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      Incidence and risk factors of hepatitis B virus reactivation in patients with multiple myeloma in an era with novel agents: a nationwide retrospective study in Japan

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          Abstract

          An estimated two billion people worldwide have been infected with the hepatitis B virus (HBV). Specifically, the prevalence of HBV infection is particularly high in Asia, including Japan. HBV reactivation (HBVr) can occur in HBV carriers and in patients with resolved HBV infection who are receiving cancer chemotherapy. HBVr can induce severe flares of hepatitis and lead to fatal fulminant hepatitis. With the increasing availability of rituximab-based regimens, HBVr has become a well-known complication of lymphoma chemotherapy. However, before the era of novel agents, such as proteasome inhibitors and immunomodulatory drugs (IMiDs), there were few reports of HBVr in patients with multiple myeloma (MM). Since the approval of these novel agents, the number of reports has increased 1–3 . In our previous study of 641 patients with MM, we reported that 9 of 99 (9.1%) patients with resolved HBV infection experienced HBVr 4 . Furthermore, the cumulative incidences of HBVr at 2 and 5 years were 8% and 14%, respectively. While our previous study concluded that HBVr was not rare, reasonable risk factors were not identified 4 . Therefore, this nationwide retrospective study aimed to evaluate the actual incidence and risk factors of HBVr in Japanese patients with MM. This study included patients who were diagnosed with symptomatic MM using the International Myeloma Working Group diagnostic criteria between January 2006 and February 2016 at board certified institutes of the Japanese Society of Hematology. The terminology and definitions used remain the same as in our previous report 4 . This study was performed in accordance with the ethical principles of the Declaration of Helsinki and was approved by the ethics review board of each participating institution. Informed consent was obtained from all patients. A multivariate logistic regression model was applied to identify independent risk factors related to HBVr using SAS statistical analysis software (version 9.4.; SAS Institute Inc., Cary, NC, USA). The other analyses were performed using the same methods as our previous report 4 . This study collected data from 5078 patients, including data on 641 patients evaluated in our previous study, from 76 Japanese hospitals 4 . All patients had been treated with either novel agents (bortezomib, thalidomide, lenalidomide, pomalidomide, panobinostat, carfilzomib elotuzumab, and ixazomib) or had undergone autologous stem cell transplantation (auto-SCT). Of these patients, 52 (1.0%) were HBV carriers, and 760 (15.0%) exhibited resolved HBV infection. Prophylactic antiviral agents were administered to 46 (88.5%) of the 52 HBV carriers to prevent hepatitis; one of the remaining 6 developed hepatitis. Baseline characteristics of MM patients with resolved HBV infection are shown in Table 1. We identified 180 (23.7%) patients who underwent auto-SCT (156 cases: upfront single, 13 cases: upfront tandem, 8 cases: relapse, 3 cases: upfront and relapse), and 178 patients received high-dose melphalan with or without bortezomib as a conditioning regimen. Sixty-one patients received post-auto-SCT maintenance therapy. During a median follow-up period of 101 weeks (range: 1–541 weeks), 58 of 758 (7.7%) patients with resolved HBV infection experienced HBVr. The cumulative incidence rates of HBVr at 2 and 5 years were 7.9% and 14.1%, respectively (Fig. 1a). Ten of fifty-eight (17.2%) patients with HBVr developed hepatitis, and one died of fulminant hepatitis despite the administration of antiviral agent. In these 10 patients, HBVr was diagnosed after an elevation of alanine aminotransferase levels was observed. Conversely, the other patients who had regular monitoring of HBV-DNA and/or preemptive antiviral therapy according to the Japan Society of Hepatology guidelines did not develop hepatitis 5 . Table 1 Baseline characteristics of patients with resolved hepatitis B virus infection HBV reactivation (n = 58) No HBV reactivation (n = 702) p-Value Age <0.0001    Mean (range) 64 (44–83) 70 (43–93) Male, n (%) 34 (58.6) 397 (56.6) 0.7600 MM subtype, n (%) 0.1769  IgG 30 (51.7) 376 (53.6)  IgA 12 (20.7) 181 (25.8)  IgD 4 (6.9) 15 (2.1)  Light chain only 12 (20.7) 115 (16.4)  Othersa 0 (0.0) 15 (2.1) Durie–Salmon staging system, n (%) 0.9108  IA 4 (6.9) 58 (8.3)  IB 0 (0.0) 6 (0.9)  IIA 16 (27.6) 164 (23.4)  IIB 1 (1.7) 26 (3.7)  IIIA 29 (50.0) 336 (47.9)  IIIB 7 (12.1) 104 (14.8)  Unknown 1 (1.7) 8 (1.1) International staging system, n (%) 0.0943  I 19 (32.8) 131 (18.7)  II 21 (36.2) 297 (42.3)  III 16 (27.6) 267 (38.0)  Unknown 2 (3.4) 7 (1.0) HBV serological marker, n (%) 0.1447  Anti-HBs negative 17 (29.3) 163 (23.2) WBC (×10% μL) 0.4892  Mean (range) 5.2 (2.1–9.3) 5.3 (1.3–52.9) Lymphocyte (×10% μL) 0.3978  Mean (range) 1.6 (0.3–3.1) 1.5 (0.1–13.9) Albumin (g/dL) 0.0250  Mean (range) 3.6 (2.1–5.0) 3.4 (1.0–5.3) ALT (IU/L) 0.2574  Mean (range) 23 (7–73) 20 (2–160) Gamma-GTP (IU/L) 0.0035  Mean (range) 31 (9–115) 43 (6–540) Novel agent, n (%)  Bortezomib 48 (82.8) 613 (87.3) 0.3210  Lenalidomide 22 (37.9) 401 (57.1) 0.0047  Thalidomide 7 (12.1) 138 (19.7) 0.1574 Steroid, n (%)  Dexamethasone 53 (91.4) 648 (92.3) 0.7973  Prednisolone 14 (24.1) 259 (36.9) 0.0516 Stem cell transplantation, n (%)  Auto-SCT 38 (65.5) 142 (20.2) <0.0001   Maintenance therapyb 12(31.6) 49 (34.5) 0.7913  Allo-SCT 1 (1.7) 2 (0.3) 0.2122 Follow up (week) n = 58 n = 700 —  Median (range) 74 (4–280) 105 (1–541) Among the 5078 patients with MM, 760 patients exhibited resolved HBV infection. Of these 760 patients, 58 patients experienced HBV reactivation. Univariate analysis revealed that age, elevated serum albumin levels, and auto-SCT treatment were significant risk factors of HBV reactivation. Conversely, the administration of lenalidomide was significantly associated with a lower prevalence of HBV reactivation Anti-HBs antibodies against hepatitis B surface antigen, WBC white blood cells, ALT alanine aminotransferase, gamma-GTP gamma-glutamyl transpeptidase, auto-SCT autologous stem cell transplantation, allo-SCT allogeneic stem cell transplantation aOthers, includes IgM, non-secretary, and biclonal gammopathy (IgG and IgA) bMaintenance therapy was compared in patients who received auto-SCT Fig. 1 Cumulative incidences of HBV reactivation a, and with or without auto-SCT b HBV reactivation occurred in 7.6% (58/760) of all patients with resolved HBV infection. The cumulative incidences of HBV reactivation at 2 years and 5 years were 7.9% and 14.1%, respectively a. HBV reactivation occurred in 21.1% (38/180) of patients who received auto-SCT treatment and 3.4% (20/580) of patients who received novel agent treatment. The cumulative incidences at 2 years and 5 years in the auto-SCT group were 16% and 30.6%, respectively. The cumulative incidences at 2 and 5 years in the novel agents group were 4.4% and 4.8%, respectively. The incidence rate was significantly higher in the auto-SCT group than in the novel agents group (p < 0.0001) b In the univariate analysis, a high incidence of HBVr was observed in groups with elevated serum albumin levels, of younger age, with decreased gamma-glutamyl transpeptidase levels, and who received auto-SCT (Table 1). Multivariate analysis revealed that auto-SCT was a powerful risk factor for HBVr (adjusted odds ratio (OR) 11.56, 95% confidence interval (CI): 4.61–29.0) (Table 2). The cumulative incidence of HBVr in patients treated with auto-SCT at 2 and 5 years was significantly higher (16% vs. 30.6%, respectively) than those not treated with auto-SCT (4.4% vs. 4.8%, respectively) (log-rank test, p < 0.0001) (Fig. 1b). Contrastively, lenalidomide treatment was associated with a low HBVr prevalence (adjusted OR 0.47 (95% CI: 0.26–0.83)) (Table 2). Table 2 Multivariate analysis of risk factors associated with hepatitis B virus reactivation HBV reactivation (%) (n = 58) No HBV reactivation (%) (n = 702) Total (%) (n = 760) Unadjusted OR (95% CI) Adjusted ORa (95% CI) Age (years old)  <70 40 (11.0) 324 (89.0) 364 (47.9) 2.59 (1.458–4.611) 0.52 (0.200–1.341)  ≥70 18 (4.5) 378 (95.5) 396 (52.1) 1 1 Albumin (g/dL)  <3.4 39 (9.4) 374 (90.6) 413 (54.3) 1 1  ≥3.4 19 (5.5) 328 (94.5) 347 (45.7) 1.80 (1.020–3.177) 1.50 (0.820–2.739) Gamma-GTP (IU/mL)  <25 29 (8.7) 304 (91.3) 333 (43.8) 1.31 (0.766–2.238) 1.52 (0.858–2.693)  ≥25 29 (6.8) 398 (93.2) 427 (56.2) 1 1 Auto-SCT  Done 38 (21.1) 142 (78.9) 180 (23.7) 7.49 (4.229–13.275) 11.56 (4.606–28.994)  Not done 20 (3.4) 560 (96.6) 580 (76.3) 1 1 Lenalidomide  Received 22 (5.2) 401 (94.8) 423 (55.7) 0.46 (0.264–0.796) 0.47 (0.261–0.830)  Not received 36 (10.7) 301 (89.3) 337 (44.3) 1 1 Multivariate analysis revealed that only auto-SCT was independently associated with a high prevalence of HBV reactivation. In contrast, lenalidomide significantly decreased the incidence of HBV reactivation aThe adjusted OR was calculated by a conditional logistic regression, which was adjusted for age, albumin levels, gamma-GTP levels, auto-SCT treatment, and lenalidomide treatment OR odds ratio, CI confidence interval, gamma-GTP gamma-glutamyl transpeptidase, auto-SCT autologous stem cell transplantation There have only been a few reports of HBVr among MM patients who were treated with lenalidomide or pomalidomide 6 , but this adverse effect is mentioned in the drug information sheets of both drugs in the EU. In this study, only one patient did not receive auto-SCT or novel agents (except lenalidomide). Lenalidomide is an IMiD that targets cereblon (CRBN) to induce antitumor activity. The argonaute2 (AGO2) is the only member with catalytic activity and plays an essential role within the RNA-induced silencing complex; thus, it regulates small RNA-guided gene splicing processes 7 . Recently, Xu et al. 8 showed that AGO2 was a CRBN binding partner and was negatively regulated by CRBN in MM cells. In the study, administration of lenalidomide significantly increased expression of CRBN and decreased the levels of AGO2 and microRNAs in MM cell lines. Another study reported that the knock down of AGO2 induced decreased levels of HBsAg and HBV-DNA in cells transfected with plasmids of HBV components 9 . These results suggest that lenalidomide may decrease AGO2 levels and inhibit HBV proliferation in patients with MM. In our previous study, auto-SCT was not significantly associated with HBVr 4 ; however, in the present study, auto-SCT was shown to be a powerful risk factor for HBVr. This discrepancy could be a result of different samples sizes. Auto-SCT is a well-known risk factor for HBVr 10 , and a previous Korean retrospective study that analyzed 230 patients with resolved HBV infection similarly reported that auto-SCT significantly increased the prevalence of HBVr in patients with MM 1 . Conversely, only 17 patients with MM who experienced HBVr were reported from non-Asian regions, 14 (82.4%) of these received auto-SCT. It is possible that auto-SCT is a risk factor for HBVr not only in Asia but also worldwide. Recently, several guidelines recommend antiviral prophylaxis for patients at high risk of HBVr from the initiation of chemotherapy 11, 12 . The present study and a prospective study on lymphoma showed that patients who received preemptive antivirals following HBV-DNA monitoring did not experience HBVr-related hepatitis 13 . Additionally, HBV-DNA monitoring is more economical than antiviral prophylaxis; these results suggest that prophylactic antiviral therapy might not always be recommended in MM. There are three differences in results between the present study and the previously described Korean study 1 . First, the cumulative incidence of HBVr in the auto-SCT group was higher in the current study (16 and 7% at 2 years), which could be attributable to the different definitions of HBVr used. In the Korean study, HBVr was defined as the reappearance of HBsAg in the blood; therefore, our definition may lead to earlier and higher incidences of HBVr. The second difference is that the current study observed a longer time between auto-SCT and HBVr 1 . In the Korean study, all patients who underwent auto-SCT experienced HBVr within 6 months, and the investigators recommended monitoring HBV-DNA levels for at least 24 months after transplantation. In the present study, 6 of the 38 patients who received auto-SCT experienced HBVr after more than 2 years post transplantation (median, 55 weeks; range, 10–250 weeks). Two of these patients were not treated with chemotherapeutic agents after auto-SCT until they exhibited HBVr (maximum, 226 weeks). These results suggest that the appropriate period of HBV-DNA monitoring for patients with MM remains unclear; long-term monitoring may be required to prevent flares of hepatitis, especially among patients treated with auto-SCT. The third difference is that the Korean study, along with several other studies, identified negative or low titers of antibodies against the hepatitis B surface antigen (anti-HBs) to be a risk factor of HBVr 1, 14 . However, there was no significant association between anti-HBs negativity and HBVr in the present study, and serological markers could not be thoroughly assessed because each institution used different assay methods. Our study had two major limitations. First, the duration of observation was relatively short (approximately 2 years). The therapeutic outcome MM treatment using novel agents has seen significant improvements. The current systematic chemotherapy, including the consolidation and/or maintenance phase 15 , requires a longer treatment period. There was no significant association between post-transplant maintenance therapy and HBVr in our study (p = 0.7913). However, the actual prevalence of HBVr in MM patients who experienced prolonged treatment could not be determined, as the incidence of HBVr gradually increased up to 5 years (260 weeks) after initiating treatment. Secondly, the relationship between HBVr and allogeneic SCT or recently approved novel agents apart from bortezomib, thalidomide, and lenalidomide, was unclear. The sample size was too small to evaluate the relationship. In conclusion, this large-scale, nationwide retrospective study showed that HBVr in patients with MM was significantly higher, especially among patients who received auto-SCT. Additional prospective studies with long-term observation periods are needed to evaluate the optimal duration of HBV-DNA monitoring and to develop an effective strategy to prevent HBVr in patients with MM.

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          Most cited references 15

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          EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.

          Hepatitis B virus (HBV) infection remains a global public health problem with changing epidemiology due to several factors including vaccination policies and migration. This Clinical Practice Guideline presents updated recommendations for the optimal management of HBV infection. Chronic HBV infection can be classified into five phases: (I) HBeAg-positive chronic infection, (II) HBeAg-positive chronic hepatitis, (III) HBeAg-negative chronic infection, (IV) HBeAg-negative chronic hepatitis and (V) HBsAg-negative phase. All patients with chronic HBV infection are at increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC), depending on host and viral factors. The main goal of therapy is to improve survival and quality of life by preventing disease progression, and consequently HCC development. The induction of long-term suppression of HBV replication represents the main endpoint of current treatment strategies, while HBsAg loss is an optimal endpoint. The typical indication for treatment requires HBV DNA >2,000IU/ml, elevated ALT and/or at least moderate histological lesions, while all cirrhotic patients with detectable HBV DNA should be treated. Additional indications include the prevention of mother to child transmission in pregnant women with high viremia and prevention of HBV reactivation in patients requiring immunosuppression or chemotherapy. The long-term administration of a potent nucleos(t)ide analogue with high barrier to resistance, i.e., entecavir, tenofovir disoproxil or tenofovir alafenamide, represents the treatment of choice. Pegylated interferon-alfa treatment can also be considered in mild to moderate chronic hepatitis B patients. Combination therapies are not generally recommended. All treated and untreated patients should be monitored for treatment response and adherence, and the risk of progression and development of complications. HCC remains the major concern for treated chronic hepatitis B patients. Several subgroups of patients with HBV infection require specific focus. Future treatment strategies to achieve 'cure' of disease and new biomarkers are discussed.
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            JSH Guidelines for the Management of Hepatitis B Virus Infection

              (2014)
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              Argonaute 2: A Novel Rising Star in Cancer Research

              AGO2 (Argonaute 2, EIF2C2) is the only member in AGO family with catalytic activity and of extreme importance during small RNAs guided gene silencing processes. The structural investigations have provided insights into details and functional mechanisms of the four major domains within AGO2. As a multifunction player, AGO2 has been revealed involved in tumorgenesis through miRNAs-dependent or independent ways. And nowadays, AGO2 has also been more importantly found ectopically over-expressed in carcinomas and closely associated with aspects of cancers in means of interacting with well-known tumor factors. Here, we provide a review on structural insights, functional mechanisms, novel roles and relationship with carcinomas of AGO2.
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                Author and article information

                Contributors
                +81-3-3813-3111 , msasaki@juntendo.ac.jp
                Journal
                Blood Cancer J
                Blood Cancer J
                Blood Cancer Journal
                Nature Publishing Group UK (London )
                2044-5385
                23 November 2017
                23 November 2017
                2017
                : 7
                : 12
                Affiliations
                [1 ]ISNI 0000 0004 1762 2738, GRID grid.258269.2, Department of Hematology, , Juntendo University School of Medicine, ; Bunkyo-ku, Tokyo 113-8421 Japan
                [2 ]ISNI 0000 0001 2155 3497, GRID grid.410778.d, Faculty of Health Science, , Daito Bunka University, School of Sports and Health Science, ; Higashi-Matsuyama, Saitama 355-8501 Japan
                [3 ]GRID grid.415664.4, Department of Hematology, , National Hospital Organization Okayama Medical Center, ; Okayama, Okayama 701-1192 Japan
                [4 ]ISNI 0000 0004 1763 7921, GRID grid.414929.3, Department of Hematology, , Japanese Red Cross Medical Center, ; Shibuya-ku, Tokyo 150-8935 Japan
                [5 ]ISNI 0000 0004 0377 6808, GRID grid.415288.2, Department of Hematology, , Sasebo City General Hospital, ; Sasebo, 857-0056 Nagasaki Japan
                [6 ]ISNI 0000 0004 0377 4044, GRID grid.417333.1, Department of Hematology, , Yamanashi Prefectural Central Hospital, ; Kofu, Yamanashi 400-8506 Japan
                [7 ]Department of Hematology, National Hospital Organization Shibukawa Medical Center, Shibukawa, Gunma 377-0280 Japan
                [8 ]GRID grid.410783.9, First Department of Internal Medicine, , Kansai Medical University, ; Hirakata, Osaka 573-1010 Japan
                [9 ]GRID grid.460253.6, Department of Hematology/Oncology, , Japan Community Health Care Organization Kyushu Hospital, ; Kita-Kyusyu, Fukuoka 806-8501 Japan
                [10 ]GRID grid.412567.3, Department of Oncology/Hematology, , Shimane University Hospital, ; Izumo, Shimane 693-8501 Japan
                [11 ]ISNI 0000 0000 9206 2938, GRID grid.410786.c, Department of Transfusion and Cell Transplantation, , Kitasato University School of Medicine, ; Sagamihara, Kanagawa 252-0374 Japan
                [12 ]ISNI 0000 0004 1936 9959, GRID grid.26091.3c, Division of Hematology, Department of Medicine, , Keio University School of Medicine, ; Shinjuku-ku, Tokyo 160-8582 Japan
                [13 ]ISNI 0000 0001 0291 3581, GRID grid.267500.6, Department of Hematology/Oncology, , University of Yamanashi, ; Chuo, Yamanashi 409-3898 Japan
                [14 ]GRID grid.415479.a, Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, , Komagome Hospital, ; Bukyo-ku, Tokyo 113-8677 Japan
                [15 ]ISNI 0000 0001 0706 0776, GRID grid.410781.b, Division of Hematology and Oncology, Department of Medicine, , Kurume University School of Medicine, ; Kurume, Fukuoka 830-0011 Japan
                [16 ]ISNI 0000 0004 0377 8969, GRID grid.416203.2, Department of Internal Medicine, , Niigata Cancer Center Hospital, ; Niigata, Niigata 951-8566 Japan
                [17 ]ISNI 0000 0004 1762 2738, GRID grid.258269.2, Department of Gastroenterology, , Juntendo University School of Medicine, ; Bunkyo-ku, Tokyo 113-8421 Japan
                [18 ]ISNI 0000 0001 2155 3497, GRID grid.410778.d, Department of Preventive Medicine, , Daito Bunka University, Graduate School of Sports and Health Science, ; Higashi-Matsuyama, Saitama 355-8501 Japan
                Article
                2
                10.1038/s41408-017-0002-2
                5802507
                29167420
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                Oncology & Radiotherapy

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