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

35-year old patient with pre-existing autoimmune disease

Patient medical history
  • cutaneous melanoma, St. IV (AJCC 2017)
  • progredient lymph node- and skin metastases
  • BRAF wildtype
  • FBXW7 mutation
  • pre-exisiting autoimmune disease: neuromyelitis optica
Oncological therapy
  • epifocal administration of dinitrochlorobenzene (DNCB) combined with systemic chemotherapy with dacarbazine (DTIC); progressive disease
  • therapy with sorafenib; progressive disease
  • immunotherapy with ipilimumab (2 cycle); progressive disease and death
Immune related adverse event

Shortly after initiation of the immunotherapy (IT) with pembrolizumab the patient presented with acute paraplegia and urinary retention due to transverse myelitis.

How did we proceed?

We discontinued the immunotherapy due to severe adverse event (CTCAE Grade 4). Although immmunosuppressive therapy was initiated immediately the patient died six months later.

Our conclusion

In the past most patients with preexisiting autoimmune diseases have been excluded from clinical trials evaluating checkpoint inhibitors because of a possible exazerbation of the underlying disease.  Interestingly, retrospective studies show that less than 50% experienced flares which were often mild and easily managed by immunosuppressive therapy (Gutzmer et al., Eur. J. Cancer. 2016).  Nevertheless, they can be severe and potentially fatal as seen in our example. Severe side effects are especially described in preexisiting neurological autoimmune diseases (Safa et al., J. Immunother. Cancer. 2019). Further investigation is needed to understand the mechanisms of autoimmunity in the context of immunotherapy-induced side effects to evaluate the individual risk of patients before starting an immunotherapy.

74-year old patient presenting with cutaneous irAE

Patient medical history

Cutaneous melanoma, pT1a, St. IV (AJCC 2017)

03/2012 superficial spreading melanoma of the shoulder, BRAF wildtype, Breslow 0,7 mm

04/2014 axillary lymph node metastases with vascular compression

08/2014 pulmonal metastases

Oncological therapy

04-07/14 radiochemotherapy (carboplatin/paclitaxel)

08-09/2014 immunotherapy with ipilimumab (2 cycles, progressive disease)

10/14-01/16 immunotherapy with pembrolizumab (20 cycles)

Immune related adverse event

Four weaks after initiation of the immunotherapy (IT) with pembrolizumab the patient presented with shortness of breath due to irPneumonitis CTCAE grade 2. After high-dose systemic corticosteroid therapy and improvement of symptoms the immunotherapy could be continued. Within fourteen months after initiation of the therapy the patient showed painful oral mucosal erosions. Biopsy was taken and showed a typical histologic picture of lichen planus.

How did we proceed?

Systemic retinoids and local therapy with triamcinolone acetonide adhesive paste constantly led to clinical improvement and complete healing.

Could we continue the immunotherapy?

We discontinued the immunotherapy due to complete response.

Our conclusion

The skin is one of the most common manifestations of immune-related adverse events and may occur in up to 30 to 50% of patients being treated with Checkpoint-Inhibitors (Lacouture M et al., Am J Clin Dermatol. 2018). They are typically mild and can often be treated without interruption of immunotherapy. However, there are also potentially life-threatening cutaneous irAEs such as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which are treated with permanent ICI discontinuation (IW Tattersall, Leventhal JS, Yale J Biol Med. 2020). Interestingly, cutaneous irAEs, especially such as vitiligo, have been shown to be a positive prognostic indicator for the treatment, especially in melanoma patients (Quaglino P. et al., Ann. Oncol. 2010).   

76-year old patient presenting with irMyositis

Patient medical history

Cutaneous melanoma, pT3b, St. IV (AJCC 2017)

01/2015 nodular melanoma of the back, BRAF wildtype, Breslow 2,9 mm

10/2019 pulmonal metastases

01/2020 cerebral metastases

Oncological therapy

Immunotherapy with ipilimumab / nivolumab (1 cycle)

Immune related adverse event

Four  weaks after initiation of the immunotherapy (IT) the patient presented with uncertain gait, proximal muscle weakness, double vision and shortness of breath. Laboratory results showed a significant increase of serum creatine kinase (CK, 1800 U/l), elevated CK-MB (10,4 fold increase) and Troponin-I  (634 pg/ml) levels thus confirming irMyositis  with ocular involvement. To rule out myocarditis further diagnostic procedures were undertaken. A cardiac MRI showed an apical hypokinesia and a myokardial biopsy showed a lymphocytic myocarditis. Diagnosis of a CTCAE grade 3 irMyositis and irMyocarditis was confirmed.

How did we proceed?

High-dose systemic corticosteroid therapy was initiated (1 g per day over three daysand 1mg/kg per day thereafter which led to clinical improvement. Therapy was tapered over 4 weeks.

Could we continue the immunotherapy?

Immunotherapy was interrupted. Subsequent therapy due to progressive disease was initiated with Temozolomid.

Our conclusion

Checkpoint Inhibitor-induced Myositis (irMyositis) is accompanied by the involvement of the myocard in up to 32% of cases (Moreira A et al. Eur J Cancer. 2019.). It is life-threatening giving rise to cardiac arrhythmias and/or a reduced left ventricular ejection fraction and has a high fatality rate (Wang et al. JAMA Oncol. 2018). Ophthalmoplegia can be a manifestation of ocular myositis, representing a frequent manifestation of irMyositis (Garibaldi M et al. Neuromuscul Disord. 2020). It can occur isolated or combined with shoulder girdle manifestation, as shown in our patient. Clinicians should be aware of manifestations of irMyositis and monitor serum creatine kinase as well as clinical symptoms. If diagnosed immediate treatment with corticosteroids is necessary to improve outcome.

59-year old patient with asymptomatic lipase increasement and diabetes mellitus

Patient medical history
1
Melanoma of the skin, stage III B (AJCC 2017)
05/2011 superficial spreading melanoma, BRAF V600 E mutation, gluteal, Breslow 1,5mm
02/2020 nodal metastasis, inguinal right
2
Oncological therapy
05/2011 SNB (sn0/1)
02/2020 Lymph node dissection
02/2020 - 06/2020 Immunotherapy with ipilimumab / nivolumab (2 cycles), continuation with nivolumab (3 cycles)
Immune related adverse event

One month after initiation of the immunotherapy (IT) the patient experienced a irHypophysitis (CTCAE 3) that was substituted with hydrocortisone as well as an irThyroiditis that was substituted with levothyroxine. Three months after initiation of the IT the patient also developed a colitis (CTCAE 2) that was confirmed by an endoscopical biopsy. A few weeks later he also showed arthralgias in both shoulders.

5 months after initiation the patient showed a lipase increase of 559 U/l, after which we interrupted the immunotherapy. Two weeks later the lipase count increased up to 1300 U/l without any symptoms of a pancreatitis. An abdominal sonography and an abdominal MRI did no show any signs of an acute pancreatitis.

How did we proceed?

We decided to withdraw the immunotherapy due to multiple immune related adverse events (irAE). The patient did also lose 10 kg body weight after initiation of the lipase increase. One month after the lipase increase onset the lipase counts nearly resolved, but the patient developed a hyperglykemia with decreased insulin. Since then he needs insulin substitution.

Our conclusion

Patients with one irAE are more likely to develop another irAE, so that patients should be closely monitored. Asymptomatic lipase increases are common (2,3 %, Su Q. et al J Immunol Res. 2018), however a treatment without any clinical signs for a pancreatitis is not required. The development of diabetes mellitus in this case could either occur as a consequence of an occult pancreatitis (diabetes type 3) or as an new irAE (diabetes type 1). Either way glucocorticosteroids would not be recommended (Stamatouli AM et al. Diabetes 2018). As it is an endocrinological irAE, substitution therapy is needed.

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