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 patient groups (i.e. with autoimmune disease or solid organ transplant).

Myositis
Arthritis
Arthritis
Lichen ruber
Lichen ruber
Pneumonitis
Pneumonitis

Who we are

SERIO was originally initiated by dermatooncologists at the University Hospital of Erlangen in 2011, a certified cancer center and home to the German center of Immunotherapy (DZI). The first documented case of SERIO dates back to 2009. There was soon a close 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.

As of this moment, SERIO is based at the Department of Dermatooncology at the University Hospital of Munich (LMU). We now host an online register in cooperation with the Paul-Ehrlich Institute. Over the course of the last 13 years, we were able to collect more than 1832 cases of rare, complex or very severe side effects from 27 centres in 6 countries. We are cooperating with side effect specialists from all over the world and are hoping 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 to physicians for the management of irAE
  • Conduct research and support other people conducting research with regard to irAE

Case of the Month

Anti-PD-1 rechallenge after irHepatitis grade 3 and irPneumonitis grade 1 during combined anti-CTLA-4 / anti-PD-1 immunotherapy

Medical History
  • 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
Oncological therapy
  • 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
Immune-related adverse event

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.

How did we proceed?

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.

Could we continue the immunotherapy?

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.

Our conclusion

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 live-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.

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.