Side Effect Registry Immuno-Oncology

• 09/2020: cutaneous melanoma of the back (Breslow tumor thickness 4 mm)
  • initial stage: pT3a N1a M0, IIIA (AJCC 2017), BRAF wild-type, NRAS wild-type
• pre-existing diseases: three-vessel coronary artery disease, myocardial infarction (05/2020)

• 10/2020: re-excision within a safety margin of 2 cm and positive sentinel lymph node biopsy
• 10/2020: start of adjuvant immunotherapy with pembrolizumab 200 mg q3w (1 cycle)

Three weeks after initiation of the immunotherapy with pembrolizumab the patient presented to the emergency room with double vision, decreased muscle strength as well as slurred speech, dysphagia and dropped head syndrome. Laboratory results showed an elevated creatinine kinase (CK) of 4500 U/l as well as positive AChR- and Titin antibodies. Furthermore, irHepatitis (CTCAE grade III) was detected. Muscle sonography and electromyography were typical for an overlap of irMyasthenia gravis and irMyositis.

Therapy with methylprednisolone (1 g/d) was initiated for five days and was tapered in the following weeks. Furthermore, immunoglobulins (2g/kg bodyweight) were substituted for three days. CK and liver enzymes decreased under the immunosuppressive therapy and the patient slowly improved.

Approximately seven weeks after initiation of the immunotherapy and while being on prednisolone 70 mg/kg bodyweight the patient presented again to the emergency room due to a sudden deterioration of the general condition, two syncopes at night as well as flank pain and nausea. Urological work up was without pathological findings and a CT scan of the abdomen didn`t show any abnormalities. During further clinical work up, the patient suddenly lost consciousness due to asystolia. Subsequently, resuscitation was performed. Unfortunately the patient died; the cause of death remains unclear. A possible cardiac involvement of myositis was discussed but could not be confirmed due to refused autopsy by the family.

Immunotherapy was stopped due to severe immune-related adverse event (CTCAE grade IV).

Myopathies are frequently reported neurological side effects. Myositis can be accompanied by myocarditis and is associated with a high mortality rate (Knauss et al., der Nervenarzt, 2018).

Since often oligosymptomatic diagnosis can be delayed. Rapid initiation of immunosuppressive treatment is essential for better outcomes.

Myasthenic syndromes under immunotherapy mainly appear with bilateral ptosis, dysphagia and weakness of several muscle groups, as shown in our patient. Most frequently they manifest as a new-onset myasthenia, but exacerbation of preexisting disorders have been observed (Roth et al., Cancer Treatment Reviews, 2021).

Many questions remain unclear regarding immune-related neurological complications like risk factors, biomarkers for monitoring, and best options for second-line immunosuppressants in steroid refractory patients.

Controlled studies on the treatment of neurological side effects are important to improve outcome of these patients and to avoid long-term sequelae.

• 11/2017 cutaneous melanoma of the right foot (Breslow tumor thickness 6 mm)
  • initial stage: pT4bN2aM0, IIIC (AJCC 2017), BRAF wild-type, NRAS Q61R-mutation
• 01/2019: disseminated pulmonary, hepatic and lymph node metastases

• 01/2018-01/2019 adjuvant immunotherapy with ipilimumab (1 mg/kg bw) every 6 weeks and nivolumab 240 mg every two weeks (CheckMate-915 clinical trial)
• 02/2019 combined immunotherapy with ipilimumab (3 mg/kg bw) and nivolumab (1 mg/kg bw) due to progressive disease (three cycles)
• 06/2019 - today: dacarbazine (DTIC) every three weeks

Nine weeks after initiation of the combined immunotherapy with ipilimumab (3 mg/kg bw) and nivolumab (1 mg/kg bw) the patient presented to our dermato-oncological ambulance with dizziness, imbalance and an acute bilateral hearing loss due to an immune-mediated bilateral vestibulopathy. Furthermore, she suffered from progressive visual loss in both eyes (0.1 in the right eye; 0.8 in the left eye). ophthalmologic consultation confirmed a papillitis, retinal vasculitis as well as an uveitis. An alopecia areata universalis as well as leukotrichia induced by CPIs was already known. Thus, we diagnosed Vogt-Koyanagi-Harada syndrome (VKH).

Therapy with methylprednisolone (1 g/d) was initiated for three days and was tapered in the following weeks. The bilateral vestibulopathy remained irreversible; the patient still requires hearing aids on both sides. Contrary to that an improvement in vision was achieved in the right eye (0.1 à 0.32).

Immunotherapy was interrupted; instead a chemotherapy with dacarbazine was initiated. Current staging showed stable disease.  

VKH is an inflammatory disease syndrome characterized by bilateral uveitis in combination with alopecia, vitiligo or auditory manifestations, as shown in our patient. It is caused by a systemic immune reaction against melanocytes and can possibly be induced by immune checkpoint-inhibitors (Bricout et al., J Immunotherapy, 2017).

Ophthalmic irAEs occur in less than 1% of patients under immunotherapy and include uveitis, episcleritis and scleritis. Only few case reports about VKH exist (Crosson et al. J Immunotherapy, 2016). Wong et al. first reported a case of bilateral ipilimumab induced vitritis, choroiditis and retinal detachments due to VKH. As in our case, high-dose corticosteroids led to a quick improvement (Wong et al., Retin Cases Brief Rep., 2012).

Oncologists should be aware of possible ophthalmic and systemic findings induced by immunotherapy and should consider quick ophthalmologic consultation.

• 12/2019 cutaneous melanoma of the capillitium (Bresslow tumor thickness 1,2 mm)
  • Initial stage: pT2aN0M0, IB (AJCC), BRAF wild-type, NRAS mutation, c-Kit wild-type
• 12/2020: disseminated pulmonary, hepatic and lymph node metastases

multiple sclerosis, no treatment due to stable disease

12/2020 – 02/2021 combined immunotherapy with ipilimumab and nivolumab (4 cycles)

Two weeks after initiation of the immunotherapy with ipilimumab and nivolumab the patient presented to the emergency room with nausea, fatigue and dizziness. Laboratory results showed hyponatriaemia as well as a low cortisol level (> 0,2 µg/dl) that could not be stimulated through ACTH. Hydrocortisone was initiated due to an immune-related hypophysitis. One week later the patient presented again to the emergency room due to progressive increase in muscle tone of the left leg and left arm as well as the loss of the ability to walk.

MRI scan of the brain did not show any new foci that could explain the acute deterioration. A lymphomonocytic pleocytosis with liquor-specific oligoclonal gammopathy was detected in liquor analysis. An acute exacerbation of the preexisting multiple sclerosis under immunotherapy was suspected. Therapy with methylprednisolone (1 g/d) was initiated for five days. Spasticity improved and the patient was able to walk short distances again.

Immunotherapy was interrupted due to this severe neurological immune-related adverse event. The symptoms remained stable even after discontinutation of the therapy with methylprednisolone. Staging showed regressive liver as well as pulmonary metastases in March 2021. Six months after the initiation of the immunotherapy high liver enzymes were detected (GOT: 1113 U/l,
GPT: 2154 U/l ). Due to immune-related hepatitis (CTCAE grade 4) a therapy with methylprednisolone was reinitiated, under which liver enzymes decreased.

Neurological irAEs are rare in less than 1% of patients under immunotherapy (Spain et al., Ann oncol. 2017), but might be underreported due to lack of recognition. There are few case reports about MS relapse under immunotherapy, with description of rapid neurological progression and even death. As in our example all patients suffered from other immune-related adverse events. (Garcia et al., Clin Transl Oncol. 2019). Most neurological adverse events show good response to steroids, especially if initiated promptly (Larkin et al., The Oncologist 2017). Prospective studies are neccessary to provide information about risk factors, clinical presentation, outcome and therapy optimization.