Case of the Month

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.

•  04/2007 SNB (0/3)
•  07/2007 – 07/2009 Interferon-alpha 3x3 Mio IE s.c./week
• 11/2018 -11/2019 Immunotherapy with ipilimumab/pembrolizumab (4 cycles), followed by pembrolizumab
• 11/2019-12/2019 BRAF/MEK inihibitior therapy with dabrafenib/trametinib
• 12/2019-02/2020 BRAF/MEK inihibitior therapy with encorafenib/binimetinib

3 months after initiation of the immunotherapy (IT) the patient experienced a hypophysitis that was substituted with hydrocortisone. 5 months after initiation she presented with an irGastritis with a concomittant Addison crisis. Subsequently she had progressive disease and was switched to dabrafenib/trametinib. 12 months after start of IT and one month after start of BRAF/MEK inihibitor therapy she presented with sinus bradycardia, pyrexia and again Addison crisis. Dabrafenib/trametinib was replaced by encorafenib/binimetinib. Another 3 months later she developed CTCAE grade 3 irHepatitis with histological confirmation. Prednisolone was initiated at 1 mg/kg body weight and transaminases decreased. However, on tapering they increase up to 1987 U/l ALT and 1496 U/l AST. Bilirubin was measured up to 21,6 mg/dl.

Prednisiolone was increased to 1000 mg/day, mycophenolate mofetil (MMF 500 mg 1-0-1)  and infliximab were added. Supportive drugs included rifampicin 150 mg (1-0-0) and konakion.

Since she was progressive under immunotherapy no attempt to rechallenge was undertaken. After recovery of irHepatitis BRAF/MEK Inhibitor therapy with vemurafenib/cobimetinib was induced.

In general, irHepatitis is common (7-33%) and can be fatal. Thrombopenia is rare (1.2-4.7%) and can mostly be well-managed. Sequential therapy with immunotherapy and subsequent BRAF/MEK Inhibitor theapy may lead to new complex side effect profiles (Dimitriou et al. J Immunother, 2018) as in this patient with sinus bradycardia that could not clearly be attributed to any specific drug. Escalation of immunosuppresion with MMF and infliximab worked well to treat irHepatitis in this patient.