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Effect of high-dose chemotherapy plus stem cell rescue on the survival of patients with neuroblastoma modified by MYCN gene gain/amplification and remission status: a nationwide registration study in Japan

Abstract

In high-risk neuroblastoma, the presence of an MYCN gain/amplification (MYCN-GA) is not always a risk factor of cancer-specific death. We herein examined the effect modification of high-dose chemotherapy with autologous hematopoietic stem cell rescue (HDC-autoSCR) in terms of the interaction between MYCN status and remission status (complete remission or very good partial remission [CR/VGPR] vs. partial remission or less [≤PR]). The present study recruited patient data from 1992 to 2017 in the Japan Society of Hematopoietic Cell Transplantation’s national registry. The MYCN status was known in 586 of 950 patients with a single course of HDC-autoSCR. Cumulative hazard curves for neuroblastoma-specific death showed that a subgroup with MYCN-GA and ≤PR had a significantly poorer prognosis than three other subgroups, namely, the MYCN-NGA/ ≤ PR, MYCN-NGA/CR/VGPR, and MYCN-GA/CR/VGPR subgroups even after adjusting for non-infants and stage IV disease (hazard ratio: 2.79; 95% confidence interval: 1.91–4.09; P < 0.001). The interaction between MYCN-GA and ≤PR was significant (pinteraction = 0.006). Hence, the patients with MYCN-GA with non-remission status at HDC-autoSCR had a significantly poorer prognosis than the other subgroups, suggesting that HDC-autoSCR may be effective in patients with CR/VGPR regardless of MYCN gene status and in patients with MYCN-NGA regardless of remission status.

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Fig. 1: Flow-chart of study inclusion.
Fig. 2: Effect of remission status.
Fig. 3: Effect of remission status and MYCN status.
Fig. 4: Effect of remission status and MYCN status in patients with non-stage IV neuroblastoma.
Fig. 5: Effect of remission status and MYCN status in non-infant patients with stage IV neuroblastoma.

References

  1. Yalcin B, Kremer LC, van Dalen EC. High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma. Cochrane Database Syst Rev. 2015, Issue 8. https://doi.org/10.1002/14651858.CD006301.pub3.

  2. Pinto NR, Applebaum MA, Volchenboum SL, Matthay KK, London WB, Ambros PF, et al. Advances in risk classification and treatment strategies for neuroblastoma. J Clin Oncol. 2015;33:3008–17.

    Article  CAS  Google Scholar 

  3. Campbell K, Shyr D, Bagatell R, Fischer M, Nakagawara A, Nieto AC, et al. Comprehensive evaluation of context dependence of the prognostic impact of MYCN amplification in neuroblastoma: a report from the International Neuroblastoma Risk Group (INRG) project. Pediatr Blood Cancer. 2019;66:e27819.

    Article  Google Scholar 

  4. Hishiki T, Matsumoto K, Ohira M, Kamijo T, Shichino H, Kuroda T, et al. Results of a phase II trial for high-risk neuroblastoma treatment protocol JN-H-07: a report from the Japan Childhood Cancer Group Neuroblastoma Committee (JNBSG). Int J Clin Oncol. 2018;23:965–73.

    Article  Google Scholar 

  5. Morgenstern DA, Potschger U, Moreno L, Papadakis V, Owens C, Ash S, et al. Risk stratification of high-risk metastatic neuroblastoma: a report from the HR-NBL-1/SIOPEN study. Pediatr Blood Cancer. 2018;65:e27363.

    Article  Google Scholar 

  6. Ladenstein R, Poetschger U, Pearson ADJ, Brock P, Luksch R, Castel V, et al. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017;18:500–14.

    Article  CAS  Google Scholar 

  7. Kushner BH, Modak S, Kramer K, LaQuaglia MP, Yataghene K, Basu EM, et al. Striking dichotomy in outcome of MYCN-amplified neuroblastoma in the contemporary era. Cancer. 2014;120:2050–9.

    Article  Google Scholar 

  8. Atsuta Y, Suzuki R, Yoshimi A, Gondo H, Tanaka J, Hiraoka A, et al. Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP System. Int J Hematol. 2007;86:269–74.

    Article  Google Scholar 

  9. Atsuta Y. Introduction of Transplant Registry Unified Management Program 2 (TRUMP2): scripts for TRUMP data analyses, part I (variables other than HLA-related data). Int J Hematol. 2016;103:3–10.

    Article  Google Scholar 

  10. Gotoh T, Hosoi H, Iehara T, Kuwahara Y, Osone S, Sugimoto T, et al. Prediction of MYCN amplification in neuroblastoma using serum DNA and real-time quantitative polymerase chain reaction. J Clin Oncol. 2005;23:5205–10.

    Article  CAS  Google Scholar 

  11. Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993;11:1466–77.

    Article  CAS  Google Scholar 

  12. Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N. Engl J Med. 2010;363:1324–34.

    Article  CAS  Google Scholar 

  13. Ladenstein R, Pötschger U, Valteau-Couanet D, Luksch R, Castel V, Yaniv I, et al. Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19:1617–29.

    Article  CAS  Google Scholar 

  14. Cheung NK, Cheung IY, Kushner BH, Ostrovnaya I, Chamberlain E, Kramer K, et al. Murine anti-GD2 monoclonal antibody 3F8 combined with granulocyte-macrophage colony-stimulating factor and 13-cis-retinoic acid in high-risk patients with stage 4 neuroblastoma in first remission. J Clin Oncol. 2012;30:3264–70.

    Article  CAS  Google Scholar 

  15. Kushner BH, Ostrovnaya I, Cheung IY, Kuk D, Modak S, Kramer K, et al. Lack of survival advantage with autologous stem-cell transplantation in high-risk neuroblastoma consolidated by anti-GD2 immunotherapy and isotretinoin. Oncotarget. 2016;7:4155–66.

    Article  Google Scholar 

  16. Amoroso L, Erminio G, Makin G, Pearson ADJ, Brock P, Valteau-Couanet D, et al. Topotecan-vincristine-doxorubicin in stage 4 high-risk neuroblastoma patients failing to achieve a complete metastatic response to rapid COJEC: A SIOPEN Study. Cancer Res Treat. 2018;50:148–55.

    Article  CAS  Google Scholar 

  17. Kushner BH, Kramer K, Cheung NK. Chronic neuroblastoma. Cancer. 2002;95:1366–75.

    Article  Google Scholar 

  18. London WB, Castel V, Monclair T, Ambros PF, Pearson AD, Cohn SL, et al. Clinical and biologic features predictive of survival after relapse of neuroblastoma: a report from the International Neuroblastoma Risk Group project. J Clin Oncol. 2011;29:3286–92.

    Article  Google Scholar 

  19. Basta NO, Halliday GC, Makin G, Birch J, Feltbower R, Bown N, et al. Factors associated with recurrence and survival length following relapse in patients with neuroblastoma. Br J cancer. 2016;115:1048–57.

    Article  Google Scholar 

  20. Campbell K, Gastier-Foster JM, Mann M, Naranjo AH, Van Ryn C, Bagatell R, et al. Association of MYCN copy number with clinical features, tumor biology, and outcomes in neuroblastoma: A report from the Children’s Oncology Group. Cancer. 2017;123:4224–35.

    Article  CAS  Google Scholar 

  21. Ambros PF, Ambros IM, Brodeur GM, Haber M, Khan J, Nakagawara A, et al. International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. Br J cancer. 2009;100:1471–82.

    Article  CAS  Google Scholar 

  22. Park JR, Kreissman SG, London WB, Naranjo A, Cohn SL, Hogarty MD, et al. Effect of tandem autologous stem cell transplant vs single transplant on event-free survival in patients with high-risk neuroblastoma: a randomized clinical trial. JAMA. 2019;322:746–55.

    Article  Google Scholar 

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Acknowledgements

We thank Mr. James Robert Valera for his assistance with editing the paper. We thank all the clinicians and hospital and health center staff who provided us with valuable data from the Japan Society for Hematopoietic Cell Transplantation registry.

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Drafting of the paper: YS. Conception and design: YS, KM, YT. Data analysis and interpretation: YS, KM, YT, MU. Data collection and critical revision: CK, YY, KK, KW, YK, HG, AK, KO, YK, JF, MI, AS, YA.

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Correspondence to Yuya Saito.

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Saito, Y., Urashima, M., Takahashi, Y. et al. Effect of high-dose chemotherapy plus stem cell rescue on the survival of patients with neuroblastoma modified by MYCN gene gain/amplification and remission status: a nationwide registration study in Japan. Bone Marrow Transplant 56, 2173–2182 (2021). https://doi.org/10.1038/s41409-021-01303-z

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