Case of the Month

Cutaneous melanoma, pT1a, St. IV (AJCC 2017)

03/2012 superficial spreading melanoma of the shoulder, BRAF wildtype, Breslow 0,7 mm

04/2014 axillary lymph node metastases with vascular compression

08/2014 pulmonal metastases

04-07/14 radiochemotherapy (carboplatin/paclitaxel)

08-09/2014 immunotherapy with ipilimumab (2 cycles, progressive disease)

10/14-01/16 immunotherapy with pembrolizumab (20 cycles)

Four weaks after initiation of the immunotherapy (IT) with pembrolizumab the patient presented with shortness of breath due to irPneumonitis CTCAE grade 2. After high-dose systemic corticosteroid therapy and improvement of symptoms the immunotherapy could be continued. Within fourteen months after initiation of the therapy the patient showed painful oral mucosal erosions. Biopsy was taken and showed a typical histologic picture of lichen planus.

Systemic retinoids and local therapy with triamcinolone acetonide adhesive paste constantly led to clinical improvement and complete healing.

We discontinued the immunotherapy due to complete response.

The skin is one of the most common manifestations of immune-related adverse events and may occur in up to 30 to 50% of patients being treated with Checkpoint-Inhibitors (Lacouture M et al., Am J Clin Dermatol. 2018). They are typically mild and can often be treated without interruption of immunotherapy. However, there are also potentially life-threatening cutaneous irAEs such as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which are treated with permanent ICI discontinuation (IW Tattersall, Leventhal JS, Yale J Biol Med. 2020). Interestingly, cutaneous irAEs, especially such as vitiligo, have been shown to be a positive prognostic indicator for the treatment, especially in melanoma patients (Quaglino P. et al., Ann. Oncol. 2010).   

Cutaneous melanoma, pT3b, St. IV (AJCC 2017)

01/2015 nodular melanoma of the back, BRAF wildtype, Breslow 2,9 mm

10/2019 pulmonal metastases

01/2020 cerebral metastases

Immunotherapy with ipilimumab / nivolumab (1 cycle)

Four  weaks after initiation of the immunotherapy (IT) the patient presented with uncertain gait, proximal muscle weakness, double vision and shortness of breath. Laboratory results showed a significant increase of serum creatine kinase (CK, 1800 U/l), elevated CK-MB (10,4 fold increase) and Troponin-I  (634 pg/ml) levels thus confirming irMyositis  with ocular involvement. To rule out myocarditis further diagnostic procedures were undertaken. A cardiac MRI showed an apical hypokinesia and a myokardial biopsy showed a lymphocytic myocarditis. Diagnosis of a CTCAE grade 3 irMyositis and irMyocarditis was confirmed.

High-dose systemic corticosteroid therapy was initiated (1 g per day over three daysand 1mg/kg per day thereafter which led to clinical improvement. Therapy was tapered over 4 weeks.

Immunotherapy was interrupted. Subsequent therapy due to progressive disease was initiated with Temozolomid.

Checkpoint Inhibitor-induced Myositis (irMyositis) is accompanied by the involvement of the myocard in up to 32% of cases (Moreira A et al. Eur J Cancer. 2019.). It is life-threatening giving rise to cardiac arrhythmias and/or a reduced left ventricular ejection fraction and has a high fatality rate (Wang et al. JAMA Oncol. 2018). Ophthalmoplegia can be a manifestation of ocular myositis, representing a frequent manifestation of irMyositis (Garibaldi M et al. Neuromuscul Disord. 2020). It can occur isolated or combined with shoulder girdle manifestation, as shown in our patient. Clinicians should be aware of manifestations of irMyositis and monitor serum creatine kinase as well as clinical symptoms. If diagnosed immediate treatment with corticosteroids is necessary to improve outcome.

One month after initiation of the immunotherapy (IT) the patient experienced a irHypophysitis (CTCAE 3) that was substituted with hydrocortisone as well as an irThyroiditis that was substituted with levothyroxine. Three months after initiation of the IT the patient also developed a colitis (CTCAE 2) that was confirmed by an endoscopical biopsy. A few weeks later he also showed arthralgias in both shoulders.

5 months after initiation the patient showed a lipase increase of 559 U/l, after which we interrupted the immunotherapy. Two weeks later the lipase count increased up to 1300 U/l without any symptoms of a pancreatitis. An abdominal sonography and an abdominal MRI did no show any signs of an acute pancreatitis.

We decided to withdraw the immunotherapy due to multiple immune related adverse events (irAE). The patient did also lose 10 kg body weight after initiation of the lipase increase. One month after the lipase increase onset the lipase counts nearly resolved, but the patient developed a hyperglykemia with decreased insulin. Since then he needs insulin substitution.

Patients with one irAE are more likely to develop another irAE, so that patients should be closely monitored. Asymptomatic lipase increases are common (2,3 %, Su Q. et al J Immunol Res. 2018), however a treatment without any clinical signs for a pancreatitis is not required. The development of diabetes mellitus in this case could either occur as a consequence of an occult pancreatitis (diabetes type 3) or as an new irAE (diabetes type 1). Either way glucocorticosteroids would not be recommended (Stamatouli AM et al. Diabetes 2018). As it is an endocrinological irAE, substitution therapy is needed.

21 months after initiation of the immunotherapy (IT) and 3 months after switching to combinational IT the patient experienced a hypophysitis that was substituted with hydrocortisone. 1 month later she presented with severe nausea, weight loss and dysphagia. During the following hospitalisation a CTCAE grade 3 hemorrhagic irGastritis and a concomittant CTCAE grade 2 irHepatitis were diagnosed, both with histological confirmation.

Pantoprazol 40 mg twice a day was given and prednisolone was initiated at 1 mg/kg body weight and transaminases decreased. Due to steroidrefractory dysphagia and nausea, we planned a therapy with infiximab at 5 mg/kg body weight. Already 3 days after the infliximab-infusion the dysphagia improved and the nausea ceased.

We interrupted the immunotherapy and monitored the patient closely. We decided due to the severity of the immune related adverse event and the current stable disease to interrupt the treatment until the next staging. Afterwards we will discuss a rechallenge interdisciplinarily. 

Gastrointestinal irAEs are common (22-48%) (Heinzerling, L. et al. Dtsch Arztebl Int. 2019). However, solitary upper gastrointestinal events have been rarely reported. In general, an early therapy with infliximab in steroidrefractory gastrointestinal irAEs showed a quicker resolution (Johnson DH et al. J Immunother Cancer 2018) and is recommended in patients with persisting symptoms after 3-5 days (Haanen JBAG et al. Ann Oncol 2017). Escalation of immunosuppression with infliximab worked well and rapidly to treat irGastritis in this patient.