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

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.

68-year old patient with hemorrhagic irGastritis

Patient medical history
1
Melanoma of the skin, stage IV M1d (AJCC 2017)
06/1998 Cutaneous melanoma, left lower leg, Breslow 0,9 mm
07/2005 Nodular melanoma, BRAF wildtype, left lower leg, Breslow 1,25 mm
05/2008 Subcutaneous metastases, left lower leg
10/2008 Nodular metastases
since 09/2009 Recurrent subcutaneous metastases, left thigh
02/2020 Cerebral metastasis
2
Oncological therapy
08/2005 SNB (1/3)
09/2005 Lymph node dissection
09/2008 Radiotherapy, left lower leg
07/2008 - 12/2008 Interferon-alphha 3x3 Mio IE s.c./week
01/2014 - 08/2014 Radiotherapy, inguinal left
Since 04/2009 Autologous vaccination with tumor-RNA loaded dendritic cells
06/2018 - 03/2020 Immunotherapy with pembrolizumab
03/2020 Cerebral radiotherapy
03/2020 Immunotherapy with ipilimumab/nivolumab (3 cycles)
Immune related adverse event

21 months after initiation of the immunotherapy (IT) and 3 months after switching to combinational IT the patient experienced a hypophysitis that was substituted with hydrocortisone. 1 month later she presented with severe nausea, weight loss and dysphagia. During the following hospitalisation a CTCAE grade 3 hemorrhagic irGastritis and a concomittant CTCAE grade 2 irHepatitis were diagnosed, both with histological confirmation.

How did we proceed?

Pantoprazol 40 mg twice a day was given and prednisolone was initiated at 1 mg/kg body weight and transaminases decreased. Due to steroidrefractory dysphagia and nausea, we planned a therapy with infiximab at 5 mg/kg body weight. Already 3 days after the infliximab-infusion the dysphagia improved and the nausea ceased.

Could we continue the immunotherapy?

We interrupted the immunotherapy and monitored the patient closely. We decided due to the severity of the immune related adverse event and the current stable disease to interrupt the treatment until the next staging. Afterwards we will discuss a rechallenge interdisciplinarily. 

Our conclusion

Gastrointestinal irAEs are common (22-48%) (Heinzerling, L. et al. Dtsch Arztebl Int. 2019). However, solitary upper gastrointestinal events have been rarely reported. In general, an early therapy with infliximab in steroidrefractory gastrointestinal irAEs showed a quicker resolution (Johnson DH et al. J Immunother Cancer 2018) and is recommended in patients with persisting symptoms after 3-5 days (Haanen JBAG et al. Ann Oncol 2017). Escalation of immunosuppression with infliximab worked well and rapidly to treat irGastritis in this patient.

46-year old patient with prolonged irHepatitis and thrombopenia

Medical history
1
Melanoma of the skin stage IV M1c (AJCC 2017)
04/2007 Superficial spreading melanoma, nuchal left, Breslow 4,0 mm
02/2010 Naevoid melanoma, left abdomen, Breslow 3,0 mm
10/2018 Subcutaneous, nodal, pulmonary metastases
Oncological therapy
  •  04/2007 SNB (0/3)
  •  07/2007 – 07/2009 Interferon-alpha 3x3 Mio IE s.c./week
  • 11/2018 -11/2019 Immunotherapy with ipilimumab/pembrolizumab (4 cycles), followed by pembrolizumab
  • 11/2019-12/2019 BRAF/MEK inihibitior therapy with dabrafenib/trametinib
  • 12/2019-02/2020 BRAF/MEK inihibitior therapy with encorafenib/binimetinib
Immune related adverse event

3 months after initiation of the immunotherapy (IT) the patient experienced a hypophysitis that was substituted with hydrocortisone. 5 months after initiation she presented with an irGastritis with a concomittant Addison crisis. Subsequently she had progressive disease and was switched to dabrafenib/trametinib. 12 months after start of IT and one month after start of BRAF/MEK inihibitor therapy she presented with sinus bradycardia, pyrexia and again Addison crisis. Dabrafenib/trametinib was replaced by encorafenib/binimetinib. Another 3 months later she developed CTCAE grade 3 irHepatitis with histological confirmation. Prednisolone was initiated at 1 mg/kg body weight and transaminases decreased. However, on tapering they increase up to 1987 U/l ALT and 1496 U/l AST. Bilirubin was measured up to 21,6 mg/dl.

 

 

How did we proceed?

Prednisiolone was increased to 1000 mg/day, mycophenolate mofetil (MMF 500 mg 1-0-1)  and infliximab were added. Supportive drugs included rifampicin 150 mg (1-0-0) and konakion.

Could we continue with the immunotherapy?

Since she was progressive under immunotherapy no attempt to rechallenge was undertaken. After recovery of irHepatitis BRAF/MEK Inhibitor therapy with vemurafenib/cobimetinib was induced.

Our conclusion

In general, irHepatitis is common (7-33%) and can be fatal. Thrombopenia is rare (1.2-4.7%) and can mostly be well-managed. Sequential therapy with immunotherapy and subsequent BRAF/MEK Inhibitor theapy may lead to new complex side effect profiles (Dimitriou et al. J Immunother, 2018) as in this patient with sinus bradycardia that could not clearly be attributed to any specific drug. Escalation of immunosuppresion with MMF and infliximab worked well to treat irHepatitis in this patient.

54-year old male patient with rheumatic irAE

Medical history
1
Melanoma of the skin, stage IV M1b (AJCC2017)
07/2016 superficial spreading melanoma, thoracic left
09/2016 lymph node dissection, left axilla
11/2018 distant metastases: bipulmonary, pancreatic and lymph node metastases
Oncological therapy
  • 10/2016 – 08/2018 interferon-alpha 3 subcutaneous injections / week
  • 12/2018 initiation of immunotherapy with 4 cycles of ipilimumab and pembrolizumab, followed by pembrolizumab
Immune related adverse event

20 weeks after initiation of the immunotherapy the patient showed joint swelling and pain accompanied by morning stiffness of both knees. A therapy with corticosteroids was started. After an initial improvement of the symptoms and therefore the continuation of the immunotherapy, the joint effusion returned with increasing leg edemas and joint pain. After ruling out another cause of the symptoms (such as chronic heart insufficiency, thrombosis, erysipelas, bacterial joint infection) we diagnosed an immune related oligoarthritis.

Arthritis
Arthritis
How did we proceed?

Due to the corticosteroid-refractory course of the symptoms an onetime infusion with infliximab was given with a significant improvement.

Could we continue with the immunotherapy?

Due to returning symptoms after rechallenging with immunotherapy, we decided to discontinue the therapy. Fortunately the patient is in a complete response.  

Our conclusion

In general inflammatory arthritis after immune checkpoint blockade are uncommon (0,7%-5,5%) (Buder-Bakhaya et al. Cancer Immunol., Immunother. 2018 ; Le Burel et al. Eur J. Cancer 2017), but can develop a persistence of inflammation even after cessation of immunotherapy (Calabrese, L. H. et al. Nature Reviews. Rheumatology 2018). In mild courses immunotherapy can be reinitiated. However, in this case due to the recurrence of the irAE a discontinuation was necessary. 

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