Antineoplastics

Abstract

Various toxicities and lack of efficacy: case report A 68-year-old man developed drug-induced hypersensitivity syndrome (DIHS), posterior reversible encephalopathy syndrome (PRES), renal failure and acute kidney injury during treatment with ipilimumab, nivolumab, binimetinib and encorafenib for stage IV metastatic melanoma. Additionally, he exhibited treatment failure with nivolumab and ipilimumab for stage IV metastatic melanoma [dosages and routes not stated]. The man presented in May 2019 with small bowel obstruction, which required small bowel resection. The pathology demonstrated malignant melanoma stage IV positive for BRAF V600E mutation. In June 2019, he started receiving first-line treatment with nivolumab and ipilimumab. He received total 4 cycles of ipilimumab and nivolumab with rapid disease progression in September 2019. Thus, treatment failure with ipilimumab and nivolumab was considered. Therefore, his treatment was switched to binimetinib and encorafenib in September 2019. He tolerated the combination therapy (binimetinib and encorafenib) well until he developed eye pain, headaches, ataxia and blurry vision 3 weeks later. The brain MRI showed a new, grossly symmetric, abnormal T2 hyperintense signal in the cerebellum bilaterally without significant mass effect or enhancement and without cerebral involvement. The lumbar puncture and CSF analysis revealed positive results for elevated protein; however, it showed negative results for white cells and culture growth. Four days after the onset of neurological symptoms, he started experiencing chills, fevers and a diffuse pruritic rash involving the chest, abdomen, back and bilateral proximal arms. Additionally, he had erythema and mild oedema on the ears, cheek and neck. The laboratory findings revealed elevated creatinine, decreased glomerular filtration rate and elevated liver enzymes. The hepatitis panel showed positive hepatitis-A IgM antibody; however, hepatitis-B and C screens were negative. He was clinically asymptomatic despite positive hepatitis-A IgM antibody. A punch biopsy from rash on the abdomen revealed basketweave cornified layers of skin, supporting an acute rash with vacuolar alteration at the dermal-epidermal junction and moderate perifolliculitis. Additionally, a mid and upper dermal perivascular lymphohistiocytic infiltrate with a few eosinophils, and neutrophils and eosinophils in the interstitium were observed. A differential diagnosis of DIHS was made as severe cutaneous adverse reactions to drugs and collection of biological samples (RegiSCAR) score was found to 3–4. Later, his clinical presentation and laboratory findings confirmed the diagnosis of DIHS and PRES secondary to the ipilimumab, nivolumab, binimetinib and encorafenib therapy. He additionally developed renal failure and acute kidney injury secondary to the ipilimumab, nivolumab, binimetinib and encorafenib therapy. The man was admitted to the hospital, and his therapy with binimetinib and encorafenib was stopped in May 2020, and he was treated with prednisone with close monitoring and slow taper. As a result, his rash resolved and creatinine and liver function normalised through hospitalisation. Hepatitis-A was not treated as he remained clinically asymptomatic with resolving transaminitis. Despite not receiving any active therapy, his tumour continued to decrease in size clinically and radiographically. He remained asymptomatic without clear evidence of disease. After the steroid taper over a six-week period, no recurrence of rash, laboratory abnormalities and PRES symptoms were reported. The repeat disease evaluation in May 2020 revealed continued tumour response without any clinical symptoms. He subsequently experienced relapse and progression with increased size of prior left chest metastases in May 2020. Therefore, he started receiving dabrafenib followed by trametinib 3 weeks later. At the time of report, he continues to tolerate dabrafenib and trametinib therapy without any recurrence of renal dysfunction, rash, transaminitis and neurological symptoms.