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ACUTE MYELOID LEUKEMIA

High-dose cytarabine induction therapy and flow cytometric measurable residual disease monitoring for children with acute myeloid leukemia

Leukemia volume 38, pages 202–206 (2024)Cite this article

Subjects

Induction therapy “ECM” (5 days of etoposide followed by 7 days of standard-dose cytarabine [SDAC] and 5 days of mitoxantrone) has been standard induction therapy for Japanese children with acute myeloid leukemia (AML) since the early 1990s [1,2,3], and was recently adopted in the NOPHO-DBH AML 2012 (NCT01828489), an international pediatric AML study by the Nordic countries, Belgium, the Netherlands, and others [4]. In contrast, the role of high-dose cytarabine (HDAC) in initial induction therapy is controversial (Table S1), although its efficacy in post-remission consolidation phases is established [5,6,7]. In addition, stratifying patients into appropriate risk groups is crucial for improving outcomes of AML. Cytogenetics, molecular genetics, and morphological evaluation of early treatment responses have been utilized to that end, but there is increasing significant evidence for monitoring submicroscopic levels of measurable residual disease (MRD) taking the place of morphological evaluation [8, 9].

The JPLSG AML-12 trial (UMIN-CTR. Identifier: UMIN000013288/jRCT. Identifier: jRCTs041180128) conducted by the Japan Children’s Cancer Group (JCCG) aimed to improve event-free survival (EFS) rates by introducing HDAC in initial induction therapy, and at the same time evaluated the significance and feasibility of prospective monitoring of flow cytometric MRD (FCM-MRD) [10]. Patient eligibility criteria included diagnosis of previously untreated AML (excluding acute promyelocytic leukemia, AML in Down syndrome patients, secondary AML, and myeloid sarcoma) and age <18 years old at diagnosis. Informed consent was obtained from the parents or guardians according to the Declaration of Helsinki, and institutional review board approval was obtained for all aspects of the study. After the enforcement of the Clinical Trials Act in Japan in 2018, AML-12 was approved centrally by the Certified Review Board at the NHO Nagoya Medical Center on December 7, 2018. AML-12 was designed as a non-blinded, randomized, parallel, comparative, seamless phase II–III clinical trial. In the phase II (P2) part, randomization between the two initial induction therapies (ECM vs. high-dose ECM [HD-ECM]) was eligible only for the patients registered from the 79 selected P2 institutions. Patients from the other non-selected P2 institutions were accepted, but automatically allocated to the standard ECM. In the phase III (P3) part, randomization was expanded to all patients registered from all participating institutions (Table S2 and Fig. S1). Following Induction-2, patients achieving morphological complete remission (CR) were allocated to either of the three risk groups. Standard risk (SR) with core binding factor (CBF) AML group (CBF SR) was defined by presence of t(8;21)(q22;q22)/RUNX1::RUNX1T1, inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB::MYH11, concurrent with < 5% bone marrow blasts and no extramedullary disease at end of Induction-1 (EOI-1). High risk group (HR) was defined by presence of monosomy 7, 5q deletion, t(16;21)(p11;q22)/FUS::ERG, t(9;22)(q34;q11.2)/BCR::ABL1, t(6;11)(q27;q23)/KMT2A::AFDN, t(5;11)(q35;p15.5)/NUP98::NSD1, FLT3-ITD (regardless of allelic ratio or other cooperating gene mutations), or residual disease (≥5% bone marrow blasts or residual extramedullary disease) at EOI-1. Patients with non-CBF AML without HR features were classified as Non-CBF SR. The therapeutic regimen used in the AML-12 study is described in Table S3. All HR patients were allocated to receive allogeneic hematopoietic stem cell transplantation (HSCT) in first CR.

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Fig. 1: Outcomes according to the flow cytometric measurable residual disease (FCM-MRD) levels at end of Induction-1 (EOI-1: TP-1) and at end of Induction-2 (EOI-2: TP2).

Data availability

The Japan Children’s Cancer Group (JCCG) is committed to sharing, with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by the JCCG steering committee based on scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

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Acknowledgements

The authors thank Dario Campana and Elaine Coustan-Smith of National University Singapore for their technical assistance in FCM-MRD monitoring. The authors also thank the senior medical editor from the Center for Postgraduate Education and Training of the National Center for Child Health and Development for editing this manuscript.

Funding

This study was supported by Grants for Clinical Cancer Research from the Ministry of Health, Labor, and Welfare of Japan (H23-Gan Rinsho-Ippan-014, Keizo Horibe; H25-Gan Rinsho-Shitei-002, Tatsuo Tajiri; H26-Kakushinteki Gan-Ippan-061, Souichi Adachi), Grant from the National Center for Child Health and Development (22-5 and 26-20, Nobutaka Kiyokwa), and Grants for Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development (AMED) (JP17ck0106329 and JP20ck0106604, Souichi Adachi).

Author information

Authors and Affiliations

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

    Daisuke Tomizawa

  2. Center for Clinical Research and Advanced Medicine, Shiga University of Medical Science, Otsu, Japan

    Jun Matsubayashi

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

    Shotaro Iwamoto & Takao Deguchi

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

    Hidefumi Hiramatsu

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

    Daisuke Hasegawa

  6. Division of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

    Hiroshi Moritake

  7. Department of Hematology and Oncology, Hyogo Prefectural Kobe Children’s Hospital, Kobe, Japan

    Daiichiro Hasegawa

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

    Kiminori Terui

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

    Asahito Hama

  10. Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Shin-ichi Tsujimoto

  11. Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan

    Nobutaka Kiyokawa

  12. Department of Laboratory Medicine, Tokai University School of Medicine, Isehara, Japan

    Hayato Miyachi

  13. Division of Cancer Immunodiagnostics, Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan

    Takao Deguchi

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

    Yoshiko Hashii

  15. Department of Pediatrics, Osaka International Cancer Institute, Osaka, Japan

    Yoshiko Hashii

  16. Clinical Research Center, NHO Nagoya Medical Center, Nagoya, Japan

    Yuka Iijima-Yamashita, Akiko Moriya Saito & Keizo Horibe

  17. Department of Medical Technology, Kyorin University Faculty of Health Sciences, Mitaka, Japan

    Tomohiko Taki

  18. Department of Pediatrics, Japanese Red Cross Narita Hospital, Narita, Japan

    Yasushi Noguchi

  19. Department of Pediatric Hematology/Oncology, Ibaraki Children’s Hospital, Mito, Japan

    Kazutoshi Koike

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

    Katsuyoshi Koh

  21. Department of Hematology and Oncology, Tokyo Metropolitan Children’s Medical Center, Fuchu, Japan

    Yuki Yuza

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

    Takashi Taga

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

    Shiro Tanaka

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

    Souichi Adachi

Authors
  1. Daisuke Tomizawa
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Contributions

SA (principal investigator), DT (co-principal investigator), STanaka, SI, HMoritake, DaiichiroH, KT, AMS, AH, and TTaga conceived and designed the study; DT, SA, STanaka, JM, and STsujimoto reviewed the data analysis and interpretation and served as the main authors of the manuscript; STanaka and JM conducted the statistical analysis; AMS contributed to the data management of the study; HMiyachi performed the central morphological diagnosis; TD, NK, and YH performed the central immunodiagnostics; YIY and KH performed the central chimeric gene analysis and FLT3-ITD analysis; DaisukeH and TTaki performed the central cytogenetic analysis; SI, HH, and NK performed the central FCM-MRD analysis; AH, YN, KKoike, KKoh, and YY recruited patients; SA, NK, and KH contributed to the financial support of the study; SA and TTaga contributed to the administrative support of the study; and all authors contributed to the conduct of the trial, reviewed the results, and provided final approval of the manuscript.

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Correspondence to Daisuke Tomizawa.

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Tomizawa, D., Matsubayashi, J., Iwamoto, S. et al. High-dose cytarabine induction therapy and flow cytometric measurable residual disease monitoring for children with acute myeloid leukemia. Leukemia 38, 202–206 (2024). https://doi.org/10.1038/s41375-023-02075-9

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