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The Journal of Clinical Endocrinology & Metabolism 92(4):1201–1202 Copyright © 2007 by The Endocrine Society doi: 10.1210/jc.2006-2484
IMAGE IN ENDOCRINOLOGY: Transient Hypophysitis after Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA4) Blockade Stephanie A. Shaw, Luis H. Camacho, Ian E. McCutcheon, and Steven G. Waguespack Department of Endocrine Neoplasia and Hormonal Disorders (S.A.S., S.G.W.), Phase I Program (L.H.C.), and Department of Neurosurgery (I.E.M.), The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
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YTOTOXIC T LYMPHOCYTE-associated antigen 4 (CTLA4) blockade using the human anti-CTLA4 monoclonal antibody CP-675,206 has antitumor activity in melanoma (1). Blockade of CTLA4 binding to its B7 ligands results in disruption of peripheral immune tolerance and enhanced T cell activation (2), which can cause secondary autoimmune endocrinopathies, including hypophysitis and thyroiditis (1, 3, 4). We herein present a more detailed clinical history of a patient who developed transient hypophysitis after receiving CP-675,206 (1). A 44-yr-old male with stage IV melanoma developed extreme fatigue, headache, and decreased libido 3 months after a single 15-mg/kg infusion of CP-675,206. Magnetic resonance imaging (Fig. 1) demonstrated new diffuse enlargement of the pituitary gland, and laboratory analyses revealed TSH, prolactin, and gonadotropin deficiencies; GH and ACTH production were normal (Table 1). Previous thyroid function studies obtained 1 wk before drug infusion had been normal: free T4 1.2 ng/dl (range 0.7–1.9) and TSH 0.72 mU/liter (range 0.3–5.5). Although a biopsy was not performed to confirm the diagnoAbbreviation: CTLA4, Cytotoxic T lymphocyte-associated antigen 4. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.
TABLE 1. Laboratory evaluation
IGF-I (90.0 –360.0 ng/ml) TSH (0.5–5.5 mU/liter) Free T4 (0.9 –1.8 ng/dl) Prolactin (2.1–17.7 ng/ml) Cortisol (4.3–22.4 g/dl) ACTH (⬍70 pg/ml) LH (1.5–9.3 mIU/ml) Testosterone (260 –1000 ng/dl)
A
B
250.0 0.02 0.6 ⬍1.0 6.6/19.2a 46.0 1.5 126.0
133.0 1.03 1.2 ⬍1.0 17.1b 1.8 719.0
A, At presentation to endocrinology 3 months after CP-675,206 infusion. B, Nine months after presentation (12 months after CP675,206 therapy) while taking no hormone replacement. a Baseline and peak values during a 1-g cosyntropin stimulation test. b Random morning value.
sis, the patient’s clinical presentation was felt to be consistent with hypophysitis. Appropriate hormone replacement was initiated, and the patient was monitored while receiving no immunosuppressant therapy. Follow-up imaging performed 6 months after the CP-675,206 infusion revealed resolution of the pituitary gland abnormality (Fig. 1). Twelve months after the CP-675,206 infusion, the patient required no hormone replacement and had no biochemical evidence of hypopituitarism, except for a persistently undetectable prolactin level (Table 1).
FIG. 1. Coronal post contrast T1 weighted magnetic resonance images through the sella turcica showing: a normal pituitary gland 2 wk before CP-675,206 therapy (A), an enlarged pituitary (arrow) 3 months after CP-675,206 infusion at the time of presentation with headaches and multiple anterior pituitary hormone deficiencies (B), and complete resolution of the pituitary enlargement with a return to baseline appearance 3 months after initial presentation and 6 months after CP-675,206 therapy (C).
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J Clin Endocrinol Metab, April 2007, 92(4):1201–1202
To date, two anti-CTLA4 monoclonal antibodies are being developed to treat melanoma and other human malignancies, and both have caused autoimmune endocrinopathies (1, 3, 4). The current case demonstrates the clinical course of transient hypophysitis after treatment with CP-675,206 and highlights the possible role of CTLA4 in the pathogenesis of autoimmune hypophysitis. Endocrinologists should be aware of the potential endocrine toxicities that may occur in patients treated with these novel immunotherapies. Acknowledgments Received November 13, 2006. Accepted January 3, 2007. Address all correspondence and requests for reprints to: Steven G. Waguespack, M.D., FAAP, FACE, Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M.D. Anderson Cancer Center, 1400 Holcombe Boulevard, Unit 435, Houston, Texas 77030. E-mail:
[email protected].
Shaw et al. • Hypophysitis after CTLA4 Blockade
Disclosure Statement: The authors have nothing to disclose.
References 1. Ribas A, Camacho LH, Lopez-Berestein G, Pavlov D, Bulanhagui CA, Millham R, Comin-Anduix B, Reuben JM, Seja E, Parker CA, Sharma A, Glaspy JA, Gomez-Navarro J 2005 Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyteassociated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol 23: 8968 – 8977 2. Kapadia D, Fong L 2005 CTLA-4 blockade: autoimmunity as treatment. J Clin Oncol 23:8926 – 8928 3. Blansfield JA, Beck KE, Tran K, Yang JC, Hughes MS, Kammula US, Royal RE, Topalian SL, Haworth LR, Levy C, Rosenberg SA, Sherry RM 2005 Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother 28:593–598 4. Maker AV, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Hughes M, Yellin MJ, Haworth LR, Levy C, Allen T, Mavroukakis SA, Attia P, Rosenberg SA 2006 Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother 29:455– 463
JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community.
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