Correspondence

Imatinib as a Possible Cause of Severe Rhabdomyolysis

N Engl J Med 2008; 358:2746-2747June 19, 2008

Article

To the Editor:

Imatinib mesylate (Gleevec [Glivec], Novartis), a protein kinase inhibitor of c-kit receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor α (PGFR-α), is widely used for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Its common side effects (diarrhea, edema, asthenia, myalgia, and skin reactions) are most often mild and manageable.1

We describe the case of a 25-year-old woman who received imatinib mesylate (at a daily dose of 400 mg) in a clinical trial for the treatment of aggressive fibromatosis (desmoid tumors) not amenable to surgery.2 Shortly after the initiation of treatment with imatinib, she had myalgia of growing intensity and was subsequently admitted with an extensive mucocutaneous rash, pruritus, hypereosinophilia, and an elevated level of serum creatine kinase (1068 IU per liter; upper limit of the normal range, 110).

Myocardial infarction, stroke, and other medications were ruled out as causes of the elevated creatine kinase level. Common causes of rhabdomyolysis were also ruled out. A myopathic pattern was seen on electromyography. Although the patient declined to undergo muscle biopsy, there was no evidence of an underlying metabolic muscle disorder or myopathy. After the discontinuation of imatinib, the myalgia disappeared, and the creatine kinase level returned to normal (119 IU per liter) within a week.

After the patient provided written informed consent, imatinib was reintroduced under medical surveillance. Twenty-four hours after she received the first daily dose of 100 mg, severe myalgia reappeared and was accompanied by increased levels of the skeletal-muscle subtype of creatine kinase (1444 IU per liter) and aldolase and the presence of myoglobinuria. Again, imatinib was discontinued, and the myalgia disappeared in 3 days. The patient's desmoid tumors continued to grow and were treated with radiotherapy. As of January 2008, the patient had not reported any recurrence of symptoms of rhabdomyolysis.

Rhabdomyolysis is characterized by leakage of myoglobin and other intracellular proteins and electrolytes into the circulation, as a result of acute muscle necrosis. The latter may be due to direct muscle injury, infection, metabolic myopathy, or various toxic or pharmacologic agents, including antipsychotic drugs, colchicine, zidovudine, and statins.3 The rate of death from rhabdomyolysis is about 8%, as a result of acute renal failure, disseminated intravascular coagulopathy, or severe electrolyte abnormalities leading to cardiac dysrhythmias.3

We considered our patient's rhabdomyolysis to be induced by imatinib because of the temporal relationship (the rhabdomyolyis occurred within a few days after the initiation of imatinib therapy), the recurrence of rhabdomyolyis with the reintroduction of the drug, and normalization of the creatine kinase level after discontinuation of the drug. Although there is extensive clinical experience with the safe use of imatinib, this observation suggests that the drug may cause severe rhabdomyolysis in a small proportion of patients.

Nicolas Penel, M.D., Ph.D.
Centre Oscar Lambret, 59020 Lille, France

Jean-Yves Blay, M.D., Ph.D.
Hôpital Edouard Herriot, 69003 Lyon, France

Antoine Adenis, M.D., Ph.D.
Centre Oscar Lambret, 59020 Lille, France

Dr. Penel reports receiving research support from Novartis; Dr. Blay, serving on advisory boards for Novartis, Pfizer, Roche, and GlaxoSmithKline and receiving lecture fees and grant support from Pfizer and Novartis; and Dr. Adenis, serving on advisory boards for Novartis and Pfizer and receiving lecture fees from Roche. No other potential conflict of interest relevant to this letter was reported.

3 References

1. 1

   Siddiqui MA, Scott LJ. Imatinib: a review of its use in the management of gastrointestinal stromal tumours. Drugs 2007;67:805-820
   CrossRef | Web of Science | Medline

2. 2

   Penel N, Bui BN, Le Cesne A, et al. Imatinib for the treatment of aggressive fibromatosis (desmoid tumors) failing local treatment: a phase II trial of the French Sarcoma Group. Proc Am Soc Clin Oncol 2006;25:Suppl:18S-18S
   

3. 3

   Bagley WH, Yang H, Shah KH. Rhabdomyolysis. Intern Emerg Med 2007;2:210-218
   CrossRef | Medline

Citing Articles (8)

Citing Articles

1. 1

   Hani A. Kushlaf. (2011) Emerging Toxic Neuropathies and Myopathies. Neurologic Clinics 29:3, 679-687
   CrossRef

2. 2

   N. Penel, A. Le Cesne, B. N. Bui, D. Perol, E. G. Brain, I. Ray-Coquard, C. Guillemet, C. Chevreau, D. Cupissol, S. Chabaud, M. Jimenez, F. Duffaud, S. Piperno-Neumann, L. Mignot, J.- Y. Blay. (2011) Imatinib for progressive and recurrent aggressive fibromatosis (desmoid tumors): an FNCLCC/French Sarcoma Group phase II trial with a long-term follow-up. Annals of Oncology 22:2, 452-457
   CrossRef

3. 3

   Kazuya Kato, Astushi Nagase, Minoru Matsuda, Yurina Kato, Kazuhiko Onodera, Takako Kawakami, Mineko Higuchi, Yoshiaki Iwasaki, Masahiko Taniguchi, Hiroyuki Furukawa. (2011) Rhabdomyolysis Associated with Fenofibrate Monotherapy in a Patient with Chronic Myelogenous Leukemia. Case Reports in Gastroenterology 5:2, 492-496
   CrossRef

4. 4

   E. M. Ruggeri, F. L. Cecere, L. Moscetti, L. Doni, D. Padalino, F. Di Costanzo. (2010) Severe rhabdomyolysis during sunitinib treatment of metastatic renal cell carcinoma. A report of two cases. Annals of Oncology 21:9, 1926-1927
   CrossRef

5. 5

   Jessica K. Gordon, Steven K. Magid, Robert G. Maki, Martin Fleisher, Ellin Berman. (2010) Elevations of creatine kinase in patients treated with imatinib mesylate (Gleevec™). Leukemia Research 34:6, 827-829
   CrossRef

6. 6

   David Schiff, Patrick Y. Wen, Martin J. van den Bent. (2009) Neurological adverse effects caused by cytotoxic and targeted therapies. Nature Reviews Clinical Oncology 6:10, 596-603
   CrossRef

7. 7

   (2008) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 17:11, i-xvi
   CrossRef

8. 8

   Joel Shuster. (2008) ISMP Adverse Drug Reactions - Linezolid-Induced Black Hairy Tongue; Increased Intraocular Pressure Caused by Venlafaxine; Hallucinations During Voriconazole Therapy; Olanzapine-Associated, New-Onset Atrial Fibrillation; Complete Atrioventricular Block Associated With Rivastigmine; Imatinib as a Possible Cause of Severe Rhabdomyolysis; Reversible Parkinsonism Seen With Octreotide. Hospital Pharmacy 43:9, 699-702
   CrossRef