- 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.
