Hepatic iron overload, a possible consequence of treatment with imatinib mesylate: a case report
© licensee BioMed Central Ltd. 2009
Received: 11 January 2009
Accepted: 20 April 2009
Published: 26 May 2009
Imatinib, a tyrosine kinase inhibitor has revolutionized the therapy of Philadelphia chromosome positive chronic myeloid leukemia. Side effects of imatinib include grade 1-4 hepatotoxicity in a subset of patients. We report the case of a 46-year-old male with chronic myeloid leukemia, who developed hepatic hemosiderosis during treatment with imatinib. After ruling out the established congenital and acquired causes of hepatic hemosiderosis, we attribute this to a possible side effect of imatinib therapy. This condition was successfully treated with periodic phlebotomy thus precluding discontinuation of imatinib. To our knowledge, this is the first report of hepatic hemosiderosis most likely consequent to imatinib therapy.
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of Philadelphia chromosome, which is the translocated 9:22 chromosome giving rise to constitutively active BCR-Abl fusion protein [1, 2].
Imatinib mesylate, an orally administered tyrosine-kinase inhibitor, targets this fusion protein and produces anti-proliferative and pro-apoptotic effects on the neoplastic cells containing the translocation. Reported hepatic side effects observed with imatinib range from mild elevation of transaminases, to acute fulminant hepatitis and fatal liver failure -[4, 7]. We report the case of a 46-year-old male with CML who developed high levels of transaminases secondary to hemosiderosis likely induced by imatinib therapy. Intereference by imatinib in the iron metabolism is also suggested by a recent report of intradermal hemosiderosis consequent to imatinib therapy .
This is the case of a 46-year-old Caucasian male who came to us with complaints of mild fatigue and unexplained weight loss of about 28 pounds over 8 month period. Physical exam was remarkable for splenomegaly without any lymphadenopathy. Labs revealed leucocytosis with a white cell count of 63.3 × 103/μl. A manual differential count of peripheral blood smear showed neutrophil 44%, lymphocyte 1%, monocyte 3%, eosinophil 1%, basophil 6%, bands 22%, metamyelocyte 14%, myelocyte 9%. Following diagnosis of chronic phase CML by bone marrow biopsy the patient was started on 400 mg imatinib daily. Within a month of treatment, his white counts dropped from about 63,000/μl to 12,000/μl. Cytogenetic tests showed typical 9:22 translocation in all 20 banded cells examined. 4 of these cells also had an additional Philadelphia chromosome indicating a possible clonal evolution suggestive of accelerated or blast phase crisis of the disease. Thus the dosage of imatinib was increased to 600 mg daily. In another couple of weeks, his white cell count dropped to 3400/μl alongwith a drop of hemoglobin from 13.4 gm/dL to 11.1 gm/dL and platelets from 239,000/ μl to 57,000/ μl. Further drop of WBC count to 1800/ μl over the next 10 days warranted a reduction of imatinib dosage from 600 mg to 400 mg daily. His white count however continued to drop to 1500/ μl when he became febrile and was advised to discontinue imatinib for a couple weeks. His fever resolved with antibiotics and following 2 weeks of discontinuation of imatinib, his white count was back up at 5100/ μl, with absolute neutrophil count of 2700/ μl, hemoglobin 13.9 and platelets 190,000/ μl. The patient was restarted on 400 mg of imatinib daily. He tolerated this dose well for 2 weeks without any drop in cell counts and the imatinib dosage was increased to 500 mg daily. This dose was continued thereafter.
The discovery of the BCR-Abl translocation in CML culminated in the realization of the dream of targeted therapy in cancer by the small molecule tyrosine kinase inhibitor imatinib . The recently reported result of 6-year Phase III clinical trial confirms the durability of response to imatinib in addition to the declining incidence of adverse events over time . Currently, indications of imatinib include the treatment of CML and gastrointestinal stromal tumor (GIST). Most patients with newly diagnosed chronic phase CML experience complete cytogenetic responses with imatinib treatment, however continuation of treatment is required to prevent molecular or cytogenetic relapse . According to the literature, recurrent liver toxicity was the second most common reason for permanent discontinuation of imatinib therapy [4, 5]. Of all the patients undergoing treatment with imatinib, only a minor subset reportedly exhibits hepatotoxicity -. Grade 1 elevation in transaminases was observed in up to 6-12% of patients and grade3/4 in 3-8% of patients receiving imatinib therapy -. The cases of suspected imatinib induced hepatotoxicity responded to discontinuation of treatment either promptly or in a delayed manner . In some cases including a case of imatinib induced immune hepatitis, corticosteroids were helpful in resolving the hepatotoxicity and enabling resumption or continuation of imatinib treatment [4, 10]-.
In the absence of transfusional iron overload, hepatic hemosiderosis in the aforesaid case with normal transferrin saturation is a possible consequence of imatinib therapy. The elevated liver enzymes were not associated with any discernible infectious or inflammatory condition hence making hemophagocytosis a less likely possibility. While anti-nuclear antibody (ANA) was elevated at 2.3 OD ratio (ref range <1.5 OD ratio), anti-mitochondrial antibody, anti-smooth muscle antibody and alfa-1-antitrypsin antibody were negative. It seems unlikely that the mechanism of iron overload is a result of increased iron absorption or simply a higher intake in way of iron being an ingredient in imatinib mesylate tablets since there was no evidence of iron overload in any other organs including heart, spleen or pancreas. Whether it was secondary to interference of imatinib with heme metabolism in the reticuloendothelial cells remains to be elucidated. In this case report, we made an effort to understand the pathology behind imatinib induced hepatotoxicity and were able to treat the condition successfully by periodic phlebotomy. This is relatively safer than using measures as corticosteroid therapy or stopping imatinib treatment as have been shown to be effective in reversing other forms of imatinib induced hepatotoxicity. Imatinib induced disturbance in the iron homeostasis is also suggested by a recent report of intradermal hemosiderosis as a possible consequence to imatinib therapy, lending further support to our conclusion that the observed hepatic hemosiderosis is most likely a consequence imatinib therapy .
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
List of abbreviations
breakpoint cluster region - Abelson
Chronic myeloid leukemia
Gastrointestinal stromal tumor
Reverse transcriptase polymerase chain reaction.
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