Risk of hepatitis B virus reactivation with BCR-ABL tyrosine kinase inhibitors

Overseas cases of hepatitis B virus (HBV) reactivation have been observed following treatment with breakpoint cluster region-Abelson (BCR-ABL) tyrosine kinase inhibitors (TKIs) in patients who are chronic carriers of this virus. Some of these cases had resulted in acute hepatic failure or fulminant hepatitis resulting in the need for liver transplantation or a fatal outcome.

BCR-ABL TKIs that are registered in Singapore include dasatinib (Sprycel®, Bristol-Myers Squibb), imatinib (Glivec®, Novartis) and nilotinib (Tasigna®, Novartis). The BCR ABL TKIs inhibits the BCR-ABL tyrosine kinase and thus suppresses proliferation and promotes apoptosis in leukaemic cell lines over-expressing BCR-ABL[i]. They are indicated for the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML). In addition, Sprycel® is also indicated for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) while Glivec® is also indicated for the treatment of Ph+ ALL and KIT+ gastrointestinal stromal tumours.

Background

1) European Medicines Agency (EMA) ^2,3

In February 2016, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) completed a safety review which concluded that there is convincing evidence of HBV reactivation as a class effect of BCR-ABL TKIs. PRAC’s review took into consideration cumulative data from clinical trials and post-marketing experiences related to the reactivation of HBV in patients treated with BCR-ABL TKIs.

The case reports indicated that HBV reactivation may occur at any time during BCR-ABL TKIs treatment. Some of these patients had a documented history of HBV infection while in other cases, the serologic status at baseline was not known. An increase in viral load or positive serology was diagnosed upon HBV reactivation. In some of these cases, patient developed acute hepatic failure or fulminant hepatitis which required liver transplantation or resulted in a fatal outcome. The mechanism and the frequency of HBV reactivation during BCR-ABL TKIs exposure are not known at this time.

Recommendations from PRAC were to update the package inserts and to issue a safety communication to inform that patients should be tested for HBV infection before initiating treatment with BCR-ABL TKIs. It was also recommended that experts in hepatic disease and in the treatment of HBV should be consulted for patients with positive HBV serology prior to and during treatment. Patients who are carriers of HBV requiring treatment with BCR-ABL TKIs should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.

2) UK MHRA and Health Canada

The United Kingdom Medicines & Healthcare products Regulatory Agency (UK MHRA)⁴has updated the package inserts of BCR-ABL TKIs, in line with the EMA PRAC recommendations. Health Canada (HC)⁵ has also updated the respective package inserts. Both agencies have also issued safety communications to healthcare professionals to highlight this safety issue as well as recommendations for HBV screening before treatment.

Local situation and advisory

HSA has received three adverse drug reaction reports describing hepatitis B infection in patients treated with imatinib, in 2005, 2011 and 2012 respectively. In the first case, the patient had a history of chronic hepatitis B infection and developed fulminant hepatic failure about five months after initiating imatinib. In the second case, the patient was a hepatitis B carrier who developed hepatitis B and increased hepatic enzymes following seven years of treatment with imatinib. Imatinib treatment was stopped temporarily and restarted following initiation of hepatitis B treatment. In the third case, the patient developed hepatitis B infection with internal bleeding and liver cirrhosis during treatment with imatinib. However, there was insufficient information available to determine whether the condition was due to HBV reactivation or current underlying hepatitis B infection.

Novartis, in consultation with HSA, has issued two Dear Healthcare Professional Letters (DHCPLs)⁶, to communicate the risk of HBV reactivation associated with the use of Glivec® and Tasigna®, respectively. The letters highlighted the need to screen patients for HBV infection before treatment.

The local package inserts for BCR-ABL TKIs have been updated regarding this safety issue. Healthcare professionals are encouraged to be vigilant for HBV reactivation when prescribing BCR-ABL TKIs for their patients and to report any cases of HBV reactivation associated with the use of BCR-ABL TKIs to HSA.

References

Healthcare professional, Industry member, Therapeutic Products

Published: 21 Sep 2016

Safety Alerts

12 Dec 2019