Ipilimumab and nivolumab induced immune-related adverse events in metastatic mucosal melanoma

Abstract

Mucosal melanoma is a rare subtype of melanoma and represents a unique diagnosis and treatment challenge. Immune-checkpoint inhibitors (ICIs) have revolutionised metastatic melanoma treatment, and one of the leading regimens is the combination of ipilimumab (anti-cytotoxic T lymphocyte-associated antigen 4: CTLA4) and nivolumab (anti-programmed cell death protein 1: PD1). We report a case of a patient with metastatic mucosal melanoma treated with ipilimumab and nivolumab who developed multiple immune-related adverse events (irAEs) including uveitis, type I diabetes complicated by diabetic ketoacidosis, destructive thyroiditis, hepatitis and vitiligo. Endocrinopathies including type 1 diabetes and hypothyroidism were treated with insulin and levothyroxine. Hepatitis was responsive to steroids. She had sustained complete response 12 months after discontinuation of the combination therapy. With the wide usage of ICIs in multiple types of malignancies, it is important for general practioners to recognise common and serious irAEs due to ICIs.

Melanoma is the fifth most common cancer in the USA, and the mucosal subtype represents less than 1% of all melanomas.¹ Mucosal melanomas primarily involve the head and neck region such as nasal and oral cavities, followed by the gastrointestinal (GI) tract and female genital tract. Due to the unique locations, early detection of mucosal melanoma is more challenging comparing to cutaneous melanoma.²

Immune-checkpoint inhibitors (ICIs) have revolutionised metastatic melanoma treatment, and one of the leading regimens is the combination of ipilimumab (anti-CTLA4) and nivolumab (anti-PD1). In phase II and III clinical trials, combination regimen improved progression-free survival and overall response rate versus ipilimumab alone in treatment-naive patients with metastatic melanoma.^{3 4} However, grade 3 or higher adverse events were also higher in the combination group.⁵ Mucosal melanoma has a worse prognosis with lower response rate to ICIs compared with cutaneous melanoma.^{6 7}

With the increased use of ICIs, cases of immune-related adverse events (irAEs) are rising significantly. Endocrinopathies are observed in up to 10% of patients who are treated with anti-CTLA-4 inhibitors and in 4%–14% of those treated with anti-PD-1 inhibitors. The common endocrinopathies include hypophysitis, thyroid dysfunction and, less commonly, type 1 diabetes mellitus.⁸

Here, we report a case of a patient with metastatic vaginal mucosal melanoma treated with ipilimumab and nivolumab with complete response who developed multiple irAEs including uveitis, type I diabetes complicated by diabetic ketoacidosis (DKA), destructive thyroiditis, hepatitis, adrenal insufficiency, arthritis and vitiligo.

Case presentation

The patient is a 59-year-old woman with medical history of menopause syndrome on hormonal replacement therapy who initially presented with right inguinal lymphadenopathy with tenderness. The patient also noted to have nevus on right labia. Positron emission tomography (PET)/CT revealed fluorodeoxyglucose (FDG) activity in right inguinal lymph nodes, left breast and left lower lobe of the lung (figure 1A). Left breast mass biopsy and vaginal biopsy were consistent with metastatic melanoma of vaginal origin. Molecular analysis showed TP53 mutation with negative v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and c-kit mutation. PD-L1 expression was not tested. She responded well to the first cycle of ipilimumab/nivolumab with significant shrinkage of the lymphadenopathy but developed blurry vision and photosensitivity attributed to bilateral grade 2 uveitis. Her eye symptoms resolved quickly with ophthalmic and systemic steroids. She received a second cycle without complication.

Figure 1.

(A) PET (Positron emission tomography) scan prior to treatment with red circle showing breast and pelvic lymph nodes metastatsis. (B) PET scan 12 months after the third cycle of combination therapy showing resolution of breast and pelvic lymph nodes metastasis.

Three days after receiving the third cycle of ipilimumab/nivolumab, she presented to the emergency room with nausea, vomiting and generalised weakness, and was found to have DKA with pH of 6.98, bicarbonate of 6 mmol/L, anion gap of 30 mmol/L, glucose of 459 mg/dL and beta-Hydroxybutyrate (BOHB) >10 mmol/L. Her blood glucose was normal prior to the third cycle of ipilimumab/nivolumab. Workup revealed that C-peptide was <0.1 ng/mL consistent with new-onset type I diabetes. Anti-glutamic acid decarboxylase(GAD65) was negative. She was also found to have destructive thyroiditis with TSH of 0.03 mcIU/mL and free T4 of 1.85 ng/mL. Thyroid peroxidase antibody and thyroid-stimulating immunoglobulin were both negative. Ten days after the third cycle, she developed grade 3 hepatitis with peak Aspartate Amionotransferase (AST) of 185 unit/L, Alanine Amionotransferase (ALT) of 225 unit/L with normal total bilirubin. Liver function test (LFT) initially responded to prednisone but mycophenolate was required during steroid taper due to recurrent LFT elevation (figure 2). Vitiligo developed 3 months after starting first cycle of ipilimumab/nivolumab and evolved throughout this process (figure 3). Vitiligo localised diffusely throughout the body with estimated 80% of body surface area affected.

Figure 2.

AST (Aspartate Amionotransferase)and ALT (Alanine Amionotransferase) during course of disease. Y axis: unit/L.

Figure 3.

Vitiligo.

Outcome and follow-up

PET CT scan 2 months after the third cycle of combination therapy showed complete response. Blood glucose was difficult to control partly due to the prolonged use of prednisone for autoimmune hepatitis. Prednisone taper from 60 mg daily to 2.5 mg daily was attempted after LFT normalised. However, she experienced severe fatigue when attempting to taper down prednisone to 2.5 mg so she was restarted on 10 mg daily and referred to endocrinology for possible adrenal insufficiency. She was diagnosed with secondary adrenal insufficiency with low adrenocorticotropic hormone (ACTH). Physiological level of hydrocortisone 10 mg in morning and 5 mg in evening was initiated and fatigue improved significantly.

Latest PET CT scan 12 months from the last and third cycle of ipilimumab and nivolumab also showed sustained complete response without any further treatment (figure 1B).

Discussion

Although irAEs are commonly associated with ICIs, it is rare for irAEs to involve multiple organ systems. The mechanism of irAEs is autoimmune-mediated destruction of normal tissues due to immune response through T cell activation.⁹ irAEs can affect any organ system and the mainstay of treatment is corticosteroids. One exception is endocrinopathies of irAEs in which hormonal replacement is the key.

Vogt-Koyanagi-Harada disease was reported as irAEs in metastatic melanoma patients treated with nivolumab and dabrafenib/trametinib.¹⁰ This disease is caused by an autoimmune reaction with unknown aetiology, and is characterised by granulomatous uveitis accompanied by hearing loss and vitiligo. This patient had bilateral uveitis, and later developed vitiligo, but without hearing loss, retinal detachment and signs suggesting granulomatous nature.

The combination of ipilimumab and nivolumab treatment for malignant melanoma has a higher response rate but leads to a higher incidence of irAEs comparing to single agent immunotherapy. In a meta-analysis of advanced melanoma patients treated with ICIs, overall incidence of irAEs in ipilimumab and nivolumab combination group is 83%, comparing to 21% in ipilimumab alone group and 7% in nivolumab group. Among the study population, 1.06% of patients in the combination treatment group developed type I diabetes and 0.36% of patients was complicated with DKA.⁵

Our patient continued to be in remission after three cycles of ipilimumab and nivolumab, but at the cost of multiple irAEs including endocrinopathies, hepatitis, uveitis and vitiligo. It is known that the treatment response among the patients with irAEs is higher compared with patients without irAEs. In a recently published retrospective study in non-small-cell lung cancer patients treated with ICIs, development of multisystem irAEs is associated with improved survival.¹¹ Chan et al also reported improved survival in melanoma patients treated with ICIs if they developed immune-mediated cutaneous adverse events.¹²

Although durable response with ICIs is meaningful, the possibility of developing persistent adverse effects even after discontinuation of ICIs such as endocrinopathy including type 1 diabetes and chronic joint pain must be discussed with patients prior to therapy initiation. As of 2021, ICIs are indicated for melanoma, lung, renal cell, bladder, prostate, head and neck, GI, gynaecologic and breast cancers and some of haematological malignancies.¹³ With the increased use of ICIs across a broad variety of malignancies, immune-related endocrinopathies with ICIs need to be well informed.

Conclusion

It is important to recognise common and serious irAEs due to ICIs. Type I diabetes although rare, can present emergently as DKA and requires immediate recognition and treatment. Additionally, patients can present with multiple irAEs at different time points during and after treatment. For high-grade irAEs, ICI rechallenge is generally not recommended. Treatment with ICIs can achieve long-lasting response through immune modulating effects but persistent side effects might be seen even after discontinuation of therapy. Quality of life may be limited due to the development of side effects despite of primary cancer control.

Patient’s perspective.

I felt like I went into a ‘vacuum’ when I was diagnosed and treated in the middle of COVID-19 restrictions and then came out the other side with ‘no evidence of disease’ but all these new health issues and no appreciation for everything I had just been through. ‘I haven't done anything to prepare for being a dead person’.

Learning points.

• It is important for general practioners to recognise common and serious immune-related adverse events (irAEs) due to immune-checkpoint inhibitors (ICIs).

• Patients can present with multiple irAEs at different time points during and after treatment.

• Treatment with ICIs can achieve long-lasting response through immune modulating effects but persistent side effects might be seen even after discontinuation of therapy.

Ethics statements

Patient consent for publication

Obtained.