Evaluation of Hepatitis B Reactivation Among Patients with Chronic Myeloid Leukemia Treated with Tyrosine Kinase Inhibitors

Abstract

The risk of HBVr in chronic myeloid leukemia (CML) has been reported in many studies but there are no clear guidelines or recommendation regarding screening and monitoring of HBV in CML patients receiving tyrosine kinase inhibitors (TKIs). This review addresses the following questions regarding screening, monitoring, prophylaxis and treatment of HBVr in CML patients receiving TKIs: Who should be screened before starting TKIs?Which type of screening test should be used?Should HBV DNA be used to screen or monitor the patients before starting TKI?What is the best timeline to monitor HBV reactivation? METHODS: Studies from the year 2000 to date were searched on PubMed and Google Scholar, which investigated the possibility of HBV reactivation on patients with CML treated with TKIs. 11 studies were selected and reviewed. All patients are above 18 years old, diagnosed with CML on TKI treatment, were included in this review. Patients with any hepatitis serology marker at baseline (upon diagnosis of CML) were also included. Patients with active hepatitis B infection before the start of TKIs were excluded from the review. RESULTS: We identified 25 reported cases of hepatitis B reactivation after TKI treatment. 22/25 had HBsAg positive at baseline (before starting TKI) and 1/25 had HBsAg negative at baseline. The remaining 2/25 had reactivation with no clear baseline test results. These results are illustrated in Table 1. DISCUSSION: HBVr is defined by changes in (ALT) levels, HBV serological markers, or HBV DNA. Thus, HBVr is considered when: A 2- to 3-fold increase of ALT above baseline or the upper limit of normal.A reverse hepatitis B surface antigen (HBsAg) seroconversion or detection of HBV DNA in the blood in the absence of HBsAg.A newly detected HBV DNA or a ≥10-fold (1log10) rise in HBV DNA level.The risk of HBVr in patients receiving tumor necrosis factors (TNF), moderate-to-high dose steroids for 4 weeks, and TKIs was reported to be moderate (1-10%), and recommended for HBV prophylaxis as well. However, the strength of such recommendation is weak. It is advisable to screen all patients who are planned for TKI treatment. Suitable screening tests include HBV DNA, HBsAg, and ALT. It is important to identify patients with previous HBV infection, as evidenced by hepatitis B serological markers, i.e. positive hepatitis B core antibody (anti-HBc), with negative HBsAg, with or without detectable hepatitis B surface antibody (HBsAb). Nevertheless, running all tests may not be feasible due to costs and availability of testing equipment. Therefore, if unavailable, testing patients using only ALT and HBsAg, or even ALT alone would suffice, as the detection of HBVr can be deduced from ALT/HBsAg levels alone. For HBsAg positive patients, prophylaxis against Hepatitis B reactivation should be started as HBVr may happen any time after commencement of TKIs. There is no clear answer in the literature as to which antiviral should be used. However, entecavir was most commonly used in the studies (other antivirals used include tenofovir and lamivudine). The duration of prophylaxis was also not mentioned in the literature. CONCLUSION: As the definition of hepatitis B reactivation includes a rise of ALT (2- to 3-fold), HBV DNA (newly detected to 10-fold increase) and seroconversion in HBsAg negative patients, all patients with CML should have baseline values of ALT, hepatitis B serology as well as HBV DNA before starting TKI treatment and should be followed up with repeat values of these 3 parameters. However, due to the cost and limited availabilities of these tests, we suggest following up at least ALT levels (preferably with HBsAg levels) before and after treatment with TKIs. In patients with risk of HBVr (i.e. positive HBsAg on screening, as well as those with resolved HBV infection), prophylaxis is important. Based on currently available evidence, we recommend HBV prophylaxis for patients with positive HBsAg receiving TKIs to be given from the start of TKI treatment, and continued for at least 1 year after the commencement of TKIs, if feasible. In the event that this is not affordable, it is advisable to monitor markers of reactivation, as mentioned above (i.e. ALT, HBsAg, HBV DNA, whichever is available). For those with resolved HBV infection (i.e. positive anti-HBc and negative HBsAg), we recommend monitoring for signs of HBVr during the treatment duration. Table 1 Disclosures No relevant conflicts of interest to declare.

APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy

“…The major barriers appear to be related to the non-compliance of medical practitioners in other non-hepatology disciplines. This is further compounded by the recent rapid expansion on the use of new immunosuppressive agents such as tyrosine-kinase inhibitors (TKIs), [ 23 – 26 ] immune checkpoint inhibitors (ICIs) [ 27 – 29 ] used in the treatment of various cancers and tumor necrosis factor (TNF) antagonists [ 30 – 35 ] for many autoimmune diseases. Recently, in those chronic hepatitis C (CHC) patients coinfected with hepatitis B, HBVr has also been reported during and after treatment with direct-acting antiviral agents (DAAs) [ 36 – 48 ].…”

Ophthalmologic manifestations as the initial presentation of chronic myeloid leukemia: A review

“…Ophthalmic manifestation can also be categorized by severity (mild, moderate, and advanced) , by the region involved on presentation requiring ophthalmic intervention, and by the visual prognosis. 51 (Table 2).…”

Chronic Myeloid Leukemia in a Patient with Hepatitis B Virus Infection: A Case Report

“…It can be self-limited and reversible upon discontinuation of the inducing agent, and it can be serious and fatal. HBV reactivation (HBVr) is increasingly recognized as an important adverse effect with an incidence approaching 10.8 per 100 person-years in a retrospective cohort study [4]. Most of the reported cases are triggered by the use of imatinib [12][13][14][15][16].…”

“…Several definitions have been proposed for HBVr based on virologic, serologic, or both criteria; a simple definition would be an increase in HBV replication usually associated with a rise in serum aminotransferase levels [4,17,18]. Although there are recommendations to screen for HBV infection before starting immune-suppressing medications, however, guidelines about the prevention of HBVr in the context of TKIs remain uncertain.…”

“…The management of Ph chromosome-positive and BCR-ABL1-positive CML has undergone a profound evolution with the tyrosine kinase inhibitors (TKIs) [3]. Currently, there are 5 TKIs approved by the FDA for the treatment of CML, including imatinib, dasatinib, nilotinib, bosutinib, and ponatinib [4]. Hepatitis B virus (HBV) infection is a major public health problem worldwide; roughly 30% of the world's population show serological evidence of current or past infection [5].…”