Side Effect Registry Immuno-Oncology

• 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

• 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

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.

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.

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.

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).  

• 68 year old patient
• 07/2018 squamous cell carcinoma (SCC) of the head
  • initial tumor stage: cT4 cN0 M0, G3
  • p53 mutation, PDL1 expression: 25%, 70% in recurrent tumor (06/2020)
• 07/2018 extirpation
• 03 - 07/2019 resection of recurrent tumor
• 12/2019 local progression
• 06/2020 PET-CT: Metastases of bones (t1, t4, l3, l4, os ilii), lymph nodes (regional, hilar, mediastinal) and pleural metastases

• kidney transplantation in 2012 (end-stage kidney disease caused by IgA nephropathy)
• immunosuppressive therapy with tacrolimus (5mg 1-0-0), everolimus (1,5mg 1-0-1) and prednisolone (2,5mg 1-0-0 every second day)
• since 05/2020: everolimus monotherapy (0,5mg 1-0-0)

• 11/2019 bleomycin-based electrochemotherapy, local progression 
• 12/2020 radiotherapy, cumulative dose of 60 Gy, local progression and distant metastases
• 06/2020 Cetuximab (6 cycles), Carboplatin (1 cycle), mixed response
• 09/2020 Cemiplimab (5 cycles) à acute transplant rejection, partial response

After five cycles of Cemiplimab the patient presented with skin rash and an acute deterioration of the kidney function.

Because a transplant rejection was suspected, high-dose systemic corticosteroid therapy was initiated (1 mg/kg bw/day for seven days, followed by 0,5 mg/kg bw/day for seven days). Additionally, topical corticosteroids were used for the exanthema. Everolimus was continued without interruption.

Immunotherapy was interrupted. The systemic corticosteroid therapy quickly led to stabilisation of the kidney function. While maintaining the immunosuppressive therapy with everolimus in the same dosage, the therapy with cemiplimab was continued. A PET-CT showed partial response and fortunately recently ongoing stable disease. Kidney function has been stable since then.

Long-term immunosuppression is associated with a higher risk of malignancy. The decision whether to start an immunotherapy in patients with organ transplantation is complex due to potential induction of organ rejection and only limited data on predictive factors. A retrospective analysis of 64 case reports shows that the risk for a graft rejection might depend on the transplanted organ, with the highest graft rejection rate in renal allografts (44% vs. 39 % in liver and 20% in cardiac allografts). Patients who were treated with PD-1 inhibitors showed higher rates of allograft rejection compared to those who were treated with CTLA-4 inhibitors (39% vs. 23%, Kumar et al., Oncologist, 2020). Despite the immunosuppression with everolimus, cemiplimab checkpoint inhibitor therapy induced a tumor response in this heavily pretreated patient. In a retrospective analysis Abdel-Wahab et al. found that low-dose prednisolone therapy was associated with a high risk for graft rejection, whereas calcineurin inhibitors were associated with a worse tumor response (Abdel-Wahabet al. Journal for ImmunoTherapyof Cancer, 2019). A preclinical study showed that the combination of checkpoint- inhibitors with mTor inhibitors potentiates the anti-tumor immunity (Langdon et al., Oncoimmunology, 2018), suggesting a potentially beneficial combination in organ transplant patients. Further investigation and prospective clinical trials are needed to evaluate how immunotherapy can be optimized in organ transplant patients.

• cutaneous melanoma, St. IV (AJCC 2017)
• progredient lymph node- and skin metastases
• BRAF wildtype
• FBXW7 mutation
• pre-exisiting autoimmune disease: neuromyelitis optica

• 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

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

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

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.