Imatinib Mesylate Induced Fatal Hepatitis B Virus (HBV) Reactivation in a Patient with CML.

Abstract

Imatinib mesylate (Glivec; Novartis, Basel, Switzerland), which is a selective inhibitor of the Bcr/Abl tyrosine kinase, is now widely used for the treatment of Ph-positive leukemia based on the remarkable efficacy. Treatment with imatinib mesylate is generally well tolerated, and the risk for severe adverse effects is low. Hepatic toxicity is less common and usually resolves with interruption of imatinib therapy. On the other hand, although it is well known that HBV reactivations are observed in cancer patients with chronic HBV infection during chemotherapies, imatinib mesylate-induced HBV reactivation has not been reported yet. Here, we report the first case complicated by fatal fulminant HBV reactivation during imatinib mesylate treatment for CML. A 54-year-old man was diagnosed as CML on October 2003. At that time, HBsAg, HBeAb, and HBcAb were positive, whereas HBsAb was negative. HCV Ab and HCV RNA were also positive. However, hepatic examinations revealed normal findings, except slightly elevated levels of AST (50 IU/L). On November 2003, imatinib mesylate was started at the dose of 400mg/day p.o. and continued without any hepatic adverse effects. In contrast, the patient was suffered from neutropenia (grade 2) and lymphocytopenia (grade 2) on December 2003. Although dose of imatinib mesylate was reduced (300mg/day), lymphocytopenia continued. Since May 6, 2004, the patient complained general fatigue. On May 11, AST, ALT, and total bilirubin were 125 IU/L, 95 IU/L, and 0.7 mg/dl, respectively. At that time, bone marrow cytogenetics using a FISH of Bcr/Abl detected 2.0% fusion gene. Then, hepatic function deteriorated despite imatinib mesylate administration was stopped. On May 27, the patient had severe hepatic dysfunction with high 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). He was diagnosed as a fulminant hepatitis due to HBV reactivation and referred to the Second Department of Internal Medicine (Hepatology) of Fukushima Medical University. Although he received intensive treatments including plasma exchanges, he died from hepatic failure on June 21 2004. This is the first case of a fulminant hepatitis due to HBV reactivation during treatment of imatinib mesylate. Although it is not clear how HBV was reactivated in our case, one of the possible causes may be the lymphocytopenic status by imatinib mesylate. In fact, among the chemotherapeutic agents, the use of steroid is the most significant risk factor of HBV reactivation in cancer patients with chronic HBV infection (Yeo et al, Br J Cancer , 2004). Ph-positive leukemia patients receiving imatinib mesylate often develop transient lymphocytopenia and/or neutropenia (Druker et al, N Engl J Med , 2002). Therefore, in the patients with chronic hepatic viral infections such as HBV and HCV, we should take care of viral reactivation in use of imatinib mesylate. We should also consider prophylaxis of viral reactivation using antiviral drugs or alternative initial therapy with interferon-α for both anti-leukemic and anti-viral effects to treat CML patients with chronic hepatitic viral infection.