The Eyes Cannot See What the Mind Does Not Know- Endocrinological Side Effects of Ibrutinib Nikhitha Chandrashekar MD, Rachel McKenney MD Background • Vitals were stable with a normal UA, but given a history of a recent UTI, he was Discussion treated empirically for urosepsis with cefepime. Blood and urine cultures later returned with no growth. • • Ibrutinib is the first FDA-approved drug Our patient demonstrated endocrine-related side effects of designed to target Bruton's tyrosine kinase Ibrutinib, namely secondary adrenal insufficiency and central (BTK), a key protein in the B-cell receptor • The patient was thought to have SIADH, however there was only a marginal hypothyroidism. signaling complex that plays an important role improvement of his sodium level with fluid restriction. Additionally, his free T4 • in the survival and spread of malignant B cells.1 returned low (0.45 ng/dL) with a normal TSH (0.48 uU/mL) indicative of central We suspect that this was a direct result of Ibrutinib given no hypothyroidism. alternative medication exposure (other TKI or chemotherapy) to explain his presentation. • Since 2013 when it first received FDA approval for mantle cell lymphoma, ibrutinib is • On hospital day 5, he experienced a near syncopal episode and orthostasis with • Adrenal insufficiency, thyroid dysfunction, increasingly being used for numerous systolic blood pressure at 60 mm Hg. As a last resort, an ACTH stimulation test was hyperparathyroidism, and gonadal failure in tyrosine kinase indications. In 2016, it was approved as a performed. The patient had a baseline cortisol of 10.04 ug/dL which increased to inhibitors like Sunitinib, Imatinib, Sorafenib, Pazopanib, and frontline chronic lymphocytic leukemia (CLL) 14.01 ug/dL and 14.89 ug/dL at 30 and 60 minutes respectively after 250mcg of co- Axitinib have been demonstrated in previous studies. 4,5 There treatment, in 2017 for marginal zone lymphoma syntropin was administered. A baseline ACTH was not obtained, however the 21- is paucity of literature with regards to the correlation of (MZL), in 2018 for Waldenstrom hydroxylase antibody was normal ruling out an autoimmune adrenalitis. Given the endocrinological adverse outcome specifically with Ibrutinib. macroglobulinemia, and most recently in 2019 serum cortisol concentration <18 to 20 mcg/dL before and after corticotropin 3 for small lymphocytic lymphoma (SLL) along (ACTH), the patient was diagnosed with secondary adrenal insufficiency. • With the rising use of ibrutinib, awareness regarding this rare with obinutuzumab. 2 Hydrocortisone was initiated, and the serum sodium concentration rose to 134 and potentially fatal side effect is important in order to facilitate mmol/L from 129 mmol/L overnight with radical improvement in mentation to near early recognition and prompt management should such a baseline. • With its increasing use, there is a need for complication arise in clinical practice. awareness regarding potential adverse effects of this medication. • He was subsequently discharged on hydrocortisone and levothyroxine. On outpatient follow-up he was noted to have maintained normal electrolyte levels, and his overall functioning continued to improve. Case References Figure 2. Adrenal Insufficiency • An 85-year-old male with a history of CLL Figure 1. Types of adrenal insufficiency; CRH: Diagnosis Algorithm based on results 1. Raedler LA. Imbruvica (Ibrutinib), First-in-Class Bruton's corticotropin-releasing hormone, ACTH: from ACTH Stimulation Test. (diagnosed in 2013 under observation with no adrenocorticotropic hormone Tyrosine Kinase Inhibitor, Receives Expanded Indications for therapy) developed parotid lymphadenopathy in Patients with Relapsed Chronic Lymphocytic Leukemia. Am 2019 and was started on ibrutinib for disease Health Drug Benefits. 2015;8(Spec Feature):66–69. progression. He had an excellent response to 2. Cameron F, Sanford M. Ibrutinib: first global approval. Drugs. therapy with a reduction in the size of his lymph 2014;74:263-71. nodes. 3. Hawley JM, Owen LJ, Lockhart SJ, et al. Serum Cortisol: An Up-To-Date Assessment of Routine Assay Performance, Clin • Six weeks later, he became obtunded and was Chem. 2016;62:1220-1229. admitted to the hospital after having multiple 4. Illouz F, Braun D, Briet C, Schweizer U, Rodien P. (2014). syncopal episodes with increasing lethargy. His Endocrine side-effects of anti-cancer drugs: Thyroid effects of only other medications at the time were tyrosine kinase inhibitors. Eur J Endocrinol. 2014;171:R91– allopurinol, gabapentin, tamsulosin, R99. omeprazole, and furosemide. 5. Lodish MB, Stratakis CA. Endocrine side effects of broad- acting kinase inhibitors. Endocr Relat Cancer. 2010;17:R233– • Laboratory evaluation was significant for R244. leukocytosis (15,000/uL), lactate (0.5 mmol/L), hypokalemia (K 3.4 mmol/L), and hyponatremia (Na 123 mmol/L). CT and MRI head were unremarkable. Photo courtesy: US National Institutes of Health Photo Courtesy: The Cleveland Clinic Foundation.