Hypophysitis Induced by Monoclonal Antibodies to Cytotoxic T Lymphocyte Antigen 4: Challenges from a New Cause of a Rare Disease

Abstract

Learning Objectives: After completing this course, the reader will be able to: Identify symptoms of hypophysitis as an infrequent immune related side effect of ipilimumab and other anti‐CTLA‐4 monoclonal antibodies. Select the appropriate diagnostic and therapeutic work‐up for patients suspected of having anti‐CTLA‐4 monoclonal‐induced hypophysitis. This article is available for continuing medical education credit at http://CME.TheOncologist.com Specific human monoclonal antibodies antagonize cytotoxic T‐lymphocyte antigen 4 (anti–CTLA‐4 mAbs), a negative regulator of the immune system, inducing unrestrained T‐cell activation. In patients with advanced or metastatic melanoma, one of these agents, ipilimumab, produced considerable disease control rates and, for the first time, a clear improvement in overall survival outcomes. However, accumulating clinical experience with anti–CTLA‐4 mAbs identified a novel syndrome of autoimmune and autoinflammatory side effects, designated as “immune‐related adverse events,” including mainly rash, colitis, and hepatitis. Autoimmune hypophysitis has emerged as a distinctive side effect induced by anti–CTLA‐4 mAbs. This condition may be life threatening because of adrenal insufficiency if not promptly recognized, but it may easily be diagnosed and treated if clinically suspected. Hypopituitarism caused by these agents is rarely reversible and prolonged or life‐long substitutive hormonal treatment is often required. The precise mechanism of injury to the pituitary triggered by anti–CTLA‐4 mAbs is yet to be fully elucidated.

Ipilimumab, not just another anti-cancer therapy: hypophysitis as side effect illustrated by four case-reports

“…Hypophysitis secondary to ipilimumab administration, first reported in 2003 [13], is now well described, but the mechanism of pituitary injury remains unknown. It is still unclear whether the effects result from T cells specifically acting against antigens shared by tumour and normal cells or from the concomitant activation of multiple T cell populations with separate anti-host and anti-tumour activity [11][12][13].…”

“…Sometimes, the adverse events can be potentially life-threatening with an urgent need for medical intervention. An example of a lifethreatening adverse event is involvement of the pituitary gland [9,11].…”

“…Ipilimumab was approved for the treatment of melanoma by the Food and Drug Administration (FDA) in March 2011 and by the European Medicines Agency in July 2011 for use in advanced (unresectable or metastatic) malignant melanoma [7,11]. The recommended dose and schedule is 3 mg/kg by intravenous infusion given every 3 weeks for four doses.…”

Thyroid Function Abnormalities in Patients Receiving Anticancer Agents

“…The spectrum of autoimmune endocrine adverse events experienced by patients treated with anti-CTLA-4 mAbs includes hypopituitarism, primary thyroid disease, and sporadically primary adrenal insufficiency [84]. The prevalence of autoimmune hypophysitis varies among different studies (0%-17%) [85], being 3-5% in larger studies.…”

“…Symptoms like headache, visual impairment, nausea, vomiting, loss of appetite, fatigue, weakness, asthenia, fever, lethargy, hypotension, hypoglycemia and hyponatremia in patients recently treated with ipilimumab should lead physicians to suspect hypophysitis. The early diagnosis of this side-effect allows to prevent primarily a life-threatening complication such as adrenal insufficiency, but also central hypothyroidism and other endocrine consequences of hypopituitarism [84]. Monitoring thyroid function even in asymptomatic patients has emerged as a prognostic tool as well.…”