© 2007 European Society for Medical Oncology
letters to the editor |
Overdose with 6400 mg of imatinib: is it safe?
Imatinib mesylate (STI-571), a potent and selective tyrosine kinase inhibitor against BCR/ABL, is now considered as gold standard treatment of CML. The drug is generally well tolerated. A suicidal attempt with 6400 mg of Imatinib by a young CML patient without any substantial side-effects is reported. This also highlights 6400 mg of imatinib is not lethal.A number of hematological and non-hematological side-effects with imatinib have been reported which are more common with higher doses [1]. A suicidal attempt with 6400 mg of Imatinib by a young CML patient, prompted this communication.
A 21-year-old female was diagnosed as Philadelphia-positive CML in chronic phase. She was started on imatinib at a dose of 400 daily. Hematological remission was achieved after 2 months and she was on follow-up for 2 years. One day, she took 16 tablets of imatinib of 400 mg each in an allegedly suicidal attempt. Six hours following ingestion, she had severe nausea followed by vomiting. There were 20–25 episodes of emesis on the same day and 8–10 episodes on following day. There was accompanying severe abdominal pain which lasted for 2 days. On day 3, patient developed fever of 102°F and was admitted in a local hospital where she received i.v. fluids and oral antibiotics. Subsequently she noticed swelling of face and lips which progressed for 2 days. Investigation revealed: hemoglobin 10.6 gm/dl; white blood cell count 1.2 x 109/l; absolute neutrophill count (ANC) 0.36 x 109/l; platelet count 240 x 109 /l, blood urea: 36 mg/dl; serum creatinine: 0.8 mg/dl; serum bilirubin: 1.2 mg/dl; alanine aminotransferase (ALT): 310 IU/ml (normal: 10–50 IU/ml); asparate aminotransferase (AST): 370 IU/ml (normal: 10–50 IU/ml); alkaline phosphatase: 84 IU/ml. Urine routine and microscopic examination showed no abnormalities.
After 5 days, patient became afebrile and was referred to our center. She was asymptomatic with no abnormal findings. Investigation revealed: hemoglobin 10.8 gm/dl; white blood cell count 6.5 x 109/l; and platelet count 370 x 109 /l. Liver and renal functions were normal. A psychiatric evaluation showed that patient was suffering from depression and she received treatment for the same. She was restarted with imatinib after 1 month and is currently under follow-up for last 6 months.
Incidence of side-effects, both hematological and non-hematological is related to phase of CML and the dose used [2, 3]. Our patient was already on imatinib before the overdose of 6400 mg. Nausea, vomiting, edema, myalgia and skin changes are most common drug related adverse effects reported so far. Our patient had severe nausea and vomiting along with facial swelling in first two days of ingestion, which were self-limiting. In a study by Druker et al. [4] in patient receiving 500–1000 mg/day and in European Organization for Research and Treatment of Cancer study of gastrointestinal stromal tumor using 1000 mg/day, nausea and vomiting were the commonest adverse effects. Grade 3 or 4 nausea and vomiting were observed in 12% and 9%, respectively. Similarly other adverse effects like edema, diarrhea and skin rashes are dose dependent. Our patient also had transient decrease in ANC. This may indicate that imatinib may have got effect on normal stem cells. The important other adverse effect was a transient increase in ALT/AST levels.
This is the first report of toxic effect of very high dose of imatinib in humans. This also highlights 6400 mg of imatinib is not lethal.
Department of Hematology, All India Institute of Medical Sciences, New Delhi, India
* (E-mail: mrmahapatra{at}hotmail.com)
References
1. Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myeloid leukemia in myeloid blast crisis: results of a phase II study. Blood (2002) 99:3530–3539.
2. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the Bcr-Abl tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med (2001) 344:1038–1042.
3. Druker BJ, Talpaz M, Resta D, et al. Efficacy and safety of a specific inhibitor of the Bcr-Abl tyrosine kinase in chronic myeloid leukemia. N Engl J Med (2001) 344:1031–1037.
4. Van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet (2001) 358:1421–1423.[CrossRef][Web of Science][Medline]
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