Imatinib Mesylate-Induced Fatal Hepatitis B Virus Reactivation in Chronic Myeloid Leukemia

Imatinib Mesylate-induced Fatal Hepatitis B Virus Reactivation in Chronic Myeloid Leukemia Patient

Letter to the Editor

Imatinib mesylate (Glivec; Novartis, Basel, Switzerland), which is a selective inhibitor of the Bcr/Abl tyrosine kinase1, is now widely used for the treatment of chronic myeloid leukemia (CML) based on the remarkable efficacy2, 3. Treatment with imatinib mesylate is generally well tolerated, and the risk for severe adverse drug reaction is low2, 3. The hepatic toxicity is less common and usually resolves with interruption of imatinib therapy2, 3. Although it is well known that hepatitis B virus

(HBV) reactivations caused by chemotherapeutic agents are observed in cancer patients with chronic HBV infection4, these reactivations induced by imatinib mesylate have not been reported yet. Here, we report a case complicated by fatal fulminant HBV reactivation during imatinib mesylate treatment for CML.

A 54-year-old man, who had not been pointed out of liver dysfunction previously, was referred to our department to evaluate leukocytosis in October 2003. White blood cell (WBC) count, neutrophil count and lymphocyte count were 102x109/L, 54.1x109/L and 7.1x109/L, respectively. He was diagnosed as CML based on proliferation of myeloid lineage cells and Ph chromosome (20/20 cells) in bone marrow Hepatic examinations revealed normal findings, except slightly elevated level of AST (50 IU/L), and liver and spleen did not enlarge. However, HBs Ag, HBe Ab, and HBc Ab were positive, whereas HBs Ab was negative. HCV Ab and HCV RNA were also positive.

His clinical course is summarized in Fig 1. Imatinib mesylate treatment was started at the dose of 400 mg/day p.o. in November 2003, and continued without any hepatic damage. Dose of imatinib mesylate was reduced (300mg/day) in December 2003, when mild leukocytopenia was observed (WBC 2.6x109/L, neutrophil 1.45x109/L, lymphocyte

0.90x109/L). He complained general fatigue since May 6, 2004. On May 11, hepatic damage was noticed (AST 125 IU/L, ALT 95 IU/L, and total bilirubin 0.7 mg/dl), and imatinib mesylate administration was stopped. At that time, bone marrow cytogenetics using a fluorescent in situ hybridization detected 2% fusion gene of bcr/abl. On May

27, the patient had severe hepatic dysfunction with highly elevated AST, ALT, and total bilirubin (2098 IU/L, 1574 IU/L, and 5.6 mg/dl, respectively). In addition, prolonged prothrombin time (13.6%) and deterioration of consciousness were observed. HBV DNA polymerase was extremely increased (> 20000 cpm; normal range: <30), but HCV

RNA was negative. He was diagnosed as fulminant hepatitis due to HBV reactivation.

Although he received intensive treatments including administration of lamivudine, plasma exchanges, continuous hemodiafiltration and preparation for liver transplantation, he was complicated with severe pneumonia and died on June 21 2004.

Necropsy of liver revealed submassive necrosis of liver, being compatible with fulminant viral hepatitis.

This is the first case of fulminant hepatitis due to HBV reactivation induced by treatment of imatinib mesylate. Although there are some reports of hepatic toxities by imatinib mesylate, almost all cases are caused by imatinib mesylate itself. It is not clear how HBV was reactivated in our case, but one of the possible causes is the lymphocytopenic status by imatinib mesylate. In fact, patients receiving imatinib mesylate develop leukocytopenia (23.7-47%) and/or neutropenia (35.1-58%) 2, 3. It is well analyzed that among the chemotherapeutic agents, the use of steroid is the most significant risk factor of HBV reactivation in cancer patients with chronic HBV infection4 and therefore we usually avoid using steroids for such kind of patients, especially with lymphoid malignancies in clinical practice. Our case suggests that even in CML, we should take care of viral reactivation in use of imatinib mesylate in the patients with chronic hepatic viral infections such as HBV and HCV, and may consider prophylactic use of antiviral drugs7. We also may bring back interferon- as an initial therapy for CML patients with chronic hepatic viral infection in terms of both anti- leukemic and anti-viral effects. Further surveillance for these fatal complications is needed to be undertaken.

K Ikeda 1, 2 Y Shiga 3 T Kai 3 H Kimura 3 H Noji 1 K Ogawa 1 A Nakamura 1 A Takahashi 4 K Takeyama 2 Y Sato 4 Y Maruyama 1*

1 First Department of Internal Medicine, Fukushima Medical University, Fukushima, Japan 2 Division of Blood Transfusion and Transplantation Immunology, Fukushima Medical University, Fukushima, Japan 3 Department of Hematology, North Fukushima Medical Center, Fukushima, Japan 4 Second Department of Internal Medicine, Fukushima Medical University, Fukushima, Japan

*Correspondence: Yukio Maruyama, MD, PhD, First Department of Internal Medicine Fukushima Medical University Address: 1 Hikariga-oka, Fukushima, Fukushima 960-1295, Japan Tel: +81 (24) 547-1190 Fax: +81 (24) 548-1821 E-mail: [email protected] References 1 Druker BJ, Tamura S, Buchduner E, Ohno S, Segal GM, Fanning S, Zimmerman J,

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Figure 1. Time course of laboratory data. PE* indicates plasma exchange. Figure 1