Myasthenia gravis following dabrafenib and trametinib for metastatic melanoma

Zaloum, Austin; Falet, Jean-Pierre R.; Elkrief, Arielle; Chalk, Colin

doi:10.1212/wnl.0000000000008860

Cited by 8 publications

(11 citation statements)

References 7 publications

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“…From the literature search, seven reports were identified (six case reports and one case series) that describe 12 cancer patients who developed MG after targeted therapy (15)(16)(17)(18)(19)(20)(21). The included articles were all retrospective studies, so the assessment of quality and risk of bias of analysis were performed using the 9-point Newcastle-Ottawa Scale (NOS) (Table 1).…”

Section: Literature Review Resultsmentioning

confidence: 99%

“…Following the approval of imatinib in 2001, more than 40 TKIs have received hematological or oncological indications over the past 20 years, and many others are currently being tested in clinical and preclinical level, contributing to precision cancer medicine according to individual genetic alterations (14). Beyond their common toxicities (e.g., diarrhea, rash, hypertension, elevated transaminases, and fever), targeted agents have also been associated with few rare, sporadically described in the literature, but potentially severe, "off-target" sequelae, including myasthenic syndrome (15)(16)(17)(18)(19)(20)(21). Herein, we present the first patient with metastatic melanoma who developed anti-MuSK(+) MG after long-term administration of BRAF/MEK TKIs.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Neuromuscular Complications of Targeted Anticancer Agents: Can Tyrosine Kinase Inhibitors Induce Myasthenia Gravis? Getting Answers From a Case Report up to a Systematic Review

et al. 2021

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More than 40 tyrosine kinase inhibitors (TKIs) have received hematological or oncological indications over the past 20 years, following the approval of imatinib, and many others are currently being tested in clinical and preclinical level. Beyond their common toxicities, no certain agent from this large class of molecularly targeted therapies was strongly associated with “off-target” impairment of neuromuscular transmission, and although myasthenia gravis (MG) is a well-characterized autoimmune disorder, only few sporadic events proven by serologically detected causative autoantibodies and/or by positive electrophysiological tests are reported in the literature. Herein, we present the first case of anti-MUSK (+) MG in a woman with metastatic BRAF-mutant melanoma after long-term treatment with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor). Triggered by this report, a systematic literature review was conducted, summarizing all other cancer cases that developed MG, after exposure to any type of targeted agent and regardless of the underlying malignancy. All available data on the clinical diagnosis, the potential of administered TKIs to induce a seropositive myasthenic syndrome, the immune and non-immune-mediated pathogenesis of postsynaptic damage, and the challenging management of this neuromuscular toxicity were collected and discussed. In the presented case, MG was confirmed by both autoantibodies and nerve-conduction tests, while its reactivation after TKIs rechallenge supports a more than coincidental association. The following review identified 12 cancer cases with TKI-related MG in six case reports and one case series. In most of them, the myasthenia diagnosis was challenging, since the clinical symptomatology of fatigable weakness was not corroborating with consistent laboratory and electrophysiological findings. In fact, anti-AchR titers were positive in five and anti-MuSK only in the abovementioned individual. The symptomatology corresponded to TKI discontinuation and standard treatment with pyridostigmine and prednisolone; intravenous immunoglobulin was added only in three, and two required mechanical ventilation. In an era where TKIs will be prescribed more frequently for various malignancies, even in combinations with immune-checkpoint inhibitors, this report synthesizes their risk for neuromuscular complications and increases the clinicians’ awareness in order to extend the on-treatment and overall survival of TKI-treated cancer patients.

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Section: Literature Review Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neuromuscular Complications of Targeted Anticancer Agents: Can Tyrosine Kinase Inhibitors Induce Myasthenia Gravis? Getting Answers From a Case Report up to a Systematic Review

et al. 2021

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“…5 Given that this new symptoms appeared 1 month after the most recently introduced BRAF/ MEK treatment, the possibility of an additive neurotoxic ocular adverse effect 6 and worsening of ankle and knee pain from these treatments has to be considered. [7][8][9] However, BRAF/MEK inhibitors were not stopped and recovery occurred during treatment with these agents.…”

Section: Discussionmentioning

confidence: 99%

Encephalomyeloneuritis and arthritis after treatment with immune checkpoint inhibitors

Nowosielski

Pauli

Iglseder

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveImmunotherapy revolutionized melanoma treatment; however, immune-related adverse events, especially neurotoxicity, may be severe and require early and correct diagnosis as well as early treatment commencement.MethodsWe report an unusual severe multiorgan manifestation of neurotoxicity after treatment with the anti-PDL1 immune checkpoint inhibitor, nivolumab, and the anticytotoxic T-lymphocyte-associated antigen 4 immune checkpoint inhibitor, ipilimumab, in a 47-year-old male patient with metastatic melanoma.ResultsThe patient developed immune-mediated synovitis and cranial neuritis, followed by longitudinal transverse myelitis, encephalitis, and optic neuritis. Early treatment with high-dose steroids and maintenance therapy with rituximab resulted in a favorable neurologic outcome.ConclusionsThe frequency of spinal cord involvement and neuronal toxicity after cancer immunotherapy is very low and requires an extensive diagnostic workup to differentiate between disease progression and side effects. Immune checkpoint inhibitors should be discontinued and treatment with corticosteroids should be initiated early as the drug of first choice. Therapy may be escalated by other immune-modulating treatments, such as rituximab.

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“…Oral prednisolone, 50-mg daily, was initiated with gradual taper and complete resolution of symptoms was observed after 4 weeks. Dabrafenib is commonly used along with trametinib in the management of metastatic melanomas and there have been reports of bilateral panuveitis, chorioretinal folds, serous retinal detachments, [80] and myasthenia gravis [81] with these agents.…”

Section: Other Icismentioning

confidence: 99%

“…Optic neuritis has been reported, [89,90] and may require treatment discontinuation and concomitant administration of systemic steroids. [81] Second generation TKIs include dasatinib and nilotinib. Monge reported a case of optic neuropathy in a patient receiving dasatinib that manifested as vision loss and bilateral visual field involvement.…”

Section: Bcr/abl Tkismentioning

confidence: 99%