Neuromuscular complications following targeted therapy in cancer patients: beyond the immune checkpoint inhibitors. Case reports and review of the literature

Abstract

Introduction In the last years, many new drugs have been developed targeting different oncology pathways, overall improving both quality of life and survival in several malignancies. However, the increase of those therapies is associated with novel toxicities, mainly immune-related adverse events (irAEs), never observed before. Different irAEs are now well characterized, and, among them, neuromuscular complications, following immune checkpoint inhibitor (ICPi) therapy, are increasingly studied and described. However, there are also neurological complications related to the use of other targeted therapies, less known and probably underestimated. Herein we describe two oncological patients who developed neuromuscular diseases after administration of targeted therapies, different from ICPi. Case reports The first patient was treated with the combination of Vemurafenib and Cobimetinib, BRAF and MEK inhibitors, respectively, for a cutaneous melanoma. One year after the beginning of the combined treatment, she developed a sub-acute motor neuropathy with predominant cranial nerve involvement. She was successfully treated with methylprednisolone. The second patient received therapy with Imatinib, tyrosine kinase inhibitor and precursor of the targeted therapy, for a gastrointestinal stromal tumour. Few days after the first administration, he developed generalized myasthenia gravis with respiratory failure. Clinical remission was obtained with plasma-exchange, intravenous immunoglobulins and steroids. Discussion and Conclusion We strengthen the relevance of neuromuscular complications which may occur long after treatment start or in patients receiving not only the latest ICPi but also "older" and apparently better-known targeted therapies. Also in the latter cases, an immune-mediated "off-target" pathogenic mechanism can be hypothesized, and consequences can be life threatening, if not promptly diagnosed and appropriately managed.

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

“…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).…”

“…In this class of TKIs, Demichelis et al reported a case of a 65year-old man with a gastrointestinal stromal tumor (GIST) who commenced imatinib on adjuvant setting following an initial resection of the tumor (17). A few days after initiation of targeted therapy, the patient presented with dysphagia and weakness of the neck extensor muscle, which subsided after a 2-day pause of TKI.…”

“…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.…”

Peripheral neuropathies after BRAF and/or MEK inhibitor treatment: A pharmacovigilance study

“…13 Apart from this, only few case reports are present in the literature. [14][15][16][17][18][19] The incidence of PN in cancer patients is elevated due to several mechanisms, including the neurotoxic potential of antineoplastic agents. 20 Although often neglected, PN can severely impact the quality of life of cancer patients.…”

The risk of worsening of myasthenia by cardiovascular medication as reflected by reporting frequency

“…Such analyses have been carried out for statins [6], checkpoint inhibitors [7], antibiotic drugs [8], and psychiatric and antiepileptic drugs [9]. Cardiovascular drugs rank high on cautionary lists.…”