Posterior Reversible Encephalopathy Syndrome (PRES) and Drug-Induced Hypersensitivity Syndrome (DIHS) following Immunotherapy and BRAF/MEK Inhibition with Continued Response in Metastatic Melanoma

Abstract

Background. The role of immunotherapy continues to evolve across both solid and hematologic malignancies. However, while use of immunotherapy has increased via the advent of checkpoint inhibition, chimeric antigen receptors, and vaccines against malignant cells, there remains uncertainty regarding the recognition and management of delayed immune-related reactions and post treatment immune-related sensitivity to subsequent medications, such as BRAF/MEK kinase inhibitors. Furthermore, it is unclear how immunotherapy may alter the adverse effect profile and efficacy of subsequent lines of treatment. Case Presentation. Discussed is a patient with stage IV metastatic melanoma who failed first-line treatment with a combination of nivolumab and ipilimumab. He was then treated with BRAF/MEK kinase inhibition via Encorafenib and Binimetinib. Shortly thereafter, the patient developed posterior reversible encephalopathy syndrome (PRES) and a generalized pruritic rash that was biopsied with consideration toward drug reaction versus drug-induced hypersensitivity syndrome (DIHS), formerly called drug reaction with eosinophilia and systemic symptoms (DRESS). The BRAF/MEK combination was held and steroid taper initiated with continued response even beyond conclusion of the steroid taper. Discussion and Conclusions. This case highlights the diagnostic challenge presented by PRES and DIHS in the setting of immunotherapy and BRAF/MEK kinase inhibition for malignant melanoma. The clinical rationale for reinitiating therapy following severe immune reactions subsequent to immunotherapy in the setting of relapsed/refractory metastatic melanoma is discussed. Additionally, the durable response our patient experienced throughout the drug hold period and steroid taper and its clinical potential etiologies and applications are reviewed. As checkpoint inhibition and tyrosine-kinase inhibitors have become cornerstones of cancer therapy, larger studies and long-term observations are needed to investigate the risks and benefits across different sequences of therapy.

Figure 1

Visual timeline of treatment course leading up to symptoms present during case presentation.

Figure 2

T2-FLAIR Magnetic Resonance Imaging (MRI) brain with contrast demonstrating (a) symmetric T2-hyperintensity of the cerebellum on initial case presentation, (b) representative image demonstrating lack of cerebral involvement during initial case presentation, (c) subsequent 2-week follow-up MRI demonstrating resolving T2-hyperintensity in the cerebellum, and (d) complete resolution of cerebellar T2-hyperintensity 6 months postpresentation.

Figure 3

Generalized pruritic and confluent morbilliform rash involving the face, neck, chest, back, abdomen, arms, thighs, and lower legs. Erythema and mild edema on the cheek, ears, and neck.

Figure 4

(a) A low-power view showing mild upper dermal perivascular and perifollicular inflammation (H&E 40 magnification), (b) basketweave cornified layer and a upper dermal perivascular and interstitial inflammatory infiltrate (H&E 100 magnification), (c) closer view of the perivascular and interstitial inflammatory infiltrate without significant interface or epidermal abnormality (H&E 200 magnification), (d) closer view of the perifollicular inflammation (H&E 200 magnification), (e) closer view of the dermal inflammatory infiltrate of mostly small lymphocytes and a few eosinophils, consistent with drug reaction (H&E 400 magnification), and (f) high-power view of the dermal inflammatory infiltrate of lymphocytes and a few eosinophils (H&E 600 magnification).