Case of the Month

• 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.

• 05/2021 acrolentiginous melanoma of the left foot
  • Initial stage: T4bN3bM1b, IV (AJCC 2017), BRAF wild-type
  • Inguinal and iliac lymph node metastases
  • One metastasis in small pelvis

• 06/2021 – 08/2021: Combination immunotherapy with ipilimumab (3 mg/kg bw) and nivolumab (1 mg/kg bw) every three weeks
• 08/2021 – 11/2021: Interruption of immunotherapy due to irPneumonitis grade 1 and irHepatitis grade 3
• 11/2021 – 01/2022: Nivolumab 240 mg every two weeks

After 4 doses of combination immunotherapy with ipilimumab and nivolumab, a chest CT performed for staging showed a nonspecific interstitial pneumonia (NSIP)-pattern. The patient was completely asymptomatic (no dyspnoea, malaise, cough or fever). We diagnosed irPneumonitis grade 1 (CTCAE). In the follow-up laboratory check, AST and ALT were elevated > 5 x ULN. Therefore, in addition irHepatitis grade 3 (CTCAE)  was diagnosed.

The immunotherapy was interrupted. Therapy with methylprednisolone 1.5 mg/kg bw for three days was initiated and tapered over the following weeks. The transaminases declined and the pulmonary radiological findings clearly improved. The patient remained asymptomatic at all times.

After normalization of transaminases, we reinitiated monotherapy with nivolumab 240 mg every two weeks. To date, the patient has received five doses of nivolumab and has remained asymptomatic. The transaminases remained within the normal range.

A rechallenge with immunotherapy carries the risk of reexacerbation of the irAE but may be indicated in certain circumstances.

Pollack et al. studied 80 patients who had to interrupt combined immunotherapy due to an irAE. Of those patients 39% experienced recurrent (18%) or clinically significant distinct (21%) irAE with anti-PD-1 monotherapy resumption. In this study, recurrence of irAE was independent of the duration of steroid taper, use of other immunosuppressants in addition to steroids, and the severity of the initial irAE. Under rechallenge with anti-PD1 monotherapy, a complete or partial response was observed in 70% of the patients, a stable disease in 19% and a progressive disease in 11% (Pollack et al, Ann Oncol., 2018).

Patients who are rechallenged show a reexacerbation in about a third of the cases if challenged with the same immunotherapy (Abu Seibh et al, J Clin Oncol., 2019) and 18% if challenged with monotherapy after combination immunotherapy. Thus, a rechallenge with immunotherapy can be considered in side effects that are not life-threatening, as there is a high probability of good efficacy. Patients have to be informed about the risk of reexacerbation. Clinicians should use critical judgement and extreme caution in resuming immunotherapy in patients with life-threatening irAE such as myocarditis.

In our case, the rechallenge with nivolumab has been well tolerated so far.

• 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.