Christina Naoum

Background/Objectives: Treatment with immune checkpoint inhibitors (ICIs) in patients with advanced melanoma has greatly improved clinical outcomes but can induce immune-related adverse events (irAEs). ICI-induced immune-related (ir) colitis is one of the most common severe irAEs and is primarily managed by treatment with high-dose corticosteroids. Some patients are steroid-refractory and require additional immunosuppressants. Infliximab is commonly used as the additional treatment of choice, while data for other immunosuppressants such as mycophenolate mofetil (MMF) are sparse. Methods: We used MMF to treat ir colitis in a cohort of patients in Heidelberg and compared clinical data with patients who received standard irAE management with infliximab in the Cancer Centers of Heidelberg, Hannover, Mainz, and Kiel. Outcome measures included response rate, time to response, duration and amount of steroid intake, and recurrence of colitis, as well as progression-free survival (PFS) and overall survival (OS) measured from the start of steroid intake. Results: Out of 52 patients refractory to steroids, 31 were treated with additional MMF and 21 with additional infliximab. A total of 24 out of 31 patients (77.4%) experienced bowel habit normalization during treatment with MMF after a median of seven days. Seven patients required additional infliximab to achieve a resolution of symptoms. Twenty out of 21 patients (95.2%) showed a normalization of stool frequency with infliximab after a median of eleven days. One patient required additional MMF to achieve a normal bowel habit. Hence, resolution of symptoms was achieved during both treatment regimens (p = 0.081) in a comparable period of time (p = 0.858). Neither recurrence of colitis after additional immunosuppression (p = 0.760) nor rate of CMV positivity after recurrence of colitis (p = 0.898) differed between groups. We observed a tendency towards longer treatment duration (108 vs. 85 days, p = 0.052) and significantly higher cumulative corticosteroid intake (7585 mg vs. 3485 mg, p = 0.002) in the MMF group compared to the infliximab group. However, we observed significantly higher cumulative steroid intake and a longer duration of corticosteroid therapy in patients treated at the Heidelberg center compared with those treated at the other participating centers within the infliximab group. In contrast, no significant differences in corticosteroid duration or cumulative dose were observed in the center-internal comparison between MMF- and infliximab-treated patients at Heidelberg. These subgroup analyses may indicate that the observed differences in corticosteroid exposure are more likely related to center-specific management strategies rather than substance-specific effects. Neither median PFS nor OS differed between the groups (mPFS: MMF: 3.2 months; infliximab: 2.1 months (p = 0.978); mOS MMF: 12 months; infliximab: 9.5 months (p = 0.561)). Conclusions: The data point to MMF as a well-tolerated, oral treatment alternative for patients with ICI-induced ir colitis, especially in patients where infliximab is contra-indicated.

Background: Immune checkpoint inhibitors (ICIs) have shown promising anti-tumor activities and are widely used for the treatment of advanced cancers. However, they may lead to immune-related adverse events (irAEs) and some of them, such as hypophysitis, can be life-threatening. Here, early diagnosis is critical. Methods: We retrospectively analyzed 40 melanoma patients who developed hypophysitis during ICI treatment with either ipilimumab and/or anti-PD1 therapy and compared them to 40 control patients who did not develop hypophysitis during the ICI treatment, matched for age, gender, type of immunotherapy, and stage. Clinical data and blood values such as LDH, CRP, TSH, T3, T4, and absolute immune cell counts were retrieved from the medical records. Patient characteristics, laboratory values, progression-free survival, and overall survival were compared between the two groups. Results: Patients with ir-hypophysitis had a median age of 59 years, and most of them were male. Clinically, frequent symptoms were fatigue, headache, dizziness, and gastrointestinal symptoms such as nausea or abdominal pain. The onset of ir-hypophysitis differed much between ipilimumab- (median 8 weeks) and anti-PD1 (median 40 weeks)-induced hypophysitis (p < 0.001). At baseline, besides a slightly increased CRP level (p = 0.06), no differences were observed in patients who later developed hypophysitis compared to the control. After treatment started, hypophysitis patients showed a constant and significant decline in T4 levels from the start of therapy until diagnosis (p < 0.05), independent of the ICI treatment regime. However, a decline in T3 and TSH was only noted in patients with ipilimumab-induced ir-hypophysitis. Furthermore, serum sodium levels declined rapidly at the diagnosis of hypophysitis (p < 0.001). In addition, there was a constant increase in the absolute counts of eosinophils and lymphocytes from baseline in hypophysitis patients (p < 0.05). Conclusion: Ir-hypophysitis reveals different clinical pictures and onset times depending on the ICI regime used. Whereas a drop in T4 levels was indicative of developing hypophysitis independent of the ICI regime, TSH levels only declined in patients under ipilimumab-based ICI regimes. To best monitor our patients, it is important to recognize these differences.

Zusammenfassung Der plexiforme fibrohistiozytäre Tumor ist ein seltener, niedrig bis mittelgradig maligner Weichteiltumor, welcher v. a. bei Kindern und jungen Erwachsenen an der oberen Extremität auftritt. Die Diagnose muss histologisch gestellt werden. Wir berichten über eine junge Frau, welche sich mit einer größenprogredienten, schmerzlosen Hautveränderung in der Ellenbeuge vorstellte. Diskutiert werden das histologische Bild sowie der Behandlungsstandard.