Case of the Month

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.

• 10/2016 – 08/2018 interferon-alpha 3 subcutaneous injections / week
• 12/2018 initiation of immunotherapy with 4 cycles of ipilimumab and pembrolizumab, followed by pembrolizumab

20 weeks after initiation of the immunotherapy the patient showed joint swelling and pain accompanied by morning stiffness of both knees. A therapy with corticosteroids was started. After an initial improvement of the symptoms and therefore the continuation of the immunotherapy, the joint effusion returned with increasing leg edemas and joint pain. After ruling out another cause of the symptoms (such as chronic heart insufficiency, thrombosis, erysipelas, bacterial joint infection) we diagnosed an immune related oligoarthritis.

Due to the corticosteroid-refractory course of the symptoms an onetime infusion with infliximab was given with a significant improvement.

Due to returning symptoms after rechallenging with immunotherapy, we decided to discontinue the therapy. Fortunately the patient is in a complete response.  

In general inflammatory arthritis after immune checkpoint blockade are uncommon (0,7%-5,5%) (Buder-Bakhaya et al. Cancer Immunol., Immunother. 2018 ; Le Burel et al. Eur J. Cancer 2017), but can develop a persistence of inflammation even after cessation of immunotherapy (Calabrese, L. H. et al. Nature Reviews. Rheumatology 2018). In mild courses immunotherapy can be reinitiated. However, in this case due to the recurrence of the irAE a discontinuation was necessary. 

• 02/2019 initiation of immunotherapy with ipilimumab and pembrolizumab

4 weeks after the initiation of immunotherapy the patient showed an interstitial nephritis. With the creatinine levels pictured below:

Systemic steroids were given with a rapid improvement.

Immunotherapy was stopped and therapy changed to BRAF/MEK-inhibitor treatment.

In general nephrological irAE after immune checkpoint blockade are rare (1%-7%) (Heinzerling et al. Dtsch Arztebl Int 2019) but mostly quickly reversible. Often immunotherapy can be reinitiated. However, in this case the therapy was changed to BRAF/MEK-inhibitors.