Neuromuscular junction toxicity with tandutinib induces a myasthenic-like syndrome.
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.


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


METHODS
This study provides Class III evidence that tandutinib 500 mg twice daily induces reversible muscle weakness and electrophysiologic changes consistent with neuromuscular junction dysfunction.
EMG Section, NINDS, NIH, 8900 Wisconsin Ave., Bethesda, MD 20892-1404, USA. lehkyt@ninds.nih.gov
T J
TJ
Lehky
F M
FM
Iwamoto
T N
TN
Kreisl
M K
MK
Floeter
H A
HA
Fine
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000188:drug therapy; D017322:Clinical Trials, Phase II as Topic; D004334:Drug Administration Schedule; D004576:Electromyography; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000139:chemically induced* / Q000503:physiopathology; D009468:Neuromuscular Diseases / Q000139:chemically induced; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000503:physiopathology; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects*; D013577:Syndrome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000068258:Bevacizumab; C464670:tandutinib; D011505:Protein-Tyrosine Kinases
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