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Risk Factors for Ipilimumab-Induced Hypophysitis Remain Unclear

— Researchers recommend close monitoring of these patients

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BOSTON -- Among patients treated with the CTLA-4 inhibitor ipilimumab, clinical factors predicting ipilimumab-induced hypophysitis (IH) are still undetermined, researchers reported here.

In a cohort of 117 patients, nearly 13% subsequently developed IH following treatment with ipilimumab for melanoma, said Roula Zahr, MD, of Oregon Health & Science University in Portland, and colleagues.

For typically unknown causes, hypophysitis -- i.e., inflammation of the pituitary gland -- is the most common endocrinopathy from ipilimumab treatment and can cause life-threatening complications, Zahr explained during a presentation of the findings at the annual meeting of the American Association of Clinical Endocrinologists.

The retrospective study included patients who received ipilimumab treatment between 2011 -- when it originally received FDA approval for metastatic melanoma -- through 2016. The treatment was recently approved as part of a combination therapy with nivolumab, indicated for intermediate- to poor-risk, previously untreated patients with renal cell carcinoma.

In the study, among the 15 patients who developed IH, male patients were older than those who did not develop the condition (mean age of 67.7 versus 56.4, P=0.02). Additionally, male patients were significantly older than females who developed the condition (mean age of 67.7 versus 50.8 years, P=0.009).

The only other notable difference tied to a higher risk of developing IH was having no prior cancer therapy, with no patient who received systemic cancer therapy before ipilimumab developed IH (0% versus 17.2% of patients without prior therapy, P=0.011).

However, the researchers were not able to identify any other significant clinical factors that may have predicted which patients would develop IH.

Overall median survival time was not significantly different between those who developed IH (45 months) and who did not (29.5 months, P=0.253). There was also no difference between genders for those who subsequently developed the conditions (13.51% in males, 11.63% in females).

Furthermore, body-mass index, race/ethnicity, diabetes status, autoimmune disease at baseline, number of ipilimumab cycles administered, presence of primary melanoma lesion, and BRAF results all did not differ between groups.

When the researchers assessed the group of patients who did develop IH, the median time from the first cycle of treatment to IH was 9.97 weeks (8.4-14.95), with an average of three cycles prior to development of the condition.

After developing IH, 60% of patients had tumor progression, with a median time to progression of approximately 5.5 months. However, the average number of treatment cycles given was similar among those with and without progression (3.5 versus 3.1, respectively, P=0.055).

The majority (60%) of these patients did not have any other adverse events related to ipilimumab treatment prior to developing IH, although approximately 13% had colitis. Some of the other most common treatment-emergent adverse events before IH were diarrhea, headache, itching, and rash.

In regards to identifying IH, over 90% of patients showed an enlarged pituitary on magnetic resonance imaging (MRI), following showing an enhancement in the pituitary gland. Over half of patients in the study showed stalk thickening, while 45% showed stalk enhancement. Notably, one patient (10%) did not show any physical signs on MRI, and IH was identified only through positive biochemical findings -- such as low cortisol with low adrenocorticotropic hormone and commonly reported symptoms such as severe fatigue and headache. Zahr said that in cases like these, clinicians should have enough evidence to go ahead and treat patients with low-risk glucocorticoid-replacement therapy, and that MRI findings are not necessary to make a diagnosis of IH.

She added that all the patients in the cohort with IH were treated with high-dose prednisone, but explained that there is no evidence for a notable benefit with high-dose steroid treatment; still all such patients should be given glucocorticoid-replacement therapy, she emphasized.

"We recommend close monitoring with biochemical lab, imaging, and clinical monitoring of these patients. Maybe based on our results, higher incidence might be seen in patients who never received any prior systemic treatment, but more research is needed to confirm this finding."

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    Kristen Monaco is a senior staff writer, focusing on endocrinology, psychiatry, and nephrology news. Based out of the New York City office, she’s worked at the company since 2015.

Disclosures

Zahr reported having no relevant disclosures.

Primary Source

American Association of Clinical Endocrinologists

Zahr R, et al "Can we predict who will develop ipilimumab-induced hypophysitis? -- A large cohort study in patients with metastatic melanoma treated at a single academic center" AACE 2018; Abstract 838.