Neuromuscular junction toxicity with tandutinib induces a myasthenic-like syndrome

Abstract

Background: Tandutinib (MLN 518, Millennium Pharmaceuticals, Cambridge, MA) is an orally active multitargeted tyrosine kinase inhibitor that is currently under evaluation for the treatment of glioblastoma and has been used in the treatment of leukemia. In prior clinical and animal studies, a dose-dependent muscular weakness has been observed with this drug, though the etiology of the weakness has not been defined.

Methods: Standard neurophysiologic techniques, including repetitive nerve stimulation, needle EMG, and single-fiber EMG, were used to evaluate patients who developed weakness while being treated with tandutinib and bevacizumab (Avastin, Genentech, South San Francisco, CA) for glioblastoma (NCT00667394).

Results: Six patients were observed to develop a reversible weakness that correlated with the administration of the tandutinib. The onset of weakness after starting tandutinib occurred within 3 to 112 days and in less than 15 days in 3 patients. Electrophysiologic studies showed that all patients developed abnormal repetitive nerve stimulation studies. Four patients had short duration motor unit potentials. Two of these patients also had abnormal single-fiber EMG, as did a third patient who did not have standard needle EMG. The clinical and electrophysiologic abnormalities improved with the termination or reduction in the dose of tandutinib.

Conclusion: These observations suggest that tandutinib is toxic to the neuromuscular junction, possibly by reversibly binding to a molecule on the postsynaptic acetylcholine receptor complex.

Classification of evidence: This study provides Class III evidence that tandutinib 500 mg twice daily induces reversible muscle weakness and electrophysiologic changes consistent with neuromuscular junction dysfunction.

Figures

Figure. Repetitive nerve stimulation (RNS) studies

RNS of the ulnar nerve recording at the adductor digiti minimi (ADM) (A, B) and facial nerve recording at the nasalis (C, D) was performed on patient 3. Initial study (A, C) was performed while patient 3 was on tandutinib. Follow-up study (B, D) was performed while the same patient was off tandutinib for 1 week. All studies in the figure were performed by stimulating the ulnar nerve or facial nerve at 3 Hz for 5 stimuli prior to 1-minute exercise. While on tandutinib, the decremental response was 14% for the ADM and 36% for the nasalis. After the tandutinib was discontinued for 1 week, the decremental response at rest was 5% for the ADM and 11% for the nasalis. The amplitudes increased off the tandutinib for patient 3 but not in the other patients with serial studies (patients 2 and 4).