Int J Hematol DOI 10.1007/s12185-015-1788-y
CASE REPORT
Reactivation of resolved infection with the hepatitis B virus immune escape mutant G145R during dasatinib treatment for chronic myeloid leukemia Toshihiko Ando1 · Kensuke Kojima1 · Hiroshi Isoda2 · Yuichiro Eguchi3 · Takashi Honda4 · Masatoshi Ishigami4 · Shinya Kimura1
Received: 25 January 2015 / Revised: 17 March 2015 / Accepted: 24 March 2015 © The Japanese Society of Hematology 2015
Abstract Reactivation of hepatitis B virus (HBV) following immunosuppressive therapy or hematopoietic stem cell transplantation is a potentially fatal complication that may occur even in patients with prior resolution of HBV infection. Dasatinib is a small-molecule inhibitor of the tyrosine kinases SRC and ABL that has been approved for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia. Here, we report the first case of reactivation of resolved infection with the HBV immune escape mutant G145R in a CML patient receiving dasatinib. Although dasatinib is not recognized as an immunosuppressant, our observations suggest that dasatinib may enhance HBV replication and induce its reactivation in immunocompetent patients, that HBV escape mutants may contribute to the pathogenesis of HBV reactivation, and that close monitoring of HBV status is advisable in patients with current or resolved HBV infection.
* Toshihiko Ando [email protected] * Kensuke Kojima [email protected]‑u.ac.jp 1
Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5‑1‑1 Nabeshima, Saga 849‑8501, Japan
2
Division of Hepatology, Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
3
Division of Hepatology, Saga Medical School, Liver Center, Saga, Japan
4
Department of Gastroenterology and Hepatology Nagoya University School of Medicine, Nagoya, Japan
Keywords Chronic myeloid leukemia · Dasatinib · Hepatitis B virus · Reactivation · Escape mutant
Introduction Recent studies have shown that highly immunosuppressive therapies, such as rituximab (anti-human CD20 monoclonal antibody)-containing chemotherapy or hematopoietic stem cell transplantation (HSCT), increase the risk of reactivation of hepatitis B virus (HBV) [1–5]. Chemotherapyinduced HBV reactivation has been reported mostly in hepatitis B surface antigen (HBsAg)-positive and anti-hepatitis B e antibody (anti-HBe)-positive, asymptomatic carriers [3] and much less frequently in resolved HBV infection cases that are HBsAg negative, anti-hepatitis B core antibody (anti-HBc) low-titer positive and/or anti-hepatitis B surface antibody (anti-HBs) positive [4, 5]. Although the clearance of HBsAg and the appearance of anti-HBs and/or anti-HBc are generally considered to be evidence of clinical and serologic recovery from acute hepatitis B, studies have shown that HBV replication persists for decades at low levels in liver or peripheral blood mononuclear cells [6]. HBV reactivation in cases of resolved HBV infection is of particular concern, as it frequently results in severe liver dysfunction and fatal fulminant hepatitis [7, 8]. Dasatinib is a SRC/ABL tyrosine kinase inhibitor (TKI) currently approved for the treatment of Philadelphia chromosome (BCR/ABL)-positive chronic myeloid leukemia (CML) and acute lymphoblastic leukemia [9–11]. This drug’s adverse effects consist of cytopenia (anemia, neutropenia and thrombocytopenia), digestive disorders (diarrhea, nausea, vomiting and gastrointestinal hemorrhage), cutaneous eruption and fluid retention (pleural or pericardial effusion). Grade 3 or 4 elevation in serum transaminase
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T. Ando et al.
or bilirubin levels has been described in approximately 5 % of patients, who are well managed with dose reduction or interruption. The immunological effects of dasatinib have been investigated in several studies, and the results are controversial; certain studies described dasatinib as acting as an immunosuppressive agent [12–14], whereas others reported that dasatinib induces immunostimulation [15, 16]. To our knowledge, HBV reactivation has not been reported in association with dasatinib treatment. Here, we report the first case of reactivation of resolved HBV infection in a CML patient receiving single-agent dasatinib.
Case report A 74-year-old woman had been diagnosed with accelerated-phase CML in 2011 at the age of 71. On physical examination, neither hepatomegaly nor splenomegaly was noted. Her blood test results were hemoglobin (Hb), 12.9 g/ dL; white blood cell (WBC) count, 20,200/µL (with 46 % neutrophils, 1 % myelocytes, 30 % basophils, 3 % eosinophils, 1 % monocytes and 19 % lymphocytes); and platelet (PLT) count, 1,169,000/µL. A bone marrow film revealed markedly hypercellular marrow, with 87.6 % myeloid cells at various stages of maturation and 3.2 % blasts. Chromosome analysis of the marrow cells revealed a karyotype of 46, XX, t(9;22)(q34; q11) in 19 of 20 metaphases. The patient was negative for HBsAg (0.00 IU/mL, normal: 0.00–0.04 IU/mL) and positive for anti-HBs (27 mIU/mL, normal: 0–19 mIU/mL) and anti-HBc (2.92 S/CO, normal: 0.00–0.99 S/CO). She was treated with imatinib at 200 mg once daily, which resulted in a complete hematological response (CHR) within 4 weeks. Due to imatinib-related pleural effusion that developed within 5 weeks, however, the patient was switched from imatinib to a small dose of dasatinib (20 mg/day). She declined a switch to nilotinib because of its lower, twice-daily dosing. An increased dose of dasatinib (50 mg/day) resulted in the recurrence of pleural effusion within 3 weeks, and therefore, the dose was returned to 20 mg/day. She achieved a complete cytogenetic response and a major molecular response after 6 and 8 months, respectively, of dasatinib therapy. Serum levels of HBV DNA were determined at 27 months of dasatinib treatment, at which point a sensitive transcription-mediated amplification assay did not detect HBV DNA in the serum. Although a modest increase in the number of large granular lymphocytes (1000–2000/µL) was observed during dasatinib treatment, there were no episodes of cytomegalovirus disease. Three years after the initiation of dasatinib, asymptomatic elevation of aspartate transaminase (AST; 87 IU/L) and alanine transaminase (ALT; 83 IU/L) levels was observed. At that time, the patient was positive for HBsAg
13
(4357 IU/mL) and hepatitis B envelope antigen (HBeAg) (1466 S/CO, normal: 0.0–0.9 S/CO), and increased levels of HBV DNA (6.9 log 10 copies/mL) were detected by real-time PCR assay. She was still positive for anti-HBs (35 mIU/mL). A diagnosis of HBV reactivation was made. She had HBV genotype C. The patient immediately started lamivudine (100 mg/day). Two months later, her AST and ALT levels returned to normal, and her serum HBV DNA level was under the detection limit, after which dasatinib was stopped. Later, the patient was switched from lamivudine to entecavir (0.5 mg/day), and she maintained a major molecular response to CML and resolution of HBV infection (Fig. 1). The nucleotide sequence of the HBV envelope was determined in HBV-positive serum samples using PCR followed by direct sequencing. A single amino acid substitution (G145R) within the a-determinant (from amino acid 124 to amino acid 147) of HBsAg was detected (Fig. 2). G145R is the most common immune escape mutant. Three additional mutations (L97R, L176R and P178Q) were also detected.
Discussion The risk of therapy-related HBV reactivation has been associated with the pretreatment HBV viral load and the degree of induced immunosuppression. In cases of reactivation of resolved HBV infection, HBV reactivation occurs nearly exclusive in patients receiving highly immunosuppressive agents [1–5]. TKIs are not recognized as an immunosuppressant, and there have been only five reported cases of HBV reactivation in association with imatinib or nilotinib treatment [17–19]. All of the reported cases represented HBV reactivation in HBsAg-positive carriers, further supporting the idea that TKIs may not be immunosuppressive enough to induce HBV reactivation in patients with prior resolution of HBV infection. However, certain studies have reported that the TKIs imatinib [20, 21] and nilotinib [22] inhibit the proliferation and function of T cells. HBV reactivation has not been previously reported in patients receiving dasatinib. In our case, it was surprising that HBV reactivation occurred in a patient with prior resolution of HBV infection and receiving low-dose dasatinib treatment at 20 mg/day (the approved dasatinib dose is 100 mg/day). We stopped dasatinib after the resolution of HBV reactivation by antiviral treatment to avoid a possible clinical flare due to rebound of the immune attack on hepatocytes with an increased viral load [23]. Although the incidence of TKI-induced HBV reactivation is low and the mechanisms remain unclear, close monitoring of HBV status would be advisable in patients with current or resolved HBV infection.
Reactivation of resolved infection with… Fig. 1 Clinical course. Note that neither HBsAg nor HBV DNA was detected in the serum 9 months before HBV reactivation, when serum HBV DNA levels were determined by a transcription-mediated amplification assay. BCR–ABL mRNA levels were determined by the sensitive transcription-mediated amplification and hybridization protection assay (TMA–HPA), in which the detection limit is 5 copy/assay (=10 copy per microgram of RNA)
Fig. 2 The HBV G145R mutant detected in our patient
In our case, four HBV envelope mutations (L97R, G145R, L176R and P178Q) were detected at the time of reactivation. Among them, G145R is the most widely studied HBV immune escape mutation, emerging naturally or in response to vaccination or anti-HBs immunoglobulin G therapy, and can decrease the ability of neutralizing anti-HBs [24–26]. A case of fatal HBV reactivation by an escape mutant following rituximab therapy has been reported [27]. In our case, dasatinib treatment caused an increase in the number of large granular lymphocytes. Interestingly, dasatinib-induced large granular
lymphocyte expansion has been associated with immunosuppression-related cytomegalovirus reactivation [14]. We therefore speculate that, in the present case, HBV reactivation occurred through the following steps: (1) HBV replication had persisted at very low levels in the liver since resolution of acute hepatitis B, (2) dasatinib treatment inhibited cellular immune responses to HBV, (3) a gradual increase in HBV replication levels resulted in the emergence of HBV mutants, and (4) HBV reactivation by escape mutants occurred. Although rare, spontaneous reactivation of HBV infection has been reported in elderly people with resolved HBV infection in the absence of known triggers for reactivation [28]. It is therefore possible that age-related immunosuppression also played some role in enhancing HBV replication in our case. Accumulated virological data from patients with chemotherapy-induced HBV reactivation would help to determine whether the appearance of HBV escape mutants plays a key role in HBV pathology. Conflict of interest Shinya Kimura has received research grants and lecture fees from Bristol-Myers Squibb.
References 1. Hwang JP, Lok AS. Management of patients with hepatitis B who require immunosuppressive therapy. Nat Rev Gastroenterol Hepatol. 2014;11:209–19. 2. Fukushima N, Mizuta T, Tanaka M, Yokoo M, Ide M, Hisatomi T, et al. Retrospective and prospective studies of hepatitis B virus reactivation in malignant lymphoma with occult HBV carrier. Ann Oncol. 2009;20:2013–7.
13
T. Ando et al. 3. Skrabs C, Müller C, Agis H, Mannhalter C, Jäger U. Treatment of HBV-carrying lymphoma patients with Rituximab and CHOP: a diagnostic and therapeutic challenge. Leukemia. 2002;16:1884–6. 4. Yeo W, Chan TC, Leung NW, Lam WY, Mo FK, Chu MT, et al. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol. 2009;27:605–11. 5. Coppola N, Tonziello G, Pisaturo M, Messina V, Guastafierro S, Fiore M, et al. Reactivation of overt and occult hepatitis B infection in various immunosuppressive settings. J Med Virol. 2011;83:1909–16. 6. Rehermann B, Ferrari C, Pasquinelli C, Chisari FV. The hepatitis B virus persists for decades after patients’ recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med. 1996;2:1104–8. 7. Oketani M, Ido A, Uto H, Tsubouchi H. Prevention of hepatitis B virus reactivation in patients receiving immunosuppressive therapy or chemotherapy. Hepatol Res. 2012;42:627–36. 8. Umemura T, Tanaka E, Kiyosawa K, Kumada H, Japan de novo Hepatitis B Research Group. Mortality secondary to fulminant hepatic failure in patients with prior resolution of hepatitis B virus infection in Japan. Clin Infect Dis. 2008;47:e52–6. 9. Fujisawa S, Nakamae H, Ogura M, Ishizawa K, Taniwaki M, Utsunomiya A, et al. Efficacy and safety of dasatinib versus imatinib in Japanese patients with newly diagnosed chronicphase chronic myeloid leukemia (CML-CP): subset analysis of the DASISION trial with 2-year follow-up. Int J Hematol. 2014;99:141–53. 10. Kimura S, Ando T, Kojima K. Ever-advancing chronic myeloid leukemia treatment. Int J Clin Oncol. 2014;19:3–9. 11. Aoe M, Shimada A, Muraoka M, Washio K, Nakamura Y, Takahashi T, et al. ABL kinase mutation and relapse in 4 pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia cases. Int J Hematol. 2014;99:609–15. 12. Wölfl M, Langhammer F, Wiegering V, Eyrich M, Schlegel PG. Dasatinib medication causing profound immunosuppression in a patient after haploidentical SCT: functional assays from whole blood as diagnostic clues. Bone Marrow Transplant. 2013;48:875–7. 13. Sillaber C, Herrmann H, Bennett K, Rix U, Baumgartner C, Böhm A, et al. Immunosuppression and atypical infections in CML patients treated with dasatinib at 140 mg daily. Eur J Clin Invest. 2009;39:1098–109. 14. Kreutzman A, Ladell K, Koechel C, Gostick E, Ekblom M, Stenke L, et al. Expansion of highly differentiated CD8 + T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalovirus reactivation. Leukemia. 2011;25:1587–97. 15. Mustjoki S, Auvinen K, Kreutzman A, Rousselot P, Hernesniemi S, Melo T, et al. Rapid mobilization of cytotoxic lymphocytes induced by dasatinib therapy. Leukemia. 2013;27:914–24.
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16. Kim DH, Kamel-Reid S, Chang H, Sutherland R, Jung CW, Kim HJ, et al. Natural killer or natural killer/T cell lineage large granular lymphocytosis associated with dasatinib therapy for Philadelphia chromosome positive leukemia. Haematologica. 2009;94:135–9. 17. Ikeda K, Shiga Y, Takahashi A, Kai T, Kimura H, Takeyama K, et al. Fatal hepatitis B virus reactivation in a chronic myeloid leukemia patient during imatinib mesylate treatment. Leuk Lymphoma. 2006;47:155–7. 18. Kang BW, Lee SJ, Moon JH, Kim SN, Chae YS, Kim JG, 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. 19. 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. 20. Seggewiss R, Loré K, Greiner E, Magnusson MK, Price DA, Douek DC, Dunbar CE, Wiestner A. Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dosedependent manner. Blood. 2005;105:2473–9. 21. Cwynarski K, Laylor R, Macchiarulo E, Goldman J, Lom bardi G, Melo JV, Dazzi F. Imatinib inhibits the activation and proliferation of normal T lymphocytes in vitro. Leukemia. 2004;18:1332–9. 22. Chen J, Schmitt A, Chen B, Rojewski M, Rübeler V, Fei F, et al. Nilotinib hampers the proliferation and function of CD8 + T lymphocytes through inhibition of T cell receptor signalling. J Cell Mol Med. 2008;12:2107–18. 23. Liaw YF. Hepatitis viruses under immunosuppressive agents. J Gastroenterol Hepatol. 1998;13:14–20. 24. Sheldon J, Soriano V. Hepatitis B virus escape mutants induced by antiviral therapy. J Antimicrob Chemother. 2008;61:766–8. 25. Locarnini SA, Yuen L. Molecular genesis of drug-resistant and vaccine-escape HBV mutants. Antivir Ther. 2010;15:451–61. 26. Ishigami M, Honda T, Ishizu Y, Onishi Y, Kamei H, Hayashi K, et al. Frequent incidence of escape mutants after successful hepatitis B vaccine response and stopping of nucleos(t)ide analogues in liver transplant recipients. Liver Transpl. 2014;20:1211–20. 27. Westhoff TH, Jochimsen F, Schmittel A, Stoffler-Meilicke M, Schafer JH, Zidek W, et al. Fatal hepatitis B virus reactivation by an escape mutant following rituximab therapy. Blood. 2003;102:1930. 28. Kamitsukasa H, Iri M, Tanaka A, Nagashima S, Takahashi M, Nishizawa T, et al. Spontaneous reactivation of hepatitis B virus (HBV) infection in patients with resolved or occult HBV infection. J Med Virol. 2015;87:589–600.
CASE REPORT
Reactivation of resolved infection with the hepatitis B virus immune escape mutant G145R during dasatinib treatment for chronic myeloid leukemia Toshihiko Ando1 · Kensuke Kojima1 · Hiroshi Isoda2 · Yuichiro Eguchi3 · Takashi Honda4 · Masatoshi Ishigami4 · Shinya Kimura1
Received: 25 January 2015 / Revised: 17 March 2015 / Accepted: 24 March 2015 © The Japanese Society of Hematology 2015
Abstract Reactivation of hepatitis B virus (HBV) following immunosuppressive therapy or hematopoietic stem cell transplantation is a potentially fatal complication that may occur even in patients with prior resolution of HBV infection. Dasatinib is a small-molecule inhibitor of the tyrosine kinases SRC and ABL that has been approved for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia. Here, we report the first case of reactivation of resolved infection with the HBV immune escape mutant G145R in a CML patient receiving dasatinib. Although dasatinib is not recognized as an immunosuppressant, our observations suggest that dasatinib may enhance HBV replication and induce its reactivation in immunocompetent patients, that HBV escape mutants may contribute to the pathogenesis of HBV reactivation, and that close monitoring of HBV status is advisable in patients with current or resolved HBV infection.
* Toshihiko Ando [email protected] * Kensuke Kojima [email protected]‑u.ac.jp 1
Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5‑1‑1 Nabeshima, Saga 849‑8501, Japan
2
Division of Hepatology, Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
3
Division of Hepatology, Saga Medical School, Liver Center, Saga, Japan
4
Department of Gastroenterology and Hepatology Nagoya University School of Medicine, Nagoya, Japan
Keywords Chronic myeloid leukemia · Dasatinib · Hepatitis B virus · Reactivation · Escape mutant
Introduction Recent studies have shown that highly immunosuppressive therapies, such as rituximab (anti-human CD20 monoclonal antibody)-containing chemotherapy or hematopoietic stem cell transplantation (HSCT), increase the risk of reactivation of hepatitis B virus (HBV) [1–5]. Chemotherapyinduced HBV reactivation has been reported mostly in hepatitis B surface antigen (HBsAg)-positive and anti-hepatitis B e antibody (anti-HBe)-positive, asymptomatic carriers [3] and much less frequently in resolved HBV infection cases that are HBsAg negative, anti-hepatitis B core antibody (anti-HBc) low-titer positive and/or anti-hepatitis B surface antibody (anti-HBs) positive [4, 5]. Although the clearance of HBsAg and the appearance of anti-HBs and/or anti-HBc are generally considered to be evidence of clinical and serologic recovery from acute hepatitis B, studies have shown that HBV replication persists for decades at low levels in liver or peripheral blood mononuclear cells [6]. HBV reactivation in cases of resolved HBV infection is of particular concern, as it frequently results in severe liver dysfunction and fatal fulminant hepatitis [7, 8]. Dasatinib is a SRC/ABL tyrosine kinase inhibitor (TKI) currently approved for the treatment of Philadelphia chromosome (BCR/ABL)-positive chronic myeloid leukemia (CML) and acute lymphoblastic leukemia [9–11]. This drug’s adverse effects consist of cytopenia (anemia, neutropenia and thrombocytopenia), digestive disorders (diarrhea, nausea, vomiting and gastrointestinal hemorrhage), cutaneous eruption and fluid retention (pleural or pericardial effusion). Grade 3 or 4 elevation in serum transaminase
13
T. Ando et al.
or bilirubin levels has been described in approximately 5 % of patients, who are well managed with dose reduction or interruption. The immunological effects of dasatinib have been investigated in several studies, and the results are controversial; certain studies described dasatinib as acting as an immunosuppressive agent [12–14], whereas others reported that dasatinib induces immunostimulation [15, 16]. To our knowledge, HBV reactivation has not been reported in association with dasatinib treatment. Here, we report the first case of reactivation of resolved HBV infection in a CML patient receiving single-agent dasatinib.
Case report A 74-year-old woman had been diagnosed with accelerated-phase CML in 2011 at the age of 71. On physical examination, neither hepatomegaly nor splenomegaly was noted. Her blood test results were hemoglobin (Hb), 12.9 g/ dL; white blood cell (WBC) count, 20,200/µL (with 46 % neutrophils, 1 % myelocytes, 30 % basophils, 3 % eosinophils, 1 % monocytes and 19 % lymphocytes); and platelet (PLT) count, 1,169,000/µL. A bone marrow film revealed markedly hypercellular marrow, with 87.6 % myeloid cells at various stages of maturation and 3.2 % blasts. Chromosome analysis of the marrow cells revealed a karyotype of 46, XX, t(9;22)(q34; q11) in 19 of 20 metaphases. The patient was negative for HBsAg (0.00 IU/mL, normal: 0.00–0.04 IU/mL) and positive for anti-HBs (27 mIU/mL, normal: 0–19 mIU/mL) and anti-HBc (2.92 S/CO, normal: 0.00–0.99 S/CO). She was treated with imatinib at 200 mg once daily, which resulted in a complete hematological response (CHR) within 4 weeks. Due to imatinib-related pleural effusion that developed within 5 weeks, however, the patient was switched from imatinib to a small dose of dasatinib (20 mg/day). She declined a switch to nilotinib because of its lower, twice-daily dosing. An increased dose of dasatinib (50 mg/day) resulted in the recurrence of pleural effusion within 3 weeks, and therefore, the dose was returned to 20 mg/day. She achieved a complete cytogenetic response and a major molecular response after 6 and 8 months, respectively, of dasatinib therapy. Serum levels of HBV DNA were determined at 27 months of dasatinib treatment, at which point a sensitive transcription-mediated amplification assay did not detect HBV DNA in the serum. Although a modest increase in the number of large granular lymphocytes (1000–2000/µL) was observed during dasatinib treatment, there were no episodes of cytomegalovirus disease. Three years after the initiation of dasatinib, asymptomatic elevation of aspartate transaminase (AST; 87 IU/L) and alanine transaminase (ALT; 83 IU/L) levels was observed. At that time, the patient was positive for HBsAg
13
(4357 IU/mL) and hepatitis B envelope antigen (HBeAg) (1466 S/CO, normal: 0.0–0.9 S/CO), and increased levels of HBV DNA (6.9 log 10 copies/mL) were detected by real-time PCR assay. She was still positive for anti-HBs (35 mIU/mL). A diagnosis of HBV reactivation was made. She had HBV genotype C. The patient immediately started lamivudine (100 mg/day). Two months later, her AST and ALT levels returned to normal, and her serum HBV DNA level was under the detection limit, after which dasatinib was stopped. Later, the patient was switched from lamivudine to entecavir (0.5 mg/day), and she maintained a major molecular response to CML and resolution of HBV infection (Fig. 1). The nucleotide sequence of the HBV envelope was determined in HBV-positive serum samples using PCR followed by direct sequencing. A single amino acid substitution (G145R) within the a-determinant (from amino acid 124 to amino acid 147) of HBsAg was detected (Fig. 2). G145R is the most common immune escape mutant. Three additional mutations (L97R, L176R and P178Q) were also detected.
Discussion The risk of therapy-related HBV reactivation has been associated with the pretreatment HBV viral load and the degree of induced immunosuppression. In cases of reactivation of resolved HBV infection, HBV reactivation occurs nearly exclusive in patients receiving highly immunosuppressive agents [1–5]. TKIs are not recognized as an immunosuppressant, and there have been only five reported cases of HBV reactivation in association with imatinib or nilotinib treatment [17–19]. All of the reported cases represented HBV reactivation in HBsAg-positive carriers, further supporting the idea that TKIs may not be immunosuppressive enough to induce HBV reactivation in patients with prior resolution of HBV infection. However, certain studies have reported that the TKIs imatinib [20, 21] and nilotinib [22] inhibit the proliferation and function of T cells. HBV reactivation has not been previously reported in patients receiving dasatinib. In our case, it was surprising that HBV reactivation occurred in a patient with prior resolution of HBV infection and receiving low-dose dasatinib treatment at 20 mg/day (the approved dasatinib dose is 100 mg/day). We stopped dasatinib after the resolution of HBV reactivation by antiviral treatment to avoid a possible clinical flare due to rebound of the immune attack on hepatocytes with an increased viral load [23]. Although the incidence of TKI-induced HBV reactivation is low and the mechanisms remain unclear, close monitoring of HBV status would be advisable in patients with current or resolved HBV infection.
Reactivation of resolved infection with… Fig. 1 Clinical course. Note that neither HBsAg nor HBV DNA was detected in the serum 9 months before HBV reactivation, when serum HBV DNA levels were determined by a transcription-mediated amplification assay. BCR–ABL mRNA levels were determined by the sensitive transcription-mediated amplification and hybridization protection assay (TMA–HPA), in which the detection limit is 5 copy/assay (=10 copy per microgram of RNA)
Fig. 2 The HBV G145R mutant detected in our patient
In our case, four HBV envelope mutations (L97R, G145R, L176R and P178Q) were detected at the time of reactivation. Among them, G145R is the most widely studied HBV immune escape mutation, emerging naturally or in response to vaccination or anti-HBs immunoglobulin G therapy, and can decrease the ability of neutralizing anti-HBs [24–26]. A case of fatal HBV reactivation by an escape mutant following rituximab therapy has been reported [27]. In our case, dasatinib treatment caused an increase in the number of large granular lymphocytes. Interestingly, dasatinib-induced large granular
lymphocyte expansion has been associated with immunosuppression-related cytomegalovirus reactivation [14]. We therefore speculate that, in the present case, HBV reactivation occurred through the following steps: (1) HBV replication had persisted at very low levels in the liver since resolution of acute hepatitis B, (2) dasatinib treatment inhibited cellular immune responses to HBV, (3) a gradual increase in HBV replication levels resulted in the emergence of HBV mutants, and (4) HBV reactivation by escape mutants occurred. Although rare, spontaneous reactivation of HBV infection has been reported in elderly people with resolved HBV infection in the absence of known triggers for reactivation [28]. It is therefore possible that age-related immunosuppression also played some role in enhancing HBV replication in our case. Accumulated virological data from patients with chemotherapy-induced HBV reactivation would help to determine whether the appearance of HBV escape mutants plays a key role in HBV pathology. Conflict of interest Shinya Kimura has received research grants and lecture fees from Bristol-Myers Squibb.
References 1. Hwang JP, Lok AS. Management of patients with hepatitis B who require immunosuppressive therapy. Nat Rev Gastroenterol Hepatol. 2014;11:209–19. 2. Fukushima N, Mizuta T, Tanaka M, Yokoo M, Ide M, Hisatomi T, et al. Retrospective and prospective studies of hepatitis B virus reactivation in malignant lymphoma with occult HBV carrier. Ann Oncol. 2009;20:2013–7.
13
T. Ando et al. 3. Skrabs C, Müller C, Agis H, Mannhalter C, Jäger U. Treatment of HBV-carrying lymphoma patients with Rituximab and CHOP: a diagnostic and therapeutic challenge. Leukemia. 2002;16:1884–6. 4. Yeo W, Chan TC, Leung NW, Lam WY, Mo FK, Chu MT, et al. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol. 2009;27:605–11. 5. Coppola N, Tonziello G, Pisaturo M, Messina V, Guastafierro S, Fiore M, et al. Reactivation of overt and occult hepatitis B infection in various immunosuppressive settings. J Med Virol. 2011;83:1909–16. 6. Rehermann B, Ferrari C, Pasquinelli C, Chisari FV. The hepatitis B virus persists for decades after patients’ recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med. 1996;2:1104–8. 7. Oketani M, Ido A, Uto H, Tsubouchi H. Prevention of hepatitis B virus reactivation in patients receiving immunosuppressive therapy or chemotherapy. Hepatol Res. 2012;42:627–36. 8. Umemura T, Tanaka E, Kiyosawa K, Kumada H, Japan de novo Hepatitis B Research Group. Mortality secondary to fulminant hepatic failure in patients with prior resolution of hepatitis B virus infection in Japan. Clin Infect Dis. 2008;47:e52–6. 9. Fujisawa S, Nakamae H, Ogura M, Ishizawa K, Taniwaki M, Utsunomiya A, et al. Efficacy and safety of dasatinib versus imatinib in Japanese patients with newly diagnosed chronicphase chronic myeloid leukemia (CML-CP): subset analysis of the DASISION trial with 2-year follow-up. Int J Hematol. 2014;99:141–53. 10. Kimura S, Ando T, Kojima K. Ever-advancing chronic myeloid leukemia treatment. Int J Clin Oncol. 2014;19:3–9. 11. Aoe M, Shimada A, Muraoka M, Washio K, Nakamura Y, Takahashi T, et al. ABL kinase mutation and relapse in 4 pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia cases. Int J Hematol. 2014;99:609–15. 12. Wölfl M, Langhammer F, Wiegering V, Eyrich M, Schlegel PG. Dasatinib medication causing profound immunosuppression in a patient after haploidentical SCT: functional assays from whole blood as diagnostic clues. Bone Marrow Transplant. 2013;48:875–7. 13. Sillaber C, Herrmann H, Bennett K, Rix U, Baumgartner C, Böhm A, et al. Immunosuppression and atypical infections in CML patients treated with dasatinib at 140 mg daily. Eur J Clin Invest. 2009;39:1098–109. 14. Kreutzman A, Ladell K, Koechel C, Gostick E, Ekblom M, Stenke L, et al. Expansion of highly differentiated CD8 + T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalovirus reactivation. Leukemia. 2011;25:1587–97. 15. Mustjoki S, Auvinen K, Kreutzman A, Rousselot P, Hernesniemi S, Melo T, et al. Rapid mobilization of cytotoxic lymphocytes induced by dasatinib therapy. Leukemia. 2013;27:914–24.
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