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Blood Res 2022; 57(4):

Published online December 31, 2022

https://doi.org/10.5045/br.2022.2022099

© The Korean Society of Hematology

High rate of hepatitis B reactivation during tyrosine kinase inhibitor treatment among patients with chronic myeloid leukemia in Korea

Jee Hyun Kong1,2, Jae Yeon Jang1, Tae Hwa Ko3, Seong Hee Kang4, Yundeok Kim1

1Department of Hematology-Oncology, Division of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, 2Center of Evidence-Based Medicine, Institute of Convergence Science, Yonsei University, Seoul, 3Center of Biomedical Data Science, 4Department of Gastroenterology and Hepatology, Division of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea

Correspondence to : Jee Hyun Kong
Department of Hematology-Oncology, Wonju Severance Christian Hospital, 20, Ilsan-ro, Wonju 26426, Korea
E-mail: kkongg@yonsei.ac.kr

Received: May 12, 2022; Revised: October 7, 2022; Accepted: November 14, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

TO THE EDITOR: Hepatitis B virus (HBV) infection is a global public health issue and a major cause of liver-related morbidity and mortality [1]. Although the prevalence of HBV infection in other countries is decreasing owing to the HBV vaccination program, infection rates remain relatively high in South Korea [2]. Several treatment guidelines have proposed monitoring the potential reactivation of HBV infection among patients receiving chemotherapy or immunosuppressive therapy [3, 4]. The European LeukemiaNet 2020 recommends the assessment of hepatitis B serology before initiating tyrosine kinase inhibitor (TKI) therapy [5]. The risk of HBV reactivation in patients receiving TKI is considered moderate, considering data that support this notion [3, 4]. In patients with chronic myeloid leukemia (CML) who received TKI, HBV reactivation has been reported sporadically [6-10], and the HBV reactivation rates have differed [0% (N=157) [11] vs. 26.3% (N=142) [12] in recent large-scale studies.

The National Health Insurance Service (NHIS) in Korea is a mandatory health insurance scheme that covers the entire Korean population, and the Korean government facilitates standardized health examinations for all individuals. Using the national medical insurance claims and biennial health examination results, the incidence of HBV reactivation after initiating TKI therapy in patients with CML and the clinical characteristics of these patients in Korea were evaluated.

Data from the NHIS database in Korea were employed. This study included patients aged ≥20 years who were diagnosed with Philadelphia chromosome-positive CML [International Classification of Diseases (ICD) code C92.1] from 2005 to 2017 and were prescribed TKIs (including imatinib, dasatinib, nilotinib, and radotinib). Patients who were prescribed TKIs within <1 month or treated with interferon prior to TKI therapy were excluded. Data such as ICD code, age, sex, list of prescribed medications, and date of death were extracted. C921 did not differentiate the phase of CML; this included all-phase CML. Except for hepatitis B surface antigen (HBsAg) positivity (+) in patients who underwent general health examinations, laboratory data were unavailable. The expenses for antiviral agents for hepatitis B, such as lamivudine, clevudine, telbivudine, entecavir, adefovir, tenofovir disoproxil, tenofovir alafenamide, and besifovir, can be claimed only in the following cases:1) HBeAg (+) and HBV-DNA level ≥20,000 IU/mL, 2) hepatitis B e antigen (HBeAg) (-) and HBV-DNA level ≥2,000 IU/mL and alanine aminotransferase (ALT) level >80 IU; 3) HBV-DNA level ≥2,000 IU/mL in compensated liver cirrhosis; and 4) HBV-DNA (+) in decompensated liver cirrhosis or hepatocellular carcinoma. In previous studies, HBV reactivation was defined as an increase in serum ALT levels to ≥3 times the baseline level and ALT levels >100 IU/L, and either one of the following: 1) exacerbation of chronic hepatitis B was defined as a 100-fold increase in serum HBV-DNA levels when compared with the baseline level; 2) relapse of previous HBV infection was defined as seroreversion from HBsAg (-) to HBsAg (+) or detectable HBV-DNA in a patient with previously undetectable levels [4, 13]. Thus, in the present study, HBV infection was defined as 1) prescription with liver medications (drug classification code 391 according to the Ministry of Health and Welfare, which can be initiated either 1) aspartate aminotransferase (AST) or ALT is ≥60 U/L, or 2) AST/ALT is maintained ≥40 U/L for >3 months when AST or ALT fluctuates between 40 and 60 U/L [14] owing to a diagnosis of acute hepatitis B (ICD code B16) or chronic hepatitis B or hepatitis B viral carrier (ICD code B181), 2) HBsAg (+) based on health examinations, or 3) history of prescription of antiviral agents for hepatitis. HBV reactivation was defined as the prescription of an antiviral agent after initiating TKI therapy in patients who were not diagnosed with liver cirrhosis (ICD code K74) or hepatocellular carcinoma (ICD code C220). This study was approved by the research board of our institution and conducted in accordance with the Declaration of Helsinki.

In total, 2,278 patients were included in the present study (Table 1), with national health examination data available for 1,576 patients. The median age of participants was 52 (20–91) years, and approximately 61% were males. The median duration of treatment with TKI (such as imatinib, dasatinib, nilotinib, and radotinib) was 51.3 (1–160.5) months. Imatinib, dasatinib, nilotinib, and radotinib were prescribed to 1563 (68.6%), 825 (36.2%), 678 (29.8%), and 154 (6.8%) patients, respectively. Approximately 68% (N=1,552) of patients were taking one TKI, while the remaining patients were taking more than one TKI. Overall, 143 (6.3%) patients presented with HBV infection (Fig. 1, Table 1). The HBsAg (+) status was confirmed in 84 (3.7%) patients, and 39 were taking antiviral agents for HBV during the follow-up period. Moreover, 95 patients were treated with liver medications based on the diagnosis of acute or chronic hepatitis B, and 34 patients were taking antiviral agents for HBV. Except for one patient diagnosed with hepatocellular carcinoma prior to antiviral therapy, 33 (23.1%) patients initiated antiviral agents after initiating TKI therapy, that is, experienced HBV reactivation (Table 1). Among the 84 HBsAg (+) patients, 15 (17.9%) developed HBV reactivation (Table 2).

Table 1 Characteristics of the participants.

Total (N=2,278)
Median age (yr)52 (20–91)
Sex male (N, %)1,386 (60.8)
Median duration of TKI treatment, months (range)51.3 (1–160.5)
TKI
Imatinib, N (%)1,563 (68.6)
Dasatinib, N (%)825 (36.2)
Nilotinib, N (%)678 (29.8)
Radotinib, N (%)154 (6.8)
N of TKIs
1 TKI, N (%)1,552 (68.1)
2 TKIs, N (%)533 (23.4)
3 TKIs, N(%)171 (7.5)
4 TKIs, N (%)22 (1.0)
HBV infection, N (%)143 (6.3)
HBV reactivation, N (% of HBV carrier)33 (23.1)
During imatiniba), N24
During dasatinib, N6
During nilotinib, N1
During radotinib, N0
HBV reactivation events/1,000 patients-year
Imatiniba), events/1,000 patients-year3.5
Dasatinib, events/1,000 patients-year3.0
Nilotinib, events/1,000 patients-year0.6
Radotinib, events/1,000 patients-year0
Median interval (mo) from TKI initiation to HBV reactivation, (range)2 (0–67)
Death, N (%)466 (20.5)

a)This included one patient treated with imatinib alone, and HBV reactivation occurred after the discontinuation of imatinib in one patient. See Fig. 2 (patient 7).

Abbreviations: HBV, hepatitis B virus; TKI, tyrosine kinase inhibitor.



Table 2 Clinical characteristics of HBV-infected patients.

HBV reactivation
(N=33)
No HBV reactivation
(N=110)
P
Median age at CML diagnosis, years (range)46 (22–2)52 (23–74)0.12
Sex male, N (%)23 (69.7)75 (68.2)0.87
Confirmed HBsAg (+), N (%)15 (88.2)69 (84.2)0.67
Use of HBV medications prior to TKIs, N (%)9 (27.3)3 (2.7)<0.01
Duration of TKI treatment duration, median (mo)58 (8–156)78 (4–156)0.12
Liver cirrhosis, N (%)7 (21.2)13 (11.8)0.17
Hepatocellular carcinoma, N (%)10 (30.3)14 (12.7)0.02
Death4 (12.1)15 (13.6)0.82

Abbreviations: CHB, chronic hepatitis B; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; TKI, tyrosine kinase inhibitor.



Fig. 1. Diagram showing the number of patients with hepatitis B infection (N=143). (A) Number of confirmed HBsAg (+) patients based on national health examin-ations (N=84). (B) Number of patients treated with hepatitis B medications (N=95). (C) Number of patients prescribed with antiviral agents for hepatitis B (N=39).
Abbreviations: HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.

The median duration of HBV reactivation was 2 months (range, 0–67) months after TKI therapy. The duration of TKI treatment and HBV reactivation are shown in Fig. 2. Twenty-one patients (64%) were treated with one TKI, while 11 patients (36%) were treated with more than one TKI. HBV reactivation occurred during the first-line treatment, except in patients 3 and 11. HBV was reactivated during imatinib, dasatinib, nilotinib, and radotinib treatment in 24, 6, 1, and 0 patients, respectively, with incidence rates of 3.5, 3, 0.6, and 0 events/1,000 patients-year, respectively (Table 1). HBV reactivation occurred 3.2 months after imatinib discontinuation in one patient (patient 7, Fig. 2), and this patient was included in the imatinib-treated group. The cause of imatinib discontinuation remains poorly elucidated.

Fig. 2. Treatment with tyrosine kinase inhibitor in patients with hepatitis B reactivation.
Abbreviations: HBV, hepatitis B virus; TKI, tyrosine kinase inhibitor.

The clinical characteristics of the HBV-infected patients in the HBV reactivation group (N=33) and no-HBV reactivation group (N=110) are presented in Table 2. The HBV reactivation and no-HBV reactivation groups did not significantly differ considering the age at CML diagnosis and sex (P=0.12 and 0.87, respectively). However, the number of patients in the HBV reactivation group (N=9, 27.3%) with a history of antiviral treatment for HBV prior to TKI therapy was higher than that in the no-HBV reactivation group (N=3, 2.7%) (P<0.01). The incidence of liver cirrhosis did not differ significantly between the two groups (P=0.17). However, the incidence of hepatocellular carcinoma was higher in the HBV reactivation group (N=10, 30.3%) than that in the no-HBV reactivation group (N=14, 12.7%) (P=0.02). Nineteen patients died during the follow-up period. However, none of the deaths were related to liver disease.

In the present study, 143 of 2,278 CML patients were suspected to be HBV carriers or have previous HBV infection, and HBV reactivation was observed in 33 (23.1%) patients. Compared with previous studies, the current study had a high HBV reactivation rate [11, 12, 15]. Among 122 and 157 Italian patients with CML, no HBV reactivation was observed in 11 patients with resolved HBV infection [15] and 31 HBV-infected patients (HBV carriers, N=5; resolved HBV infection, N=26) [11], respectively. In a previous study undertaken in Taiwan, 5 (26.3%) of 19 HBV carriers experienced HBV reactivation [12]. However, seroconversion was also not observed in 36 patients with resolved HBV infection [12]. The underlying factors responsible for differences in HBV reactivation rates remain unclear. Ethnic differences could contribute to the observed discrepancies, given that two studies from Asian countries, Korea and Taiwan, have shown higher HBV reactivation rates than two separate studies from Italy.

According to the present study, routine screening of HBV serology prior to initiating TKI therapy should be performed to identify HBsAg-positive patients and closely monitor hepatic function and HBV serology during TKI therapy. This monitoring should be undertaken within the first two months, given that HBV reactivation occurred at a median of two months after initiating TKI therapy, especially in patients with a history of antiviral treatment for HBV.

The current study has several limitations. First, laboratory data, such as HBV serology or AST/ALT, were unavailable for all patients. Second, the use of prophylactic antiviral medications was not determined, as these agents were not covered by the NHIS. These limitations might lead to an overestimation of the HBV reactivation rate. However, the present study had a large sample size, and 3.7% of patients were positive for HBsAg, which was comparable with that of a previous report on the prevalence of HBV carriers in Korea [2]. Thus, considering the high incidence of HBV reactivation following TKI therapy, concomitant antiviral prophylaxis should be considered in HBsAg-positive patients receiving TKI treatment. Further prospective studies are required.

This study was supported by a grant from the Chronic Myeloid Leukemia Working Party of The Korean Society of Hematology (CMLWP2018-02).

Authors’ Disclosures of Potential Conflicts of Interest

No potential conflicts of interest relevant to this article were reported.

  1. World Health Organization. Hepatitis B. Geneva, Switzerland: WHO, 2019 (Accessed April 1, 2020, at https://www.who.int/news-room/fact-sheets/detail/hepatitis-b).
  2. Cho EJ, Kim SE, Suk KT, et al. Current status and strategies for hepatitis B control in Korea. Clin Mol Hepatol 2017;23:205-11.
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  3. European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol 2017;67:370-98.
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  4. Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67:1560-99.
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  5. Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia 2020;34:966-84.
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  6. Ikeda K, Shiga Y, Takahashi A, et al. Fatal hepatitis B virus reactivation in a chronic myeloid leukemia patient during imatinib mesylate treatment. Leuk Lymphoma 2006;47:155-7.
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  7. Kang BW, Lee SJ, Moon JH, et al. Chronic myeloid leukemia patient manifesting fatal hepatitis B virus reactivation during treatment with imatinib rescued by liver transplantation: case report and literature review. Int J Hematol 2009;90:383-7.
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  8. Lai GM, Yan SL, Chang CS, Tsai CY. Hepatitis B reactivation in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor. World J Gastroenterol 2013;19:1318-21.
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  9. Ando T, Kojima K, Isoda H, et al. Reactivation of resolved infection with the hepatitis B virus immune escape mutant G145R during dasatinib treatment for chronic myeloid leukemia. Int J Hematol 2015;102:379-82.
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  10. Temel T, Gunduz E, Sadigova E, Uskudar Teke H, Meric Ozgenel S, Harmanci Ozakyol A. Hepatitis B virus reactivation under treatment with nilotinib. Euroasian J Hepatogastroenterol 2015;5:112-4.
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  11. Orlandi EM, Elena C, Bono E. Risk of hepatitis B reactivation under treatment with tyrosine-kinase inhibitors for chronic myeloid leukemia. Leuk Lymphoma 2017;58:1764-6.
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  12. Wang YH, Liang JD, Sheng WH, Tien FM, Chen CY, Tien HF. Hepatitis B reactivation during treatment of tyrosine kinase inhibitors-experience in 142 adult patients with chronic myeloid leukemia. Leuk Res 2019;81:95-7.
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  13. Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2019;25:93-159.
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  14. Health Insurance Review & Assessment Service. Drug Classification Codes. Wonju, Korea: HIRA, 2020 (Accessed April 1, 2020, at https://opendata.hira.or.kr/op/opc/selectMeftDivList.do).
  15. Sorà F, Ponziani FR, Laurenti L, et al. Low risk of hepatitis B virus reactivation in patients with resolved infection and chronic myeloid leukemia treated with tyrosine kinase inhibitors. Leuk Lymphoma 2017;58:993-5.
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Article

Letter to the Editor

Blood Res 2022; 57(4): 290-293

Published online December 31, 2022 https://doi.org/10.5045/br.2022.2022099

Copyright © The Korean Society of Hematology.

High rate of hepatitis B reactivation during tyrosine kinase inhibitor treatment among patients with chronic myeloid leukemia in Korea

Jee Hyun Kong1,2, Jae Yeon Jang1, Tae Hwa Ko3, Seong Hee Kang4, Yundeok Kim1

1Department of Hematology-Oncology, Division of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, 2Center of Evidence-Based Medicine, Institute of Convergence Science, Yonsei University, Seoul, 3Center of Biomedical Data Science, 4Department of Gastroenterology and Hepatology, Division of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea

Correspondence to:Jee Hyun Kong
Department of Hematology-Oncology, Wonju Severance Christian Hospital, 20, Ilsan-ro, Wonju 26426, Korea
E-mail: kkongg@yonsei.ac.kr

Received: May 12, 2022; Revised: October 7, 2022; Accepted: November 14, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Body

TO THE EDITOR: Hepatitis B virus (HBV) infection is a global public health issue and a major cause of liver-related morbidity and mortality [1]. Although the prevalence of HBV infection in other countries is decreasing owing to the HBV vaccination program, infection rates remain relatively high in South Korea [2]. Several treatment guidelines have proposed monitoring the potential reactivation of HBV infection among patients receiving chemotherapy or immunosuppressive therapy [3, 4]. The European LeukemiaNet 2020 recommends the assessment of hepatitis B serology before initiating tyrosine kinase inhibitor (TKI) therapy [5]. The risk of HBV reactivation in patients receiving TKI is considered moderate, considering data that support this notion [3, 4]. In patients with chronic myeloid leukemia (CML) who received TKI, HBV reactivation has been reported sporadically [6-10], and the HBV reactivation rates have differed [0% (N=157) [11] vs. 26.3% (N=142) [12] in recent large-scale studies.

The National Health Insurance Service (NHIS) in Korea is a mandatory health insurance scheme that covers the entire Korean population, and the Korean government facilitates standardized health examinations for all individuals. Using the national medical insurance claims and biennial health examination results, the incidence of HBV reactivation after initiating TKI therapy in patients with CML and the clinical characteristics of these patients in Korea were evaluated.

Data from the NHIS database in Korea were employed. This study included patients aged ≥20 years who were diagnosed with Philadelphia chromosome-positive CML [International Classification of Diseases (ICD) code C92.1] from 2005 to 2017 and were prescribed TKIs (including imatinib, dasatinib, nilotinib, and radotinib). Patients who were prescribed TKIs within <1 month or treated with interferon prior to TKI therapy were excluded. Data such as ICD code, age, sex, list of prescribed medications, and date of death were extracted. C921 did not differentiate the phase of CML; this included all-phase CML. Except for hepatitis B surface antigen (HBsAg) positivity (+) in patients who underwent general health examinations, laboratory data were unavailable. The expenses for antiviral agents for hepatitis B, such as lamivudine, clevudine, telbivudine, entecavir, adefovir, tenofovir disoproxil, tenofovir alafenamide, and besifovir, can be claimed only in the following cases:1) HBeAg (+) and HBV-DNA level ≥20,000 IU/mL, 2) hepatitis B e antigen (HBeAg) (-) and HBV-DNA level ≥2,000 IU/mL and alanine aminotransferase (ALT) level >80 IU; 3) HBV-DNA level ≥2,000 IU/mL in compensated liver cirrhosis; and 4) HBV-DNA (+) in decompensated liver cirrhosis or hepatocellular carcinoma. In previous studies, HBV reactivation was defined as an increase in serum ALT levels to ≥3 times the baseline level and ALT levels >100 IU/L, and either one of the following: 1) exacerbation of chronic hepatitis B was defined as a 100-fold increase in serum HBV-DNA levels when compared with the baseline level; 2) relapse of previous HBV infection was defined as seroreversion from HBsAg (-) to HBsAg (+) or detectable HBV-DNA in a patient with previously undetectable levels [4, 13]. Thus, in the present study, HBV infection was defined as 1) prescription with liver medications (drug classification code 391 according to the Ministry of Health and Welfare, which can be initiated either 1) aspartate aminotransferase (AST) or ALT is ≥60 U/L, or 2) AST/ALT is maintained ≥40 U/L for >3 months when AST or ALT fluctuates between 40 and 60 U/L [14] owing to a diagnosis of acute hepatitis B (ICD code B16) or chronic hepatitis B or hepatitis B viral carrier (ICD code B181), 2) HBsAg (+) based on health examinations, or 3) history of prescription of antiviral agents for hepatitis. HBV reactivation was defined as the prescription of an antiviral agent after initiating TKI therapy in patients who were not diagnosed with liver cirrhosis (ICD code K74) or hepatocellular carcinoma (ICD code C220). This study was approved by the research board of our institution and conducted in accordance with the Declaration of Helsinki.

In total, 2,278 patients were included in the present study (Table 1), with national health examination data available for 1,576 patients. The median age of participants was 52 (20–91) years, and approximately 61% were males. The median duration of treatment with TKI (such as imatinib, dasatinib, nilotinib, and radotinib) was 51.3 (1–160.5) months. Imatinib, dasatinib, nilotinib, and radotinib were prescribed to 1563 (68.6%), 825 (36.2%), 678 (29.8%), and 154 (6.8%) patients, respectively. Approximately 68% (N=1,552) of patients were taking one TKI, while the remaining patients were taking more than one TKI. Overall, 143 (6.3%) patients presented with HBV infection (Fig. 1, Table 1). The HBsAg (+) status was confirmed in 84 (3.7%) patients, and 39 were taking antiviral agents for HBV during the follow-up period. Moreover, 95 patients were treated with liver medications based on the diagnosis of acute or chronic hepatitis B, and 34 patients were taking antiviral agents for HBV. Except for one patient diagnosed with hepatocellular carcinoma prior to antiviral therapy, 33 (23.1%) patients initiated antiviral agents after initiating TKI therapy, that is, experienced HBV reactivation (Table 1). Among the 84 HBsAg (+) patients, 15 (17.9%) developed HBV reactivation (Table 2).

Table 1 . Characteristics of the participants..

Total (N=2,278)
Median age (yr)52 (20–91)
Sex male (N, %)1,386 (60.8)
Median duration of TKI treatment, months (range)51.3 (1–160.5)
TKI
Imatinib, N (%)1,563 (68.6)
Dasatinib, N (%)825 (36.2)
Nilotinib, N (%)678 (29.8)
Radotinib, N (%)154 (6.8)
N of TKIs
1 TKI, N (%)1,552 (68.1)
2 TKIs, N (%)533 (23.4)
3 TKIs, N(%)171 (7.5)
4 TKIs, N (%)22 (1.0)
HBV infection, N (%)143 (6.3)
HBV reactivation, N (% of HBV carrier)33 (23.1)
During imatiniba), N24
During dasatinib, N6
During nilotinib, N1
During radotinib, N0
HBV reactivation events/1,000 patients-year
Imatiniba), events/1,000 patients-year3.5
Dasatinib, events/1,000 patients-year3.0
Nilotinib, events/1,000 patients-year0.6
Radotinib, events/1,000 patients-year0
Median interval (mo) from TKI initiation to HBV reactivation, (range)2 (0–67)
Death, N (%)466 (20.5)

a)This included one patient treated with imatinib alone, and HBV reactivation occurred after the discontinuation of imatinib in one patient. See Fig. 2 (patient 7)..

Abbreviations: HBV, hepatitis B virus; TKI, tyrosine kinase inhibitor..



Table 2 . Clinical characteristics of HBV-infected patients..

HBV reactivation
(N=33)
No HBV reactivation
(N=110)
P
Median age at CML diagnosis, years (range)46 (22–2)52 (23–74)0.12
Sex male, N (%)23 (69.7)75 (68.2)0.87
Confirmed HBsAg (+), N (%)15 (88.2)69 (84.2)0.67
Use of HBV medications prior to TKIs, N (%)9 (27.3)3 (2.7)<0.01
Duration of TKI treatment duration, median (mo)58 (8–156)78 (4–156)0.12
Liver cirrhosis, N (%)7 (21.2)13 (11.8)0.17
Hepatocellular carcinoma, N (%)10 (30.3)14 (12.7)0.02
Death4 (12.1)15 (13.6)0.82

Abbreviations: CHB, chronic hepatitis B; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; TKI, tyrosine kinase inhibitor..



Figure 1. Diagram showing the number of patients with hepatitis B infection (N=143). (A) Number of confirmed HBsAg (+) patients based on national health examin-ations (N=84). (B) Number of patients treated with hepatitis B medications (N=95). (C) Number of patients prescribed with antiviral agents for hepatitis B (N=39).
Abbreviations: HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.

The median duration of HBV reactivation was 2 months (range, 0–67) months after TKI therapy. The duration of TKI treatment and HBV reactivation are shown in Fig. 2. Twenty-one patients (64%) were treated with one TKI, while 11 patients (36%) were treated with more than one TKI. HBV reactivation occurred during the first-line treatment, except in patients 3 and 11. HBV was reactivated during imatinib, dasatinib, nilotinib, and radotinib treatment in 24, 6, 1, and 0 patients, respectively, with incidence rates of 3.5, 3, 0.6, and 0 events/1,000 patients-year, respectively (Table 1). HBV reactivation occurred 3.2 months after imatinib discontinuation in one patient (patient 7, Fig. 2), and this patient was included in the imatinib-treated group. The cause of imatinib discontinuation remains poorly elucidated.

Figure 2. Treatment with tyrosine kinase inhibitor in patients with hepatitis B reactivation.
Abbreviations: HBV, hepatitis B virus; TKI, tyrosine kinase inhibitor.

The clinical characteristics of the HBV-infected patients in the HBV reactivation group (N=33) and no-HBV reactivation group (N=110) are presented in Table 2. The HBV reactivation and no-HBV reactivation groups did not significantly differ considering the age at CML diagnosis and sex (P=0.12 and 0.87, respectively). However, the number of patients in the HBV reactivation group (N=9, 27.3%) with a history of antiviral treatment for HBV prior to TKI therapy was higher than that in the no-HBV reactivation group (N=3, 2.7%) (P<0.01). The incidence of liver cirrhosis did not differ significantly between the two groups (P=0.17). However, the incidence of hepatocellular carcinoma was higher in the HBV reactivation group (N=10, 30.3%) than that in the no-HBV reactivation group (N=14, 12.7%) (P=0.02). Nineteen patients died during the follow-up period. However, none of the deaths were related to liver disease.

In the present study, 143 of 2,278 CML patients were suspected to be HBV carriers or have previous HBV infection, and HBV reactivation was observed in 33 (23.1%) patients. Compared with previous studies, the current study had a high HBV reactivation rate [11, 12, 15]. Among 122 and 157 Italian patients with CML, no HBV reactivation was observed in 11 patients with resolved HBV infection [15] and 31 HBV-infected patients (HBV carriers, N=5; resolved HBV infection, N=26) [11], respectively. In a previous study undertaken in Taiwan, 5 (26.3%) of 19 HBV carriers experienced HBV reactivation [12]. However, seroconversion was also not observed in 36 patients with resolved HBV infection [12]. The underlying factors responsible for differences in HBV reactivation rates remain unclear. Ethnic differences could contribute to the observed discrepancies, given that two studies from Asian countries, Korea and Taiwan, have shown higher HBV reactivation rates than two separate studies from Italy.

According to the present study, routine screening of HBV serology prior to initiating TKI therapy should be performed to identify HBsAg-positive patients and closely monitor hepatic function and HBV serology during TKI therapy. This monitoring should be undertaken within the first two months, given that HBV reactivation occurred at a median of two months after initiating TKI therapy, especially in patients with a history of antiviral treatment for HBV.

The current study has several limitations. First, laboratory data, such as HBV serology or AST/ALT, were unavailable for all patients. Second, the use of prophylactic antiviral medications was not determined, as these agents were not covered by the NHIS. These limitations might lead to an overestimation of the HBV reactivation rate. However, the present study had a large sample size, and 3.7% of patients were positive for HBsAg, which was comparable with that of a previous report on the prevalence of HBV carriers in Korea [2]. Thus, considering the high incidence of HBV reactivation following TKI therapy, concomitant antiviral prophylaxis should be considered in HBsAg-positive patients receiving TKI treatment. Further prospective studies are required.

Acknowledgments

This study was supported by a grant from the Chronic Myeloid Leukemia Working Party of The Korean Society of Hematology (CMLWP2018-02).

Authors’ Disclosures of Potential Conflicts of Interest

No potential conflicts of interest relevant to this article were reported.

Fig 1.

Figure 1.Diagram showing the number of patients with hepatitis B infection (N=143). (A) Number of confirmed HBsAg (+) patients based on national health examin-ations (N=84). (B) Number of patients treated with hepatitis B medications (N=95). (C) Number of patients prescribed with antiviral agents for hepatitis B (N=39).
Abbreviations: HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.
Blood Research 2022; 57: 290-293https://doi.org/10.5045/br.2022.2022099

Fig 2.

Figure 2.Treatment with tyrosine kinase inhibitor in patients with hepatitis B reactivation.
Abbreviations: HBV, hepatitis B virus; TKI, tyrosine kinase inhibitor.
Blood Research 2022; 57: 290-293https://doi.org/10.5045/br.2022.2022099

Table 1 . Characteristics of the participants..

Total (N=2,278)
Median age (yr)52 (20–91)
Sex male (N, %)1,386 (60.8)
Median duration of TKI treatment, months (range)51.3 (1–160.5)
TKI
Imatinib, N (%)1,563 (68.6)
Dasatinib, N (%)825 (36.2)
Nilotinib, N (%)678 (29.8)
Radotinib, N (%)154 (6.8)
N of TKIs
1 TKI, N (%)1,552 (68.1)
2 TKIs, N (%)533 (23.4)
3 TKIs, N(%)171 (7.5)
4 TKIs, N (%)22 (1.0)
HBV infection, N (%)143 (6.3)
HBV reactivation, N (% of HBV carrier)33 (23.1)
During imatiniba), N24
During dasatinib, N6
During nilotinib, N1
During radotinib, N0
HBV reactivation events/1,000 patients-year
Imatiniba), events/1,000 patients-year3.5
Dasatinib, events/1,000 patients-year3.0
Nilotinib, events/1,000 patients-year0.6
Radotinib, events/1,000 patients-year0
Median interval (mo) from TKI initiation to HBV reactivation, (range)2 (0–67)
Death, N (%)466 (20.5)

a)This included one patient treated with imatinib alone, and HBV reactivation occurred after the discontinuation of imatinib in one patient. See Fig. 2 (patient 7)..

Abbreviations: HBV, hepatitis B virus; TKI, tyrosine kinase inhibitor..


Table 2 . Clinical characteristics of HBV-infected patients..

HBV reactivation
(N=33)
No HBV reactivation
(N=110)
P
Median age at CML diagnosis, years (range)46 (22–2)52 (23–74)0.12
Sex male, N (%)23 (69.7)75 (68.2)0.87
Confirmed HBsAg (+), N (%)15 (88.2)69 (84.2)0.67
Use of HBV medications prior to TKIs, N (%)9 (27.3)3 (2.7)<0.01
Duration of TKI treatment duration, median (mo)58 (8–156)78 (4–156)0.12
Liver cirrhosis, N (%)7 (21.2)13 (11.8)0.17
Hepatocellular carcinoma, N (%)10 (30.3)14 (12.7)0.02
Death4 (12.1)15 (13.6)0.82

Abbreviations: CHB, chronic hepatitis B; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; TKI, tyrosine kinase inhibitor..


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