Case of the Month

• 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.

• 01/2021 non-small-cell lung cancer (adenocarcinoma)
  • Initial stage: cT2N0cM0, IIB, PD-L1 expression 10%

• 01/2021 – 03/2021 Radiochemotherapy with cisplatin, vinorelbine and radiation 66,6 Gy
  • Partial response
• 05/2021 - 02/2022 Immunotherapy with durvalumab 10 mg/kg bw every 2 weeks (19 doses)
  • Partial response

After 9 months (and 19 doses) of immunotherapy with the anti-PD1 antibody durvalumab 10 mg/kg bw every 2 weeks, the patient developed a “rash”. Initially, the immunotherapy was discontinued and the patient treated with topical steroids and systemic prednisolone 60 mg p.o. for 10 days, which led to an initial improvement of the skin condition. While tapering the steroids, there was another exacerbation and 150 mg prednisolone i.v. were administered. Since there was no improvement under this therapy, the patient was referred to the department of Dermatology.

The patient presented with erythema and erythematous plaques covering approximately 18% of the body surface area, predominantly on the distal extremities. There was also lamellar desquamation and blistering, particularly on the hands. Histology showed vesicular detachment at the level of the basement membrane zone, a perivascular lymphocytic infiltrate, single-cell apoptosis and single eosinophils. The fluorescence pattern was non-specific. In summary, the findings corresponded to an erythema multiforme (EM)-like drug reaction.

The dose of corticosteroids was increased to 250 mg prednisolone i.v. for 3 days and then reduced to 80 mg p.o. The steroids were then tapered very slowly, but had to be increased again twice. In parallel, topical therapy with mometason cream was carried out. Due to the steroid-refractory or steroid-dependent course, secondline immunosuppression (therapy with intravenous immunoglobulins (IVIG) as well as extracorporal photophereses) was discussed.

Four months after the onset of the erythema multiforme, currently, a cortisone dose of 30 mg is required. Secondline immunosuppression was not started and the checkpoint inhibitor therapy was not yet re-initiated.

Cutaneous side effects are observed in 46-62% of patients on checkpoint inhibitor therapy and occur after a median of 2-3 weeks, but also up to two years after the start of immunotherapy. Rash, pruritus, and vitiligo-like lesions are the most common; lichenoid reactions, blistering reactions, psoriasis, and sarcoid-like lesions are less common. In 90% of cases, cutaneous irAE are mild and can be treated with topical therapy. Serious and potentially fatal cutaneous adverse events include DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms), Stevens-Johnsons Syndrome, toxic epidermal necrolysis, bullous skin lesions, and dermatitis herpetiformis (Heinzerling et. al, Dtsch Arztebl, 2019; Belum et. al., Eur J Cancer, 2016). The literature on erythema multiforme under immunotherapy is limited to individual case reports. Cases have been reported with ipilimumab, nivolumab and pembrolizumab. Treatment was mostly with systemic steroids, in one case also with IVIG. EM often led to discontinuation of immunotherapy (Zimmer, L et al, J Transl. Med, 2015; Jour et. al., J Cutan Pathol., 2016; Sundaresan et. al., Dermatol Online J., 2017; Utsunomiya et. al., Case Rep Dermatol., 2018; Yano et. al., Trends in Immunotherapy, 2021; Hashimoto et al, J Clin Med., 2021; Ambur et. al., Cureus, 2021).

Cutaneous irAEs are often mild but can be severe, requiring discontinuation of immunotherapy and initiation of systemic therapy. Dermatologists should be involved in managing cutaneous side effects, since specific skin findings may require varying treatments.

• 01/2021 melanoma of unknown primary (MUP)
  • Initial stage: pTxNxM1c(0), IV (AJCC 2017), BRAF wild-type
  • Metastases in lungs, liver, duodenum, gastric corpus, esophagus, and peritoneal carcinosis

• 02/2021 Combination immunotherapy with ipilimumab 3 mg/kg bw and nivolumab 1 mg/kg bw, every three weeks (3 doses in total)
• 05/2021 - 04/2022 Immunotherapy with nivolumab 240 mg, every 2 weeks

After three doses of combination immunotherapy with ipilimumab 3 mg/kg bw and nivolumab 1 mg/kg bw, the patient developed visual impairment due to iritis that was treated topically with cortisone eye drops. Shortly thereafter, the patient reported dizziness, tinnitus, hearing impairment and balance disorder. An ENT examination showed caloric near-areflexia on both sides and a videooculographically pathological Halmagyi head impulse test. The ability to hear in the high-frequency range was limited in the audiogram. A bilateral vestibulopathy was diagnosed.

The patient received three bilateral intratympanic cortisone injections. The imbalance disorder improved significantly on the right and slightly on the left. The hearing ability in the high-frequency range improved. Subjectively, the patient also reported a significant improvement in gait and mobility stability.

After the patient’s general condition improved, we continued immunotherapy with nivolumab monotherapy. There was no exacerbation of the vestibulopathy, but the patient developed irColitis and also Uveitis and Vitiligo, suggesting Vogt-Koyanagi-Harada disease. With regard to the melanoma, the course of the disease remained stable.

Vestibulopathies are rare immune-mediated side effects and have been described with various immunotherapies (nivolumab, ipilimumab+nivolumab, ipilimumab and pembrolizumab). Both with and without therapy, patients often show little or no improvement in vestibular symptoms (Voskens et al., J Clin Oncol, 2012; Mendis et al. Eur J Canc, 2021; Lemasson et al., Eur J Canc, 2019; Koch et al., J Immuother, 2021; Stürmer et al., J Immunother, 2021). Intratympanical cortisone application is an alternative to systemic cortisone administration (Salt et al., Drug Discov Today, 2005). A correlation between the time from the onset of vestibulopathy to the start of therapy and the response is probable. Therefore, physicians should be aware of immune-mediated vestibulopathy and conduct a prompt ENT consultation in suspected cases.

• 04/2021 melanoma of unknown primary (MUP)
  • Initial stage: pTxNxM1d(0), IV (AJCC 2017), BRAF wild-type
  • Cerebral metastases

• 06/2021: Stereotactic radiosurgery of cerebral metastases
• 06/2021: Combination immunotherapy with ipilimumab 3 mg/kg bw and nivolumab 1 mg/kg bw, every three weeks
• 09/2021: Stereotactic radiosurgery of cerebral metastases
• 09/2021: Chemotherapy with temozolomide 200 mg/m²
• 10/2021: Re-Immunotherapy with ipilimumab 1 mg/kg bw and nivolumab 3 mg/kg bw (flip dose), every three weeks
• 10/2021: Stereotactic radiosurgery of cerebral metastases
• 01/2022: Chemotherapy with gemcitabine 1000 mg/m² and treosulfan 3500 mg/m²

After one dose of ipilimumab + nivolumab, irHepatitis grade 1 (CTCAE) and irColitis grade 1 (CTCAE) occurred. The immunotherapy was interrupted. Initial therapy:

• Methylprednisolone 1 mg/kg bw

During an attempt to taper off the steroids, irColitis grade 2 (CTCAE) developed with diarrhea up to 7 times per day. Therapy:

• Methylprednisolone 1.5 mg/kg bw
• Infliximab 5 mg/kg bw i.v.

After this therapy, the patient was initially symptom-free. But when the steroids were tapered off, there was a recurrence of irColitis (grade 2) on 10 mg prednisolone. The patient had to be admitted to the hospital. Therapy:

• Methylprednisolone 1 mg/kg bw
• 2nd Dose of infliximab 5 mg/kg bw i.v.
• Start of extracorporeal photopheresis (ECP)

Initially, there was a further deterioration of the irColitis. The patient developed severe diarrhea, some with blood, fecal incontinence and dehydration (irColitis grade 4). Therapy:

• Methylprednisolone 2 mg/kg bw
• Continuation of extracorporeal photopheresis (weekly)
• Vedolizumab 300 mg i.v.

With this therapy, the symptoms improved over time. A second dose of vedolizumab was administered. The intervals of the ECP could be extended to every 2 weeks. Due to cerebral progress, stereotactic radiosurgery was repeated and chemotherapy with temozolomide 200 mg/m² was initiated.

Due to renewed significant cerebral tumor progression, the decision was made to reinitiate a combined immunotherapy with ipilimumab 1 mg/kg bw and nivolumab 3 mg/kg bw (flip dose), every three weeks after a risk-benefit assessment and thorough patient information. Stereotactic radiosurgery was performed again. Unfortunately, the colitis symptoms returned. Tumor therapy was switched to chemotherapy with gemcitabine and treosulfan.

For the treatment of steroid-refractory irColitis, most guidelines recommend therapy with infliximab as the first step for patients who do not show any improvement within 3-5 days with steroids (Thompson et. al, J Natl Compr Canc Netw., 2020; Brahmer et. al., J Clin Oncol., 2018).
The integrin antagonist vedolizumab may be considered in infliximab-refractory irColitis according to ESMO-, NCCN- and ASCO guidelines for the management of immune-related adverse events. In a study from 2017, vedolizumab relieved symptoms in 6 of 7 patients with steroid-dependent or steroid-refractory irColitis; no side effects were reported (Bergqvist et. al., Cancer Immunol Immunother., 2017).  

ECP consists of the three steps of leukapheresis, photoactivation and reinfusion and has immunomodulatory effects (modulation of dendritic cells, change in cytokine profile, induction of T cell subpopulations). Indications are currently the treatment of Sézary syndrome, Graft-versus-host disease (GvHD), organ transplant rejection and systemic scleroderma. Importantly, there is no attenuation of the anti-tumor response as far as reported from lymphoma patients in contrast to potential effects of immunosuppression with drugs. Apostoleva et. al. reported on a case of a 29-year-old patient with steroid-refractory irColitis who showed only slight improvement or recurrence after administration of infliximab and ciclosporin, and in whom combined drug therapy with ECP was able to achieve freedom from symptoms and recurrence (N Eng J Med., 2020). This indicates that an off-label use of ECP for the treatment of irAE is possible and promising.