Category: Pituitary Disorders/Neuroendocrinology
Immune Checkpoint Inhibitors (ICPi) are promising therapies for advanced malignancies, including melanoma, lung cancer, and prostate cancer. However, their use can induce mechanism-based toxicities called as immune-related adverse events (irAE) that can potentially affect various organ tissues, including the endocrine system. We present the case of a patient who developed panhypopituitarism and central diabetes insipidus (DI) (presumably due to hypophysitis) after three cycles of ipilimumab, an anti-CTLA4-Ab ICPi.
Results : N/A
Discussion : A 47-year-old female with metastatic malignant melanoma, post-surgical excision, was treated with ipilimumab (2016), after she developed adverse events with initial treatment with interferon-gamma. She received three doses (3 mg/kg, cycles 1 & 2; 5 mg/kg, cycle 3) of ipilimumab at 3-week intervals. Within the next 2-3 weeks, she developed symptoms of extreme weakness, lethargy, lightheadedness, and confusion. Fourth cycle of ipilimumab was withheld, and an endocrine work up revealed panhypopituitarism (central hypothyroidism, secondary adrenal insufficiency: AM cortisol was 0.9 mcg/dL, GH deficiency, and central DI (symptoms & serum Na 151 mmol/L with inappropriately normal urine osmolality: 343 mosmol/kg post-8-hour water deprivation). MRI done a month later, showed crescentic non-enhancing focus in the right anterior pituitary gland with a normal T1 hyper-intense posterior pituitary signal. No history of headaches, visual disturbances, seizures, galactorrhea, infiltrative diseases of the pituitary, cranial irradiation or trauma, and autoimmune diseases. She had oligo-amenorrhea since 1.5 years (post-Mirena IUD insertion) and was not on hormone replacement therapy. She was put on hydrocortisone (30 mg/day), levothyroxine (50 mcg/day), and tab desmopressin 0.1 mg daily. Reassessment of endocrine status (08/2018) on above replacements revealed FT4 1.31 ng/dL, TSH 1.53 uIU/mL, IGF-1 48 ng/mL, prolactin < 3 ng/mL, LH <0.5 mU/mL, FSH 1.1 mU/mL, E2 <5 pg/mL, Na 138 mmol/L, serum osmolality 285 mosmol/kg, and urine osmolality 547 mosmol/kg. Temporal sequence of hypophysitis with panhypopituitarism is consistent with literature evidence. However, to the best of our knowledge, this is the first reported case of ipilimumab-induced DI. Our patient continues to have persistent pituitary deficiencies for >2 years since diagnosis. Recovery of pituitary-thyroid axis is reported in 37-50% cases, while recovery of adrenal axis is rare.
Novel ICPi can cause immune imbalance and irAE involving the endocrine system. Careful monitoring for and treatment of endocrinopathies is required during ICPi therapy.
Vidita Divan– Fellow, SUNY Upstate Medical Center, Camillus, New York
Ramachandra Naik– Professor of Medicine, SUNY Upstate Medical University, syracuse, New York
Vidita Divan– Fellow , SUNY Upstate Medical University, Camillus, New York
SUNY Upstate Medical Center
Camillus, New York
I graduated from SMIMER (Surat Municipal Institute of Medical Education and Research) from Surat, India. I did my Internal Medicine residency training from Aurora Health Care, Milwaukee, WI (2014-2017). I was delighted to accept the position of a Chief resident at Aurora Health Care which helped to enhance my mentorship skills, time management and leadership skills. I was fortunate to start my fellowship in Endocrinology at SUNY Upstate Medical University in July 2018.
I strongly believe in Evidence based medicine and was involved in quality improvement project and committee during residency training. I also got opportunity to do poster presentation at American Geriatric Society Annual meeting (May, 2016) and Endocrine Society (March, 2018) as well as an oral presentation at American College of Physician (September,2015). I also wrote a book chapter on thyroid disease in the elderly which was published in "Encyclopedia for the Elderly".
As an Endocrine fellow, and ultimately a practicing internist, I plan on committing my life to the betterment of my patients, and the profession.
Professor of Medicine
SUNY Upstate Medical University
syracuse, New York
Ramachandra (Ram) G. Naik, MD, is an endocrinologist with three decades of global institutional experience in patient care, clinical research and teaching, in both academic- and private-practice settings, and in drug and device development and medical affairs in biopharmaceutical industry. He is currently working as a Professor of Medicine in the Division of Endocrinology, Diabetes, and Metabolism at SUNY Upstate Medical University, Syracuse, NY, and spends 50-60% of his time in patient care (ambulatory diabetes and endocrinology practice at the Joslin Diabetes Center Affiliate at Upstate), and the remaining time in clinical research, teaching, and administrative activities. He holds clinical privileges at the Upstate University Hospital, Crouse Hospital (an Affiliate of Northwell Health), and the Syracuse VA Medical Center. He also serves as an Assistant Dean and Director for Clinical & Translational Research Programs, and in this University-wide administrative role, he leads external academic collaboration and partnership initiatives.
Dr. Naik received his medical degree from M. R. Medical College, Gulbarga, India (1984) where he completed his medical school with distinction (1979-84), followed by rotating internship (1984-85), and internal medicine residency training (1986-89) and board certification (1989). He did his endocrinology post-doctoral fellowship training (1989-93) and endocrinology board certification (1993) from All India Institute of Medical Sciences, New Delhi, India, followed by an additional accredited post-doctoral clinical and research fellowship in metabolism, endocrinology, and nutrition at the University of Washington and the Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA (1996-98). He was a recipient of Juvenile Diabetes Research Foundation (JDRF) post-doctoral fellowship award at the University of Washington, and worked under the mentorship of Dr. Jerry Palmer, on elucidating the pathophysiology of latent autoimmune diabetes in adults (LADA). Subsequently, Dr. Naik completed an executive business education as well, from Kellogg School of Management, Northwestern University, Evanston, IL (2010-11).