- 09/2019 - Cutaneous Melanoma (tumor thickness 2.8 mm, Mitose index > 4)
- 01/22 - pT3 N1c M1b
- Pulmonary and lymph node metastases
- Excision of In-transit metastasis on right nasal septum
- Histologically confirmed lung metastasis
- 03/22 – Staging - PR
- BRAF wild type
- 09/22 – Staging – SD
- CT chest/abdomen and cMRI: persistent PR, DD avitality of the pulmonary lesions
- 02-05.2022 – 4 cycles of combined immunotherapy with ipilimumab 3 mg/kg + nivolumab 1 mg/kg) followed by
- 9 x nivolumab q2w
After the 2nd cycle( on week 3) of combined immunotherapy with immune checkpoint inhibitors (ICI) ipilimumab and nivolumab, the patient presented with immune-related hepatitis (irHepatitis) and immune-related thyroiditis (Grade II) (irThyroiditis).
After week 20 of ICI (4th cycle ipilimumab/nivolumab and 4th nivolumab), the patient suffered from weight loss (110 kg) and muscle loss. As the ACTH provocation was positive, immune-related hypophysitis (Grade II) (irHypophysitis) was diagnosed.
After completion of 4th ipilimumab/ nivolumab and 9th nivolumab (week 30), the patient complained of severe vertigo and left sided hearing loss (irVestibulopathy and irCochleitis).
irThyroiditis (Grade 3 CTCAE) at week 3
Hyperthyroidism was treated with a beta-blocker on 03/22, and subsequently Hypothyroidism with L-thyroxine (50 µg) from 05/22 onwards.
Oral Corticosteroid therapy (50 mg) was started and then tapered.
Hyperthyroidism in irThyroiditis is a result of direct immune induced destruction of thyreocytes which releases the stored thyroid hormone from the thyroid follicles into the blood circulation. Hence, carbimazole is not useful in irThyroiditis induced hyperthyroidism as it acts by decreasing the uptake and concentration of inorganic iodine by thyroid and also reduces the formation of di-iodotyrosine and thyroxine.
irHypophysitis (Grade 2 CTCAE) at week 20
Hydrocortisone 20 mg/day was substituted.
irVestibulopathy and irCochleitis (Grade 3/4) at week 30
The patient was referred to an ENT specialist and started on prednisone (SDH) 200 mg i.v. for 3-5 days.
Upon therapy, the hearing loss improved, the vertigo subsided and the patient gained bodyweight and muscle mass.
On account of stable disease, the ICI was stopped on 9/22.
Most frequently, immune-related Adverse Events (irAEs) affect a wide range of organs like skin, colon, liver, pituitary, thyroid, and lungs, although uncommon events involving the heart, nervous system, and other organs do occur. The onset develops predominantly within the first 6-12 weeks after treatment initiation.
Combining treatment with ipilimumab and nivolumab has resulted in a reported 18%-22% all-grade hepatitis and overall with 8%-11% having severe hepatitis. (Remash D, et al. World J Gastroenterol. 2021)
Hyperthyroidism due to irThyroiditis occurs on account direct thyreocyte destruction and hence carbimazole, which acts by inhibiting thyroid hormone synthesis is not indicated in irHyperthyroidism. (Iyer PC, et al. Thyroid. 2018).
Neurological immune-related adverse events occur in 1%–5% of patients on ICI therapy (Koch EAT, et al. J Immunother. 2021). Moreover, ICI-mediated ototoxicity is rare or under reported due to a small number of case reports published till date. (Rosner S, et al. J Immunother Cancer, 2020) of patients (refs voskens JCO, and others). It may develop isolated as a single irAE or in concert with other irAEs as in this case. Manifestation of ICI-mediated ototoxicity ranges from isolated hearing loss, tinnitus, vestibular symptoms with hearing loss, visual and hearing loss or Vogt-Koyanagi-Harada syndrome (VKH) with ocular, dermatologic and neurologic involvement. It is important to distinguish between isolated hearing changes and hearing changes as part of a collective syndrome to institute appropriate management.
In the absence of ocular involvement, a diagnosis of Cogan Syndrome was not made.
ICI-mediated ototoxicity occurs early in the treatment course (within ~4 months of initiating ICI). The association between irAEs and ICI efficacy is controversial and may depend on the site of toxicity. Retrospective studies suggest that site-specific toxicities may have a correlation with ICI efficacy (Martins F, et al. Nat Rev Clin Oncol, 2019)
The mechanisms underlying the development of ICI-mediated ototoxicity are currently unknown. Preclinical rat models of ICI-mediated ototoxicity demonstrated significant differences in auditory brainstem responses (ABR) in those treated with ICIs vs controls, as well as pathologic evidence of a reduction in the outer hair cells and flattening of the organ of Corti in those treated with ICI. (Kuzucu İhsan, et al . Cureus 2019) Interestingly, ototoxicity has also been reported from adoptive cell therapy for melanoma. The proposed mechanism of this toxicity could involve auto-antigenicity against melanocyte specific antigens such as MART-1 present in the inner ear, uvea and epithelium of the skin (Plonka PM et al. Exp Dermatol, 2009).
ICI related ototoxicity is a rare side effect of immune checkpoint inhibitors that health care providers should be aware of and that requires interruption of ICI therapy and prompt administration of systemic corticosteroids to ensure restitution ad integrum.
