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Busulfan conditioning and prognostic impact of jaundice in late-onset sinusoidal obstruction syndrome following allogeneic hematopoietic cell transplantation

Bone Marrow Transplantation volume 60, pages 418–421 (2025)Cite this article

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The first report of late-onset SOS in 1999 described four older patients who underwent autologous peripheral blood stem cell transplantation (auto-PBSCT) with Bu & cyclophosphamide (Bu/Cy) conditioning for lymphoma or multiple myeloma [3]. Another study also in 1999 analyzed 253 patients who received auto-PBSCT or autologous bone marrow transplantation following Bu/Mel & thiotepa (Bu/Mel/TT) conditioning, with 28% diagnosed with SOS [4]. Compared to historical control with Cy [5], Bu/Mel/TT showed delayed jaundice onset (mean 15.4 vs. 5.9 days) and fewer severe cases (4% vs. 19%). A separate analysis of patients receiving Bu/Mel or Mel alone for multiple myeloma found Bu/Mel led to higher SOS incidence (8% vs. 0.4%) and more late-onset SOS (median 29 vs. 9–13 days) [6]. These studies suggest that auto-PBSCT with multiple alkylating agents, particularly Bu, may increase the risk of late-onset SOS, potentially due to other alkylating agents affecting the metabolism of Bu [7]. Building on these previous findings and using a cohort in which approximately half of the patients received Bu/Mel regimens, our study further clarifies the impact of Bu-containing regimens on late-onset SOS risk and provides new insights into factors affecting patient prognosis. First, the study demonstrates that Bu-containing conditioning regimens are a substantial risk factor for late-onset SOS, consistent with a previous report which identified Bu as the sole risk factor [8]. Second, the study clarified the prognosis of late-onset SOS, contributing clinically relevant insights, as few prior reports address this [9]. Third, jaundice at diagnosis emerged as a key prognostic factor, making the first observation of its effect on late-onset SOS prognosis. Lastly, late-onset SOS was the most frequent subtype, representing 70% of all SOS events in the present study. The study provided an overall picture of SOS diagnosed retrospectively according to the EBMT 2016 criteria. Previous EBMT findings support that late-onset SOS is often undiagnosed, as it underlies 35% of deaths from multi-organ failure [1]. There are several limitations to this study. First, this is a retrospective study conducted at a single institution. Although the possibility of contamination by other complications cannot be ruled out, the OS rate of SOS cases is consistent with previous reports and does not appear to be a major issue for the reliability of the study’s accuracy. Second, the majority of cases were from prior to 2019, when defibrotide was approved in Japan. The therapeutic effect of defibrotide is scarcely reflected. Third, the analyzed population had a higher SOS risk than the general transplant recipient population, with most myeloid neoplasm patients receiving Bu/Mel as conditioning [10]. Therefore, the frequency and risk factors for late-onset SOS should be validated in a broader cohort. In conclusion, Bu use was a significant risk factor for late-onset SOS, and jaundice affected the prognosis of late-onset SOS. Prospective studies are warranted to further elucidate late-onset SOS.

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Fig. 1: Cumulative incidences and outcomes of SOS.

Data availability

The data that support the findings of this study are available from the corresponding author, S. Takagi, upon reasonable request.

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Acknowledgements

We thank the patients, the donors, and their families. We also thank the physicians, nurses, pharmacists, physical therapists, hematopoietic cell transplantation coordinators (Ms. Madoka Narita, Ms. Rumiko Tsuchihashi, Ms. Tomoko Amemiya, and Ms. Rina Hino), data managers (Ms. Kaori Kobayashi and Ms. Rumiko Tsuchihashi), secretariat members of the Hematopoietic Cell Transplantation Promotion Base Hospital Project (Ms. Naomi Watanabe), other co-medical staff, and support personnel for their care of the patients involved in this study.

Funding

This study is funded by Okinaka Memorial Institute for Medical Research.

Author information

Authors and Affiliations

  1. Department of Hematology, Toranomon Hospital, Tokyo, Japan

    Shinsuke Takagi, Otoya Watanabe, Daisuke Kaji, Yuki Taya, Aya Nishida, Hisashi Yamamoto, Go Yamamoto, Shuichi Taniguchi & Naoyuki Uchida

  2. Center for Long-Term Follow-Up After Hematopoietic Cell Transplantation, Toranomon Hospital, Tokyo, Japan

    Shinsuke Takagi, Hisashi Yamamoto, Yuki Asano-Mori & Atsushi Wake

  3. Okinaka Memorial Institute for Medical Research, Tokyo, Japan

    Shinsuke Takagi, Atsushi Wake & Naoyuki Uchida

  4. Department of Hematology, Toranomon Hospital Kajigaya, Kawasaki, Japan

    Kyosuke Yamaguchi, Kosei Kageyama, Kazuya Ishiwata & Atsushi Wake

  5. Department of Transfusion and Cellular Therapy, Toranomon Hospital, Tokyo, Japan

    Daisuke Kaji, Yuki Taya & Yuki Asano-Mori

  6. Center for Cellular Therapy, Toranomon Hospital, Tokyo, Japan

    Daisuke Kaji, Yuki Taya, Yuki Asano-Mori & Go Yamamoto

Authors
  1. Shinsuke Takagi
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  2. Otoya Watanabe
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  3. Kyosuke Yamaguchi
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  8. Kazuya Ishiwata
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  13. Shuichi Taniguchi
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  14. Naoyuki Uchida
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Contributions

STakagi is the principal investigator and takes primary responsibility for the paper; STakagi wrote the manuscript; STakagi, OW, KY, KK, DK, YT, AN, KI, HY, YA-M, GY, AW, STaniguchi, and NU treated patients and reviewed the final manuscript; STakagi designed the research; and STaniguchi and NU organized the project.

Corresponding author

Correspondence to Shinsuke Takagi.

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Competing interests

The authors declare no competing interests.

Ethics approval

All procedures performed in the study was in accordance with the ethical standards of the institutional and national research committee and with the Declaration of Helsinki in 1964 and its later amendments or comparable ethical standards. The Institutional Review Board of Toranomon Hospital approved this study (approval number, 1939).

Patient consent

An opt-out consent approach was permitted for this study in accordance with ethical guidelines for observational studies using existing data, and patients who declined registration were excluded.

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Takagi, S., Watanabe, O., Yamaguchi, K. et al. Busulfan conditioning and prognostic impact of jaundice in late-onset sinusoidal obstruction syndrome following allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 60, 418–421 (2025). https://doi.org/10.1038/s41409-024-02501-1

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