International Journal of Hematology

, Volume 105, Issue 3, pp 383–386 | Cite as

Fulminant type I diabetes mellitus associated with nivolumab in a patient with relapsed classical Hodgkin lymphoma

  • Wataru MunakataEmail author
  • Ken Ohashi
  • Nobuhiko Yamauchi
  • Kensei Tobinai
Case Report


We report the case of a patient with relapsed classical Hodgkin lymphoma who developed fulminant type I diabetes mellitus as a severe adverse event of treatment with the anti-programmed cell death-1 (PD-1) antibody, nivolumab. On the first day of the sixth cycle, the blood glucose level was markedly elevated (375 mg/dL). Although neither ketoacidosis nor ketonuria was detected, the markedly acute onset of the hyperglycemia was consistent with the typical clinical course of fulminant type I diabetes mellitus, and this diagnosis was supported by clinical data. All autoantibodies associated with type I diabetes mellitus were negative. The endogenous insulin secretion ceased completely within 2 weeks. After the blood glucose level was brought under control, nivolumab was resumed and continued without other major adverse events. Human leukocyte antigen (HLA) analysis revealed that the patient carried the HLA-B*4002 haplotype, a susceptibility allele for this type of diabetes mellitus. This case suggests that fulminant type I diabetes mellitus may be triggered by nivolumab in patients with a genetic background associated with the condition, warranting careful future consideration of this particular adverse event.


Fulminant type I diabetes mellitus Anti-PD-1 antibody Immune-related adverse events Nivolumab 



ONO-4538-15 study was funded by Ono Pharmaceutical Co., Ltd.

Compliance with ethical standards

Conflict of interest

K. Tobinai: Research funding from Ono Pharmaceutical Co., Ltd.


  1. 1.
    Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311–9.CrossRefPubMedGoogle Scholar
  2. 2.
    Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30.CrossRefPubMedGoogle Scholar
  3. 3.
    Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–35.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627–39.CrossRefPubMedGoogle Scholar
  5. 5.
    Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51–60.CrossRefPubMedGoogle Scholar
  6. 6.
    Hatake K, Kinoshita T, Fukuhara N, Choi I, Taniwaki M, Ando K, et al. Phase II study of nivolumab in Japanese patients with relapsed or refractory Hodgkin lymphoma previously treated with brentuximab vedotin (ONO-4538-15): an interim analysis. J Clin Oncol. 2016; 34 (suppl: abstr e19018). Google Scholar
  7. 7.
    Okamoto M, Okamoto M, Gotoh K, Masaki T, Ozeki Y, Ando H, et al. Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy. J Diabetes Investig. 2016. doi: 10.1111/jdi.12531.
  8. 8.
    Miyoshi Y, Ogawa O, Oyama Y. Nivolumab, an anti-programmed cell death-1 antibody, induces fulminant type 1 diabetes. Tohoku J Exp Med. 2016;239:155–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Mellati M, Eaton KD, Brooks-Worrell BM, Hagopian WA, Martins R, Palmer JP, et al. Anti-PD-1 and anti-PDL-1 monoclonal antibodies causing type 1 diabetes. Diabetes Care. 2015;38:e137–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Martin-Liberal J, Furness AJ, Joshi K, Peggs KS, Quezada SA, Larkin J. Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. Cancer Immunol Immunother. 2015;64:765–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Hughes J, Vudattu N, Sznol M, Gettinger S, Kluger H, Lupsa B, et al. Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy. Diabetes Care. 2015;38:e55–7.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Gaudy C, Clevy C, Monestier S, Dubois N, Preau Y, Mallet S, et al. Anti-PD1 pembrolizumab can induce exceptional fulminant type 1 diabetes. Diabetes Care. 2015;38:e182–3.CrossRefPubMedGoogle Scholar
  13. 13.
    Imagawa A, Hanafusa T, Miyagawa J, Matsuzawa Y. A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Osaka IDDM Study Group. N Engl J Med. 2000;342:301–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Kawasaki E, Imagawa A, Makino H, Uga M, Abiru N, Hanafusa T, et al. Differences in the contribution of the CTLA4 gene to susceptibility to fulminant and type 1A diabetes in Japanese patients. Diabetes Care. 2008;31:1608–10.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kawabata Y, Ikegami H, Awata T, Imagawa A, Maruyama T, Kawasaki E, et al. Differential association of HLA with three subtypes of type 1 diabetes: fulminant, slowly progressive and acute-onset. Diabetologia. 2009;52:2513–21.CrossRefPubMedGoogle Scholar
  16. 16.
    Imagawa A, Hanafusa T, Uchigata Y, Kanatsuka A, Kawasaki E, Kobayashi T, et al. Fulminant type 1 diabetes: a nationwide survey in Japan. Diabetes Care. 2003;26:2345–52.CrossRefPubMedGoogle Scholar
  17. 17.
    Cho YM, Kim JT, Ko KS, Koo BK, Yang SW, Park MH, et al. Fulminant type 1 diabetes in Korea: high prevalence among patients with adult-onset type 1 diabetes. Diabetologia. 2007;50:2276–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Imagawa A, Hanafusa T. Fulminant type 1 diabetes—an important subtype in East Asia. Diabetes Metab Res Rev. 2011;27:959–64.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2016

Authors and Affiliations

  1. 1.Department of HematologyNational Cancer Center HospitalTokyoJapan
  2. 2.Department of General Internal MedicineNational Cancer Center HospitalTokyoJapan

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