Immune checkpoint inhibitors

Abstract

Immune-related adverse events: 6 case reports A case series described 6 patients (4 men and 2 women) aged 40–62 years, who developed sensorineural hearing loss, anterior uveitis, dermatitis, hypophysitis, arthritis, thyroiditis or pancreatitis during treatment with ipilimumab, nivolumab, denenicokin or pembrolizumab for metastatic melanoma [routes not stated; not all dosages stated]. Case 1: A 40-year-old man, who had metastatic melanoma involving liver, spleen and bones, received first-line treatment with ipilimumab 3 mg/kg and nivolumab 1 mg/kg. Two weeks following the initiation of treatment, he developed grade 3 immunemediated dermatitis and grade 2 anterior uveitis. He was treated with prednisone. However, after one more week, while the treatment with prednisone was continued, he developed tinnitus and aural fullness. An audiometric examination revealed bilateral moderately severe high-frequency sensorineural hearing loss. Bilateral speech reception thresholds exhibited reduced word recognition ability. Tympanometry showed normal middle ear pressure bilaterally. The dose of prednisone was increased, which resulted in subjective hearing improvement within two weeks following the dose increase. Due to the multiple immune-related adverse events (irAEs) and likely immune checkpoint inhibitor (ICI)-ototoxicity, ICIs were stopped following a single dose of each drug. Case 2: A 61-year-old woman, who had melanoma of the urethra metastatic to brain, received first-line treatment with ipilimumab 3 mg/kg and nivolumab 1 mg/kg. She underwent stereotactic radiosurgery for a brain metastasis. At 3.5 weeks following initiation of the treatment, she developed grade 2 hypophysitis. Prednisone was started as treatment. Over the subsequent 3 months, she reported progressive hearing loss, tinnitus and dizziness. A brain MRI exhibited stability of the intracranial metastasis. An audiogram showed moderate-severe bilateral SNHL with reduced speech recognition threshold in the left ear, but preserved word recognition ability. As her hearing loss did not improve with prednisone, her SNHL was treated with bilateral hearing aids. Case 3: A 41-year-old man, who had melanoma metastatic to liver and lymph nodes, received interleukin-2 followed by carboplatin and paclitaxel combination chemotherapy. However, his disease progressed. Thereafter, he received nivolumab 3 mg/kg. At 2 weeks following the initiation of nivolumab, he experienced tinnitus and left-sided hearing loss. Audiometry exhibited mild-moderate SNHL in the right ear and mild to profound SNHL in the left ear. Speech discrimination ability was poor in the left ear and normal in the right ear. Over the subsequent 5 months, nivolumab was continued. However, an increasing subjective hearing decline, with unchanged tinnitus was noted. At seven months, repeat audiometric evaluation showed mild SNHL in the right ear and moderate-severe to profound SNHL in the left hear. Word discrimination was 100% in the right ear and 60% in the left ear. Tympanometry exhibited normal middle ear pressure bilaterally. His symptoms stabilised without intervention. Case 4: A 52-year-old man, who had metastatic melanoma, received first-line treatment with denenicokin [recombinant interleukin-21] and nivolumab 3 mg/kg. At 4 weeks, he developed grade 1 immune-mediated dermatitis and grade 1 inflammatory arthritis. At 4 months following the initiation of ICIs, he reported new bilateral tinnitus. Audiometry showed mild SNHL in the right ear and moderate SNHL in the left. Bilateral speech reception threshold was down to 10dB HL and speech recognition was 100%. A brain MRI scan revealed new cerebellar mass, which was treated with a single fraction of stereotactic radiosurgery (SRS), without reported changes in tinnitus symptoms. Based on location of the intracranial lesion, it was considered an unlikely cause for his tinnitus. After seven months, a repeat audiogram showed unchanged bilateral high-frequency mild to moderate SNHL. His hearing loss was managed with hearing aids including tinnitus maskers. Case 5: A 62-year-old man, who had metastatic melanoma involving groin and scrotum, received first-line treatment with nivolumab 3 mg/kg. At 2 months following the initiation of ICIs, he developed tinnitus without subjective hearing loss. At that time, a brain MRI scan exhibited no evidence of intracranial metastases. ENT evaluation with audiometry showed normal hearing sensitivity bilaterally. Speech recognition thresholds showed excellent word discrimination bilaterally. He refused hearing aid placement. Nivolumab was continued without subjective worsening of symptoms. Case 6: A 55-year-old woman, who had metastatic melanoma and underwent surgical resection with SRS for brain metastases, received first-line treatment with pembrolizumab 2 mg/kg. The metastatic lesions in the body regressed, but the brain metastasis progressed and was treated with whole-brain radiotherapy and concomitant temozolomide. At that time, pembrolizumab was held, and subsequently restarted. Her clinical course was complicated by grade 2 immune-mediated thyroiditis and grade 3 pancreatitis. At approximately 3 years following the initiation of pembrolizumab, she reported new bilateral ear fullness and decreased hearing. A brain MRI scan was negative for leptomeningeal disease. Audiometry showed mild left-sided SNHL. Word recognition was 88% with the right ear and 100% with the left ear. Tympanometry was normal bilaterally. She refused to use hearing aids.