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Phase 2 study of combination chemotherapy with bortezomib in children with relapsed and refractory acute lymphoblastic leukemia

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Abstract

Treatment outcomes for children with relapsed and refractory acute lymphoblastic leukemia (R/R-ALL) remain poor, and the optimal induction therapy has not been determined. Bortezomib is a proteasome inhibitor that acts synergistically and additively with standard chemotherapy for ALL. We evaluated the efficacy and safety of combination chemotherapy with bortezomib in children with R/R-ALL. This single-arm, multicenter, phase 2 study was conducted in Japan between 2016 and 2020. Eligible patients were divided into two cohorts: a high-risk first-relapse cohort of untreated patients with high-risk first-relapsed ALL and an expansion cohort of patients with refractory ALL, including multiple relapses, relapse after allogeneic hematopoietic cell transplantation, and induction failure. All patients received a single course of chemotherapy as induction therapy. Sixteen patients (10 in the high-risk first-relapse cohort, six in the expansion cohort) were evaluable. The overall remission rate after induction therapy was 60% in the high-risk first-relapse cohort and 16.7% in the expansion cohort. All patients had minimal residual disease. Adverse events were acceptable except for interstitial lung disease and hypoxia in a patient in the expansion cohort, but addition of bortezomib to conventional chemotherapy did not produce obvious improvement in children with R/R-ALL.

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Data availability

The data generated and analyzed in this study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank all patients and parents as well as clinical staff involved in this study. This study was an investigator-initiated clinical trial and supported by a research grant from the Japan Agency for Medical Research and Development (AMED) (Grant number: 20ck0106419h0003). Bortezomib was provided as an investigational agent from Janssen Pharmaceutical K.K. (Tokyo, Japan).

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Authors and Affiliations

  1. Division of Hematology and Oncology, Kanagawa Children’s Medical Center, 2-138-4 Mutsukawa, Minami-Ku, Yokohama, Kanagawa, 232-8555, Japan

    Naoyuki Miyagawa & Hiroaki Goto

  2. Department of Pediatrics, Niigata Cancer Center Hospital, Niigata, Japan

    Atsushi Ogawa

  3. Department of Pediatric Oncology, Fukushima Medical University Hospital, Fukushima, Japan

    Atsushi Kikuta

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

    Yoshiyuki Kosaka

  5. Department of Pediatrics, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Masahiro Sekimizu

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

    Daisuke Tomizawa

  7. Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan

    Hidemi Toyoda

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

    Hidefumi Hiramatsu

  9. Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan

    Junichi Hara

  10. Department of Pediatrics, Hiroshima University Hospital, Hiroshima, Japan

    Shinji Mochizuki

  11. Department of Pediatrics, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan

    Hideki Nakayama

  12. Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan

    Kenichi Yoshimura

  13. Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Yuka Iijima-Yamashita & Masashi Sanada

  14. Department of Pediatric Oncology, National Cancer Center Hospital, Tokyo, Japan

    Chitose Ogawa

Authors
  1. Naoyuki Miyagawa
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  2. Hiroaki Goto
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  16. Chitose Ogawa
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Contributions

NM performed the research and data collection as a sub-investigator and wrote the manuscript. CO designed the study and obtained a research grant as a primary investigator. HG, AK, YK, MS, HN, and CO worked as investigators and performed the research and collected data. AO, DT, HT, HH, JH, and SM worked as investigators. All investigators helped with the development and conduct of the study. KY helped with statistical analyses. YIY and MS performed gene analyses. HG and CO assisted with writing the manuscript. All authors contributed to the revision and approval of the final manuscript.

Corresponding author

Correspondence to Naoyuki Miyagawa.

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All authors have no conflicts of interest to disclose that are associated with the manuscript.

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Miyagawa, N., Goto, H., Ogawa, A. et al. Phase 2 study of combination chemotherapy with bortezomib in children with relapsed and refractory acute lymphoblastic leukemia. Int J Hematol 118, 267–276 (2023). https://doi.org/10.1007/s12185-023-03609-8

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  • DOI: https://doi.org/10.1007/s12185-023-03609-8

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