pyrimidinones and Vitiligo

In the last few years, melanoma treatment has been revolutionized by the development of immune checkpoint-blocking antibodies or immune checkpoint inhibitors including ipilimumab, vemurafenib, dabrafenib, trametinib, nivolumab, and pembrolizumab. Although they have shown promising results, they also have caused multiple adverse events (AEs), particularly immune-related AEs (irAEs). Specialists should be familiar with these AEs.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Drug Eruptions; Gastrointestinal Diseases; Humans; Hypophysitis; Hypothyroidism; Imidazoles; Immunosuppressive Agents; Indoles; Ipilimumab; Melanoma; Mycophenolic Acid; Nivolumab; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Sweet Syndrome; Thyrotoxicosis; Tumor Necrosis Factor-alpha; Vemurafenib; Vitiligo

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Vitiligo

The combination of BRAF and MEK inhibitors, such as dabrafenib and trametinib, respectively, is an established treatment option for patients with advanced BRAFV600-mutated melanoma. With the wide adoption of these therapies, a range of cutaneous adverse effects has been reported. We describe the case of a 47-year-old woman with BRAFV600E-mutated stage IV melanoma treated with dabrafenib and trametinib for 30 months who presented to our attention for painful skin lesions that had been present on her limbs since the start of targeted therapy. We also observed vitiligo-like lesions on the extensor surface of both legs. Despite achieving a complete oncological response, the patient had to discontinue the treatment because of persisting fever, nausea and painful skin nodules that significantly impaired her quality of life. The recognition of cutaneous signs of efficacy of such drugs for advanced melanoma is of primary importance in order to identify patients with potential long-term clinical benefits.

Topics: Combined Modality Therapy; Female; Humans; Imidazoles; Melanoma; Middle Aged; Neoplasm Staging; Oximes; Panniculitis; Pyridones; Pyrimidinones; Skin Neoplasms; Vitiligo

Panniculitis and vitiligo-like lesions have been recently identified as rare cutaneous side effects of the combination of BRAF and MEK inhibitors, a standard of care in metastatic and locally advanced BRAF V600 mutated melanoma. An immune-mediated mechanism has been advocated in the pathogenesis of these skin lesions. Herein we retrospectively reviewed our institutional experience with the aim to explore the association between the occurrence of panniculitis and vitiligo-like lesions during combination therapy with dabrafenib (D) and trametinib (T) and outcome of advanced melanoma patients. Among 52 consecutive BRAF V600 mutated melanoma patients submitted to DT in our center, 12 (23%) developed immune related skin lesions (IRSLs): 8 panniculitis and 4 vitiligo. Patients with IRSLs diagnosis obtained a better disease response (83% versus 25%) (p = 0.001) than their counterpart and had a longer progression free survival and overall survival. The association of IRSLs and lower risk of disease progression (HR 0.19; CI 95% 0.04-0.90; p = 0.043) was confirmed after adjusting for major prognostic factors in multivariate analysis. IRSLs might represent an easy predictive surrogate marker for treatment response and favourable outcome in melanoma patients submitted to DT combination therapy.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Kaplan-Meier Estimate; Male; MAP Kinase Signaling System; Melanoma; Middle Aged; Mutation; Oximes; Panniculitis; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Vitiligo