BRAF Inhibitor Therapy‐Related Encephalitis in a Patient with Metastatic Melanoma

Abstract

Introduction

BRAF inhibitors such as encorafenib and vemurafenib in combination with MEK inhibitors are commonly used for the treatment of patients with BRAF V600–mutant melanoma.

Case Presentation

A patient with relapsed metastatic melanoma with a BRAF V600 mutation was started on treatment with vemurafenib and cobimetinib. Within 2 weeks of treatment start, he was hospitalized and diagnosed with encephalitis through a lumbar puncture and treated with corticosteroids, with subsequent normalization of cerebrospinal fluid (CSF) findings. When he recovered and was switched to encorafenib treatment, the same symptoms recurred, and the patient was treated with high‐dose steroids and intravenous immunoglobulin, again with improvement in his CSF. He has not had a relapse of his symptoms since BRAF inhibitor treatment was permanently discontinued.

Conclusion

This is the first known report of a patient who has developed encephalitis because of treatment with BRAF inhibitors.

Short abstract

This article reports the first known case of a patient who developed encephalitis because of treatment with BRAF inhibitors.

Case Presentation

We describe a patient with BRAF V600E–mutant metastatic melanoma who developed encephalitis during BRAF/MEK inhibitor treatment. A 60‐year‐old man was diagnosed with melanoma of his back, with a right axilla sentinel lymph node biopsy positive for melanoma stage IIIa (pT1N1a) in 2014. After a complete right axillary lymph node dissection, he received 3 months of adjuvant biochemotherapy (cisplatin, vinblastine, and temozolomide with interleukin‐2 and interferon α‐2b).

Computed tomography (CT) scans several years later revealed a 1‐cm lesion in his lungs, treated with a video‐assisted thoracic surgery wedge resection, confirming BRAF V600E–mutant melanoma. Brain magnetic resonance imaging (MRI) performed next month for new‐onset headaches showed a 7‐mm lesion in the right parietal lobe, treated with stereotactic radiation therapy (SRS). The patient was started on anti–PD‐1 therapy with nivolumab. Seven months later, nivolumab was discontinued because of an episode of grade 3 pancreatitis (presented with lipase of 1,580 U/L [normal range, 10–140 U/L] and abdominal pain) as it was not possible to rule out immune‐related pancreatitis versus other etiologies at the time. The patient also had gallstones and underwent a cholecystectomy; however, given the possibility of an immune‐mediated reaction, he was nevertheless treated with 1 mg/kg prednisone at diagnosis of pancreatitis.

Four months later, restaging CT scans showed a right adrenal nodule and a new soft tissue mass anterior to the pancreatic tail, concerning for metastases. The following month, the patient was started on BRAF/MEK inhibitor therapy with standard‐dose vemurafenib and cobimetinib. After 13 days of treatment, the patient was hospitalized with fatigue, grade 3 skin rash, fever (39.3°C), vertigo, nausea, vomiting, and severe headache. He had a maculopapular rash on his back, chest, and abdomen, blisters on his fingers, and laboratory results with grade 1 aspartate transaminase/alanine transaminase and grade 1 creatinine elevation. The patient had no recent travel history. Vemurafenib and cobimetinib were stopped, and the patient was administered empiric antibiotics with cefepime and 125 mg i.v. methylprednisolone, given the severity of his drug rash. Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome was initially considered but thought to be unlikely given the lack of peripheral blood eosinophilia, as well as mild creatinine and liver function test elevations that quickly returned to baseline. He continued with 90 mg i.v. methylprednisolone for 3 days, then converted a rapid prednisone taper. Skin punch biopsy of the rash showed mild interface dermatitis and superficial perivascular lymphocytic infiltrate (Fig. 1A). On the fourth day of hospitalization, the patient also developed arthralgias and grade 2 oral mucositis. On the fifth day of hospitalization, while on prednisone (40 mg daily) the patient's headache acutely worsened, and he also developed visual/auditory hallucinations, short‐term memory problems, and photo/phonophobia. An electroencephalogram showed background slowing with no seizures. MRI and magnetic resonance venography of the brain showed no evidence of metastases, no leptomeningeal enhancement, and no acute abnormalities.

Figure 1.

(A): Mild interface dermatitis and superficial perivascular lymphocytic infiltrate. (B, C): Day 17 cerebrospinal fluid specimen, stained with H&E, with T‐cell–predominant lymphocytosis: magnification, ×20 (B); magnification, ×60 (C).

A lumbar puncture (LP) revealed a cerebrospinal fluid (CSF) opening pressure (OP) of 22.5 cm H₂O (normal range, 8–20 cm H₂O), with white blood cells (WBCs) significantly elevated at 71 cells/μL (normal range, 0–5 cells/μL) and elevated protein levels of 52 mg/dL (normal range, 23–38 mg/dL) (Table 1). CSF culture, a bacterial and viral encephalitis panel (Escherichia coli; Haemophilus influenzae; Listeria monocytogenes; Neisseria meningitidis; Streptococcus agalactiae; cytomegalovirus; enterovirus; herpesvirus types 1, 2, and 6; human parechovirus; varicella‐zoster virus; and Cryptococcus neoformans/gattii), and blood cultures were negative; the patient was also negative for human T‐cell lymphotropic virus types 1 and 2, HIV, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. CSF cytology was negative for malignant cells but showed lymphocytic infiltration, and CSF flow cytometry detected T‐cell–predominant lymphocytosis (73% of the total, with CD4:CD8 ratio of 2.93). The patient reported some relief of symptoms after 28 cc of CSF was removed.

Table 1.

Serial cerebrospinal fluid results

Results (normal values)	First LP Day 1 (onset of encephalitis)	Second LP Day 10 (after dexamethasone switch)	Third LP Day 17 (after restarting BRAF inhibitor therapy)	Fourth LP Day 27 (after increasing steroids/IVIG)
WBCs/mm3 (<5)	71	6	84	14
RBCs/mm3 (<5)	0	1	22	4
Glucose, mg/dL (50–80)	58	55	49	68
Protein, mg/dL (23–38)	52 (↑)	43	58 (↑)	45
OP, cm H2O (8–20)	22.5	17	17	22.5
Cytology	Atypical cells of uncertain origin	Benign lymphocytes, monocytes	Benign lymphocytes, monocytes	Benign lymphocytes, monocytes

Abbreviations: ↑, elevated levels; IVIG, intravenous immunoglobulin; LP, lumbar puncture; OP, opening pressure; RBC, red blood cell; WBC, white blood cell.

Steroids were changed to dexamethasone (24 mg i.v. once, then 8 mg p.o. twice per day); valproic acid was added to help with the headache, and the patient's symptoms slowly improved. One week after discharge, repeat LP showed improvement with CSF WBC count down to 6, protein of 43 mg/dL, and OP of 17 cm H₂O (Table 1). Two weeks after discharge, the patient had near resolution of symptoms. He was started on encorafenib 300 mg monotherapy to treat his known metastatic melanoma (no interim CT imaging was done), as it was felt that his drug‐related encephalitis may have been specific to the vemurafenib plus cobimetinib combination only, as opposed to a class effect of BRAF inhibitors. On the day he started encorafenib, the patient was down to 4 mg/day of dexamethasone.

Three days later, the patient was rehospitalized for increased headaches, neck pain, and stiffness. He did not have rash or significant laboratory abnormalities. A repeat LP demonstrated a CSF WBC count (normal value, up to 5/mm³) significantly elevated again to 84. Cytology analyses again showed T‐cell–predominant lymphocytosis (Fig. 1B, C). Repeat MRI and magnetic resonance angiography of the brain were unremarkable. Encorafenib was discontinued. Dexamethasone was increased to 24 mg i.v. once, followed by 8 mg twice daily. Patient also received i.v. immunoglobulin (IVIG) infusion of 1 mg/kg for 2 days. (IVIG has been used in the treatment of autoimmune encephalitis [1].) His symptoms had resolved by a clinic visit 4 days after IVIG. The results of the fourth LP performed 3 weeks after the second hospital admission are listed in Table 1, with CSF WBCs back down to 14 (normal value, up to 5/mm³).

Restaging CT scans revealed a slight improvement of the metastases, but with inability to resume any BRAF‐targeted therapy, SRS was delivered to the right adrenal gland metastasis at a total dose of 60 Gy in five fractions. Subsequent brain metastases diagnosed several months later required a craniotomy because of hemorrhagic conversion of right parietal lesion with a 4.4‐cm hematoma and increase in size of the left parietal lesion to 5.1 cm. Afterward, the patient had 1.6‐cm left frontal and 2‐cm right occipital metastases. Therefore, despite concern for recurrence of his prior pancreatitis while on nivolumab, the patient restarted on immunotherapy with ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) for four cycles. He remains on nivolumab monotherapy 1.5 years later, with subsequent shrinkage of both his brain and all systemic metastases. He had no development of any immune‐mediated toxicities, encephalitis or pancreatitis, or any other significant side effects during his immunotherapy treatment.

Conclusion

To the best of our knowledge, this is the first report of a suspected drug‐related encephalitis in a patient treated with BRAF inhibitor therapy. Although anti–PD‐1 antibodies can cause immune‐mediated encephalitis and this patient had received prior immunotherapy, the last dose of nivolumab was administered 5 months prior to starting on BRAF‐targeted therapy, and subsequent retreatment with nivolumab did not cause any toxicity. Furthermore, the symptoms of encephalitis started 13 days after initiation of vemurafenib plus cobimetinib, improved with corticosteroids and medication cessation, and flared up again 3 days after restarting BRAF inhibitor monotherapy with encorafenib. This pattern demonstrates a clear temporal association of symptoms with BRAF inhibitor therapy. Other associated symptoms, including grade 3 dermatitis, fever, and mucositis, and the quick response of the encephalitis to corticosteroids and IVIG therapy, suggest an immune‐mediated reaction to the drug.

Although polyneuropathy and encephalopathy have been reported in studies on BRAF/MEK inhibitor therapies, neurological side effects overall are rare, and the pathophysiology of these side effects is unknown [2, 3]. Immune‐mediated mechanisms may play a role in the development of these side effects, given the effect of BRAF‐targeted therapies on the immune system. The MAPK pathway affects T‐cell receptor signaling, and BRAF inhibitors like vemurafenib can lead to paradoxical activation of this pathway in normal tissues and cause activation of T cells [4]. There are multiple ways for BRAF inhibitor therapy to reestablish the immune microenvironment, such as increasing expression of immune‐stimulatory molecules and cytokines, reducing expression of immunosuppressant molecules and cytokines, and reducing the accumulation of regulatory immune cells such as regulatory T cells and myeloid‐derived suppressor cells [5, 6, 7]. Thus, BRAF‐targeted therapy, even without a direct immune‐related working mechanism, may cause immune‐mediated toxicity [8]. Despite the 5‐month gap, it is also possible that the prior nivolumab therapy may have “primed” the immune system and predisposed the patient to more severe toxicities from BRAF inhibitor therapy, which has been described in patients receiving BRAF‐targeted therapy immediately following anti–PD‐1 therapy [9, 10].

In summary, this is the first reported case of a patient who developed BRAF inhibitor–related encephalitis. This reaction may potentially be from an immune‐mediated mechanism, and rapid diagnosis and initiation of high‐dose corticosteroids and immunomodulatory agents like IVIG may be lifesaving.

Disclosures

Peter Forsyth: AbbVie, Ziopharm, Novellus, PSON (C/A), Pfizer, CDMRP, Boehringer‐Ingelheim, NCRI, NIH, Bristol‐Myers Squibb, Tocagen (RF), Novocure, BTG, Inovio, Bayer (SAB); Zeynep Eroglu: SunPharma (C/A), Novartis (RF), Array, Genentech, Regeneron, Novartis (SAB). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board