, Volume 22, Issue 5, pp 488–496 | Cite as

Ipilimumab-induced hypophysitis, a single academic center experience

  • Travis SnydersEmail author
  • Daniel Chakos
  • Umang Swami
  • Emile Latour
  • Yiyi Chen
  • Maria Fleseriu
  • Mohammed Milhem
  • Yousef Zakharia
  • Roula Zahr



Immune checkpoint inhibitors, single or in combination, have recently become a cornerstone for the treatment of many malignancies. Ipilimumab, a CTLA-4 inhibitor, was initially FDA approved for treatment of unresectable or metastatic melanoma and subsequently in combination therapy for other cancers. Ipilimumab-induced hypophysitis (IH) risk of development varies in different studies between 0 and 17%. Furthermore, little is known on how to predict which patients will develop IH and its impact on efficacy of Ipilimumab and survival for these patients. Here we reviewed IH and its impact on progression-free survival (PFS) and overall survival (OS).


Retrospective, IRB- approved review of consecutive 117 melanoma patients who received ipilimumab between 2011 and 2016 was undertaken. Demographic and clinical characteristics, treatment timing and doses, time to progression after therapy, and survival data were reviewed. Patients were predefined in two groups: patients with and without IH. Descriptive statistics were used to summarize the demographic and clinical characteristics of the study sample. All values are shown as means and standard deviation [mean (SD)] unless indicated otherwise. P < 0.05 was considered to be statistically significant.


Of the 117 patients, 15 (12.8%) with a median age of 62.1 years developed IH. In the IH cohort, 10 (66.7%) were male and were significantly older than females (median 67.7 vs. 50.8; P = 0.009). This difference was not seen in non-IH group. Male patients with IH were significantly older than males without IH (67.7 vs. 56.4 years, P = 0.020), however this difference was not observed in females. No patient who received prior cancer systemic therapy (0/30) developed IH vs. 17.2% (15/72) without prior therapy developed IH (OR 0.00; 95% CI 0.00 to 0.73, P = 0.011). Between IH and non-IH patients, there was no difference in gender, race, ethnicity, BMI, diabetes or autoimmune disease at baseline, number of administered ipilimumab cycles, presence of primary melanoma lesion, or BRAF status. IH and non-IH patients had a similar median PFS (8.1 vs. 6.8 months, HR = 0.51, 95% CI 0.24 to 1.05 P = 0.062) and OS (53.3 vs. 29.5 months; HR 0.66, 95% CI 0.30 to 1.46; P = 0.307).


In this study of melanoma patients treated with Ipilimumab, risk of developing IH was high (almost 13%). Older age in men and no prior cancer therapy were associated with IH higher risk. Development of IH was not associated with PFS or OS. Increased use of immune checkpoint inhibitors in the future will impact IH overall risk, thus awareness is needed. Given the lack of reliable identifiable risk factors, close monitoring of signs and symptoms after each therapy cycle is critical for early detection and treatment of hypophysitis.


Malignant melanoma Ipilimumab Hypophysitis Immunotherapy Immune related adverse side effects 



Biostatics support was provided by the Biostatistics Shared Resource, Knight Cancer Institute [NCI P30CA069533] (EL, YC).

Compliance with ethical standards

Conflict of interest

Travis Snyders declares that he has no conflict of interest. Daniel Chakos declares that he has no conflict of interest. Umang Swami declares that he has no conflict of interest. Emile Latour declares that he has no conflict of interest. Yiyi Chen declares that she has no conflicts of interest. Maria Fleseriu declares that she has no conflict of interest. Mohammed Milhem is a member of advisory boards for Amgen, Trieza, Biontech, Blueprint medicines corporation, Immunocore, and Array BioPharma, Inc. Yousef Zakharia is a member of advisory boards for Amgen, Roche diagnostics, Novartis, Jansen, Eisai, Exelixis, Castle Bioscience, Array, and Bayer. Roula Zahr declares that she has no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

The Institutional Review Board at the University of Iowa Hospitals and Clinics approved this study. As this was a retrospective review of patient data, individual informed consent was exempted by the Institutional review board.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Internal MedicineUniversity of Iowa Hospitals and ClinicsIowa CityUSA
  2. 2.Division of Oncology, Department of Internal Medicine, Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA
  3. 3.Biostatistics Shared Resource, Knight Cancer InstituteOregon Health and Science UniversityPortlandUSA
  4. 4.Division of Endocrinology, Department of MedicineOregon Health and Science UniversityPortlandUSA

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