Side Effect Registry Immuno-Oncology

Side Effect Registry Immuno-Oncology

SERIO is a registry for adverse events of immunotherapies (immune-related adverse events, irAE): The aim of SERIO is to collect rare, complex and therapy-refractory cases to obtain knowledge for better side effect management and eventually be able to understand pathogenesis and predict side effects also in special patients (i.e. with autoimmune disease or solid organ transplant).

Myositis
Arthritis
Arthritis
Lichen ruber
Lichen ruber
Pneumonitis
Pneumonitis

Case of the Month

79 year old patient with checkpoint-inhibitor induced myositis and myasthenia gravis overlap syndrome

Medical history
  • 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)
Oncological therapy
  • 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)
Immune-related adverse event

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.

How did we proceed?

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.

Could we continue the immunotherapy?

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

Our conclusion

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.

54 year old woman with checkpoint-inhibitor induced Vogt-Koyanagi-Harada syndrome (VKH)

Medical history
  • 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
Oncological therapy
  • 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
Immune-related adverse event

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).

How did we proceed?

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).

Could we continue the immunotherapy?

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

Our conclusion

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.

51 year old woman with exacerbation of multiple sclerosis under immunotherapy

medical history
  • 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
Risk profile

multiple sclerosis, no treatment due to stable disease

Oncological therapy

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

Immune-related adverse event

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.

How did we proceed?

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.

Could we continue the immunotherapy?

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.

Our conclusion

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.

Pleuritis and peripheral edema due to Immunotherapy

Patient medical history
  • 73 year old patient
  • Melanoma of unknown primary
    • stage IV M1d (1), BRAF wildtype, NRAS Mutation, c-Kit wildtype
  • 08/2016: iliac lymph node metastasis (3,5 x 2,5 x 1,5 cm)
  • 10/2017: hemorrhagic cerebral metastasis
  • 11/2019: lymph node metastasis of the left tigh
  • 03/2020: cutaneous metastases
Oncological therapy
  • 10/2016 – 11/2016: radiotherapy
  • 01/2017: lymph node dissection inguinal left
  • 10/2017: resection of cerebral melanoma metastasis 
  • 11/2017: stereotactic radiotherapy in area of resected metastasis
  • 11/2017 – 11/2018: pembrolizumab
  • 11/2019: resection of lymph node metastasis
  • 03/2020 – 05/2020: intratumoral oncolytic viral therapy
Immune-related adverse event

One year after initiation of the immunotherapy with Pembrolizumab the patient presented with massive edema of both lower legs, thighs and scrotum as well as dyspnea due to pleural effusion.

How did we proceed?

A cardiovascular as well as nephrological genesis of the edema and pleural effusions could be excluded (normal left ventricular function, serumelectrophoresis without pathological findings, exclusion of proteinuria).

Pleura puncture was conducted. Pleural fluid did not show any malignant cell but lots of lymphocytes, expecting it to be the result of an immune-related pleuritis. Prednisone with 30 mg per day was initiated.

Could we continue the immunotherapy?

Immunotherapy was interrupted. The prednisone in combination with diuretic therapy initially led to a reduction of the edemas. A few weaks after tapering off the steroids, recurrent pleural effusion was observed. Therefore Pembrolizumab could not be rechallenged again. Unfortunately the patient died due to deterioration of his general condition.

Our conclusion

Only few publications report the occurence of immune-related serositis, mostly affecting patients with metastatic lung cancer and pericardial effusions. Most patients present with dyspnea, but also asymtomatic pericardial effusion was described, expecting the incidence to be higher than initially thought (Anastasia et al., Journal for ImmunoTherapy of Cancer, 2019). Other authors describe rapidly accumulating effusions under Nivolumab especially in patients with malignant involvement of visceral spaces. Sometimes it might be hard to differentiate between tumour progression and immune-related adverse event. In such cases the detection of lymphocytes in the pleural or pericardial fluid might be helpful, pointing out a positive effect of steroids (Kolla and Patel, Journal for ImmunoTherapy of Cancer, 2016).  

Who we are

SERIO was originally initiated by dermatooncologists at the University Hospital of Erlangen in 2011 with the first documented case dating back to 2009. We are a certified cancer center and home to the German center of Immunotherapy (DZI). There was soon an intensive collaboration with endocrinologists, cardiologists and gastroenterologists that led to our interdisciplinary tox-board. We have also continuously collaborated within the Working Group Dermatooncolgy (ADO) to conduct projects, share experiences and gain new insights. More than 1000 cases of rare complex or very severe side effects from five countries were collected in a period of almost 10 years. We now host an online register in cooperation with the Paul-Ehrlich Institute. Today, we are cooperating with side effect specialists all over the world and hope to improve side effect management for cancer patients.

SERIO is there to help physicians manage side effects and obtain better knowledge on side effects induced by immunotherapy.

What we do 

  • Collect and analyze cases of rare, complex, severe and therapy-refractory side effects induced by immunotherapy
  • Give recommendations for treating physicians confronted with difficult irAE
  • Conduct research and support for people conducting research with regard to irAE