Case of the Month

• 09/2019 - Cutaneous Melanoma (tumor thickness 2.8 mm, Mitose index > 4)
• 01/22 - pT3 N1c M1b
• Pulmonary and lymph node metastases
• Excision of In-transit metastasis on right nasal septum
• Histologically confirmed lung metastasis
• 03/22 – Staging - PR
• BRAF wild type
• 09/22 – Staging – SD
• CT chest/abdomen and cMRI: persistent PR, DD avitality of the pulmonary lesions

• 02-05.2022 –  4 cycles of combined immunotherapy with ipilimumab 3 mg/kg + nivolumab 1 mg/kg) followed by
• 9 x nivolumab q2w

After the 2nd cycle( on week 3) of combined immunotherapy with immune checkpoint inhibitors (ICI) ipilimumab and nivolumab, the patient presented with immune-related hepatitis (irHepatitis) and immune-related thyroiditis (Grade II) (irThyroiditis).

After week 20 of ICI (4th cycle ipilimumab/nivolumab and 4th nivolumab), the patient suffered from weight loss (110 kg) and muscle loss. As the ACTH provocation was positive, immune-related hypophysitis (Grade II) (irHypophysitis) was diagnosed.

After completion of 4th ipilimumab/ nivolumab and 9th nivolumab (week 30), the patient complained of severe vertigo and left sided hearing loss (irVestibulopathy and irCochleitis).

irThyroiditis (Grade 3 CTCAE) at week 3

Hyperthyroidism was treated with a beta-blocker on 03/22, and subsequently Hypothyroidism with L-thyroxine (50 µg) from 05/22 onwards.

Oral Corticosteroid therapy (50 mg) was started and then tapered.

Hyperthyroidism in irThyroiditis is a result of direct immune induced destruction of thyreocytes which releases the stored thyroid hormone from the thyroid follicles into the blood circulation. Hence, carbimazole is not useful in irThyroiditis induced hyperthyroidism as it acts by decreasing the uptake and concentration of inorganic iodine by thyroid and also reduces the formation of di-iodotyrosine and thyroxine.

irHypophysitis (Grade 2 CTCAE) at week 20

Hydrocortisone 20 mg/day was substituted.

irVestibulopathy and irCochleitis (Grade 3/4) at week 30

The patient was referred to an ENT specialist and started on prednisone (SDH) 200 mg i.v. for 3-5 days.

Upon therapy, the hearing loss improved, the vertigo subsided and the patient gained bodyweight and muscle mass.

On account of stable disease, the ICI was stopped on 9/22.

Most frequently, immune-related Adverse Events (irAEs) affect a wide range of organs like skin, colon, liver, pituitary, thyroid, and lungs, although uncommon events involving the heart, nervous system, and other organs do occur. The onset develops predominantly within the first 6-12 weeks after treatment initiation.

Combining treatment with ipilimumab and nivolumab has resulted in a reported 18%-22% all-grade hepatitis and overall with 8%-11% having severe hepatitis. (Remash D, et al. World J Gastroenterol. 2021)

Hyperthyroidism due to irThyroiditis occurs on account direct thyreocyte destruction and hence carbimazole, which acts by inhibiting thyroid hormone synthesis is not indicated in irHyperthyroidism. (Iyer PC, et al. Thyroid. 2018).

Neurological immune-related adverse events occur in 1%–5% of patients on ICI therapy (Koch EAT, et al. J Immunother. 2021). Moreover, ICI-mediated ototoxicity is rare or under reported due to a small number of case reports published till date. (Rosner S, et al. J Immunother Cancer, 2020) of patients (refs voskens JCO, and others). It may develop isolated as a single irAE or in concert with other irAEs as in this case. Manifestation of ICI-mediated ototoxicity ranges from isolated hearing loss, tinnitus, vestibular symptoms with hearing loss, visual and hearing loss or Vogt-Koyanagi-Harada syndrome (VKH) with ocular, dermatologic and neurologic involvement. It is important to distinguish between isolated hearing changes and hearing changes as part of a collective syndrome to institute appropriate management.

In the absence of ocular involvement, a diagnosis of Cogan Syndrome was not made.

ICI-mediated ototoxicity occurs early in the treatment course (within ~4 months of initiating ICI). The association between irAEs and ICI efficacy is controversial and may depend on the site of toxicity. Retrospective studies suggest that site-specific toxicities may have a correlation with ICI efficacy (Martins F, et al. Nat Rev Clin Oncol, 2019)

The mechanisms underlying the development of ICI-mediated ototoxicity are currently unknown. Preclinical rat models of ICI-mediated ototoxicity demonstrated significant differences in auditory brainstem responses (ABR) in those treated with ICIs vs controls, as well as pathologic evidence of a reduction in the outer hair cells and flattening of the organ of Corti in those treated with ICI. (Kuzucu İhsan, et al . Cureus 2019) Interestingly, ototoxicity has also been reported from adoptive cell therapy for melanoma. The proposed mechanism of this toxicity could involve auto-antigenicity against melanocyte specific antigens such as MART-1 present in the inner ear, uvea and epithelium of the skin (Plonka PM et al. Exp Dermatol, 2009).

ICI related ototoxicity is a rare side effect of immune checkpoint inhibitors that health care providers should be aware of and that requires interruption of ICI therapy and prompt administration of systemic corticosteroids to ensure restitution ad integrum.

• 01/2021 Nodular malignant melanoma left knee
  • 06/2022: lymph node metastasis left inguinal, complete resection
  • pT2aN1bM0, IIIB (AJCC 2017)

• 07/2022 Adjuvant immunotherapy with pembrolizumab

After 2 doses of adjuvant immunotherapy with the immune checkpoint inhibitor pembrolizumab, the patient presented with bilateral hearing loss. Furthermore, they developed dyspnea and leg edema. Troponin and nt-pro-BNP were slightly elevated. The D-dimer was slightly elevated and the ECG showed an S1Q3 type, thus we ruled out a pulmonary artery embolism using CT angiography. Echocardiography showed preserved systolic function and diastolic dysfunction (HFpEF, heart failure with preserved ejection fraction). A cardiac catheter examination could rule out a stenosis requiring intervention.

A cardiac MRI showed focal transmural late gadolinium enhancement (LGE) of the basal inferior wall. Since, in addition to inflammatory changes, cardiac metastases were also part of the differential diagnosis, a PET-CT was performed for further clarification. Finally, we agreed on ICI-myocarditis as the most likely cause. A myocardial biopsy was not performed due to the difficult localization.

We initiated systemic therapy with prednisolone with an initial dose of 1000 mg, which was reduced to 1 mg/kg after 5 days and then tapered. A weight reduction of 4 kg could be achieved through a negative fluid balance. A follow-up cardiac MRI is planned.

The immunotherapy was permanently discontinued.

Myocarditis is a rare side effect of immunotherapy (incidence ca. 1%) with a very high mortality (50%), therefore cardiac biomarkers should be regularly monitored during immunotherapy. Before starting therapy, a baseline ECG and troponin determination should be performed. Biomarker abnormalities or clinical symptoms should be followed by cardiac evaluation. Troponin and ECG taken together are abnormal in 50-90% of cases of ICI-myocarditis, cardiac MRI shows changes in 25-50% of cases. Echocardiography is often unremarkable. A cardiac catheter examination should be performed once to rule out coronary artery disease; myocardial biopsy is gold standard. Immunotherapy should be interrupted or discontinued and systemic corticosteroid therapy (1-2 mg/kg or even 1g/day) initiated. In therapy-refractory cases, mycophenolate mofetil (MMF), infliximab or anti-thymocyte-globuline (ATG) have been suggested as second-line therapies (ASCO-Guidelines, Schneider BJ, J Clin Oncol, 2021). Case reports reported on the successful use of abatacept and alemtuzumab as second-line therapies for ICI-myocarditis (Salem JE, N Engl J Med, 2019; Esfahani K, N Engl J Med, 2019).

Myocarditis is a rare side effect of immune checkpoint inhibitors with extremely high mortality, therefore monitoring of cardiac biomarkers and good side effect management is crucial.

• 1978 uveal melanoma right eye, HLA-A*02 negative, IV (AJCC 2017)
• 04/2021 cutaneous melanoma, IA (AJCC 2017)
  • 09/2021: subcutaneous melanoma metastasis
  • 11/2021: liver melanoma metastasis, BRAF wild type
    • Both metastases probably associated with uveal melanoma (histologically)

• 01/2022 – 02/2022 Combined immunotherapy with ipilimumab 3 mg/kg + nivolumab 1 mg/kg (3 doses)

After 3 doses of combined immunotherapy with the immune checkpoint inhibitors (ICI) ipilimumab and nivolumab, the patient presented with a burning sensation and swelling in the left eye. The ophthalmological emergency service suspected conjunctivitis, so corticoid-containing eye drops and eye ointment were used, but the swelling continued to increase. An ophthalmological examination revealed impaired ocular motility, so a cerebral MRI was performed, which revealed inflammatory changes (swelling, edema and contrast uptake) in the left lateral rectus muscle and an exophthalmos. An ipilimumab/nivolumab-induced myositis of the lateral rectus muscle was diagnosed. The creatine kinase (CK) was in the normal range.

We initiated a systemic therapy with prednisolone with an initial dose of 2 mg/kg, which was soon reduced to 1 mg/kg and then tapered off. Just two days after the start of the prednisolone treatment, the swelling had completely subsided; ocular motility also returned to normal over time. After tapering off the prednisolone to 10 mg, irColitis developed, which had to be treated with infliximab due to a steroid-refractory course.

Up to now, staging has shown stable disease, therefore immunotherapy was not reinduced due to the potential exacerbation of the steroid-refractory colitis. If necessary, reinduction should be carefully evaluated.

Myositis is a rare side effect of immunotherapy, occurring in <1% of patients and potentially fatal. An overlap with myocarditis and mysthenia gravis-like symptoms has been described. Diagnostic clues are provided by symptoms (muscle weakness, myalgia), increased CK, a myopathic pattern on electromyography, contrast uptake on MRI, and inflammatory or necrotic changes on muscle biopsy. Antibodies are mostly negative. Usually, immunotherapy should be interrupted or discontinued and systemic corticosteroid therapy (1-2 mg/kg) initiated. If therapy is refractory, plasmapheresis or IVIG, infliximab, MMF, MTX, or azathioprine can be initiated (Moreira et al., Eur J Cancer, 2019; Moslehi et al., Lancet, 2018; Kostine et al., Ann Rheum Dis, 2021).

Interestingly, in contrast to our case, three published cases of ocular myositis showed CK elevation (between 1844 and 7765 U/L), possibly due to involvement of other muscles. The 3 cases were treated with corticosteroids; in 1/3 of the cases the anti-PM-Scl 75 antibodies and anti-SRP antibodies were positive and plasmapheresis was also performed. In all three cases, the symptoms improved or resolved (Garibaldi et al., Neuromuscular Disorders, 2020; Kamo et al., BMC Neurology, 2019).

In the differential diagnosis, ocular irAE (e.g. conjunctivitis, secleritis or unveitis) also had to be considered initially. Ocular irAE occur in approximately 1% of patients receiving ICI therapy and non-muscular ocular irAE can often be treated topically, so interruption of ICI therapy may not be required.

Ocular myositis is a rare side effect of immune checkpoint inhibitors that physicians should be aware of and that requires ICI therapy interruption and systemic corticosteroids.

• 03/2021 amelanotic melanoma, BRAF wild type
  • 09/2021: Lung metastasis, complete resection
  • pT4bN0M1c, IV (AJCC 2017)

• 10/2021 – 11/2021 Immunotherapy with nivolumab 240 mg every 2 weeks (adjuvant)
• 02/2022 – 03/2022 Immunotherapy with nivolumab 240 mg every 2 weeks (adjuvant)
• 04/2022 – 05/2022 Immunotherapy with nivolumab 240 mg every 2 weeks (adjuvant)

After 1 month of adjuvant therapy with nivolumab, the patient presented with fever, myalgia without CK elevation, arthralgia and elevated inflammatory parameters. Due to a suspected systemic inflammatory reaction, most likely due to the immunotherapy, the nivolumab therapy was paused and the patient received methylprednisolone 1 mg/kg bw with subsequent taper. Shortly after resuming immunotherapy, the patient presented again with elevated inflammatory parameters, a hyperinflammatory syndrome was suspected, but the patient also described stabbing pains in his left eyebrow and ear. Nivolumab was re-initiated again, and shortly thereafter the patient complained of recurrent amaurosis fugax in the right eye. Duplex sonography showed the typical findings of a giant cell arteritis of the temporal artery. We initiated a therapy with prednisolone 1 mg/kg bw.

In summary, the patient showed laboratory signs of inflammation, fever, myalgia and arthralgia, temporal headaches and recurrent amaurosis fugax. In retrospect, the initial myalgia may be interpreted as a sign of polymyalgia rheumatica, and the stabbing pain in eyebrow and ear as a sign of arteritis temporalis.

We initiated therapy with prednisolone 1 mg/kg bw. The additional administration of tocilizumab is planned. To date, the patient has shown no recurrence of the melanoma.

A continuation of immunotherapy may be discussed after a detailed benefit-risk assessment but is currently not planned.

Giant cell arteritis (GCA) is an inflammatory autoimmune disease of large blood vessels; histology shows a granulomatous inflammatory reaction with fused macrophages (“giant cells”). Symptoms are variable and include e.g. headache, difficulty opening the mouth, flu-like symptoms, double vision and amaurosis fugax, fever, weight loss, and polymyalgia. GCA is frequently associated with polymyalgia rheumatica and has an approximately 20% risk of blindness.

GCA is a rare side effect of immunotherapy. An analysis of VigiBase revealed 18 cases of temporal GCA, 55% of the cases occurred after anti-CTLA4 therapy and one third of the cases were accompanied by visual impairment or blindness (Salem et al, Lancet Oncol., 2018). Two case reports described GCA under anti-PD1 therapy (Narala et al., Am J Ophthalmol Case Rep., 2020; Betrains et al., J Clin Rheumatol., 2021); in both cases, immunotherapy was discontinued and the patients treated with steroids. Therapy of ICI-induced GCA may also include methotrexate or tocilizumab (Heinzerling et al., Dtsch Arztebl., 2019). Evidence supports an important role of PD-1 and CTLA-4 pathways in the pathophysiology of vasculitis (Zhang et al., Proc Natl Acad Sci, 2017).

Giant cell arteritis is a rare side effect of immune checkpoint inhibitors that physicians should be aware of. In the case of typical systemic symptoms, headaches or vision disturbances, a low-threshold GCA clarification should be carried out.