoto, Japan

    Souichi Adachi

  20. Division of Leukemia and Lymphoma, Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan

    Daisuke Tomizawa

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Contributions

T.Tag (principal investigator), Daisuke H, TM, YH, HM, HN, HT, AS, and DT participated actively in the study conception and design; Ta.Ta., ST, Daisuke H, and DT reviewed the data analysis and interpretation and were the main authors of the paper; AMS and ST conducted the statistical analyses; SI and HH were responsible for immunodiagnostics and FCM-MRD analysis; KT, EI, and T.Tok were responsible for GATA1 mutation and GATA1-MRD analysis; T.Tak was responsible for coordinating the molecular biological analyses; AH was responsible for diagnosis and treatment response by morphology; MI was responsible for diagnosis by pathology; KK, Daiichiro H, and AH recruited patients; and Ta.Ta., ST, and SA contributed financial and administrative support for the study. All authors contributed to the conduct of the trial and were involved in the review of the results and the final approval of the paper.

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Correspondence to Takashi Taga.

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Taga, T., Tanaka, S., Hasegawa, D. et al. Post-induction MRD by FCM and GATA1-PCR are significant prognostic factors for myeloid leukemia of Down syndrome. Leukemia 35, 2508–2516 (2021). https://doi.org/10.1038/s41375-021-01157-w

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