Ibrutinib in Advanced Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Lower Risk of Hepatitis B Virus Reactivation

2021 ◽  
pp. 1-9
Author(s):  
Shenmiao Yang ◽  
Rong Zhu ◽  
Nan Li ◽  
Yu Feng ◽  
Rui Zuo ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Chronic Lymphocytic Leukemia ◽  
Hepatitis B ◽  
Lymphocytic Leukemia ◽  
Hbv Infection ◽  
Hbv Reactivation ◽  
Small Lymphocytic Lymphoma ◽  
European Descent ◽  
Safety And Efficacy ◽  
B Virus

<b><i>Introduction:</i></b> Therapy of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with drugs such as ibrutinib and rituximab is often associated with immune suppression, opportunistic infections, and reactivation of virus infections such as hepatitis B virus (HBV). This risk is especially important in geographical regions like Asia where many potential therapy recipients have HBV infection. Also, whether safety and efficacy of ibrutinib in Asians and Europeans with advanced CLL/SLL are similar is unknown. We determined the safety and efficacy of ibrutinib compared with rituximab in advanced CLL/SLL including persons with HBV infection. We compared outcomes with data published from trials in persons of European descent. <b><i>Methods:</i></b> This is a post hoc analysis of a multicenter, phase-3 trial (NCT01973387). Subjects with advanced CLL/SLL were randomized 2:1 to receive ibrutinib, 420 mg/day, or rituximab, 500 mg/mE + 2, for 6 cycles. Subjects with resolved HBV infection were included. Endpoints were progression-free survival (PFS), overall response rate (ORR), survival, and adverse events including resolved HBV reactivation. <b><i>Results:</i></b> 131 subjects received ibrutinib (<i>N</i> = 87) or rituximab (<i>N</i> = 44) including 53 with resolved HBV infection. Median follow-up was 31 months (95% confidence interval: 28, 32 months). ORR was 61% (50, 71%) versus 7% (2, 18%; <i>p</i> &#x3c; 0.001). Median PFS was not reached in the ibrutinib cohort but must be &#x3e;40 months versus 8 months (7, 9 months; <i>p</i> &#x3c; 0.0001) in the rituximab cohort. Median survival was not reached but must be &#x3e;40 months versus 27 months (17 months, NE; <i>p</i> = 0.0006). In multivariable analyses, receiving ibrutinib increased PFS (hazard rate [HR] for failure = 0.12 [0.06, 0.23]; <i>p</i> &#x3c; 0.001) and decreased risk of death (HR = 0.31 [0.15, 0.63]; <i>p</i> &#x3c; 0.001). Median duration of exposure to ibrutinib was significantly longer than exposure to rituximab (28 vs. 5 months). The safety profile of ibrutinib was consistent with that observed in previous studies with no new safety signal. No subject receiving ibrutinib had HBV reactivation versus 2 receiving rituximab, despite much greater use of drugs to prevent HBV reactivation in the rituximab cohort. Outcomes were like those reported in persons of European descent, except ORR which, was unreliably correlated with PFS in Asians. <b><i>Conclusion:</i></b> Ibrutinib is safe and effective in persons with advanced CLL/SLL and better than rituximab in all therapy outcomes including risk of HBV reactivation. Outcomes with ibrutinib in Chinese were like those reported in persons of predominately European descent.

scholarly journals 288. Hepatitis B Virus Reactivation in Patients with Hematologic Malignancies after Anticancer Therapy Which Included Ibrutinib

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S156-S157 ◽  
Author(s):  
Alexandre Malek ◽  
Yago Nieto ◽  
Ariel D Szvalb ◽  
Shaheer Siddiqui ◽  
Mehnaz A Shafi ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Liver Failure ◽  
Lymphocytic Leukemia ◽  
Hbv Infection ◽  
Temporal Association ◽  
Hbv Reactivation ◽  
Guidance Document ◽  
Cell Transplant ◽  
B Virus

Abstract Background Several cases of severe bacterial, fungal, and viral infections have been reported following ibrutinib therapy. Here, we report a case of a patient with non-Hodgkin lymphoma who developed hepatitis B virus (HBV)–associated liver failure after anti-cancer treatment most recently with ibrutinib. We also review reported cases of HBV reactivation (HBVr) after ibrutinib. Methods We searched the Medline and Embase databases and identified 5 patients with HBVr related to ibrutinib for a total of 6 study patients, including our case (figure). HBV-related outcomes were defined according to the 2018 AASLD HBV guidance document. Results All 6 patients were men and most (5 or 83%) had chronic lymphocytic leukemia and past HBV infection (table). Three patients (50%) developed HBV-related hepatitis and 2 of them progressed to liver failure. Four patients (67%) had a remote history (≥24 months) of other potential risk factors besides ibrutinib that could contribute to HBVr, including the use of direct-acting antivirals for hepatitis C co-infection (1 pt), hematopoietic cell transplant (HCT) (1 pt) and rituximab use (4 patients). HBVr occurred at least 6 months after initiation of ibrutinib in most patients (4 or 67%), with a median of 9.7 months (range, 1.5–42). In all 4 patients pretreated with rituximab, that treatment was completed at least 24 months before HBVr. Two of these patients received anti-HBV prophylaxis that was stopped 12 months after the completion of rituximab; the other 2 patients were only monitored without antivirals. The HCT recipient received anti-HBV prophylaxis per guidelines. None of the 6 patients treated with ibrutinib were receiving anti-HBV prophylaxis at the time of HBVr, but 5 patients were started on anti-HBV drugs at the first sign of HBVr. Four received entecavir and 1, tenofovir. All treated patients recovered from HBVr. No pt died of HBVr. Conclusion Life-threatening HBVr can occur following ibrutinib therapy in patients with past or chronic HBV infection. The temporal association between ibrutinib therapy and reactivation indicates that ibrutinib is the likely cause of the HBVr, and clinicians should be aware of the risk of HBVr in these patients. A provisional approach could be HBV monitoring at regular intervals with initiation of antiviral therapy at the earliest sign of HBV reactivation. Disclosures All authors: No reported disclosures.

scholarly journals Rituximab increases the risk of hepatitis B virus reactivation in non-Hodgkin lymphoma patients who are hepatitis B surface antigen-positive or have resolved hepatitis B virus infection in a real-world setting: a retrospective study

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7481 ◽  
Author(s):  
Yu-Fen Tsai ◽  
Ching-I Yang ◽  
Jeng-Shiun Du ◽  
Ming-Hui Lin ◽  
Shih-Hao Tang ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hodgkin Lymphoma ◽  
Hepatitis B Surface Antigen ◽  
Hbv Infection ◽  
Hbv Reactivation ◽  
Virus Reactivation ◽  
Non Hodgkin Lymphoma ◽  
B Virus ◽  
Hepatitis Flare

Background Hepatitis B virus (HBV) reactivation with a hepatitis flare is a common complication in lymphoma patients treated with immunotherapy and/or chemotherapy. Anti-HBV prophylaxis is suggested for non-Hodgkin lymphoma (NHL) patients undergoing rituximab therapy, even those with resolved HBV infection. Since anti-HBV prophylaxis for patients with resolved HBV infection is not covered by national health insurance in Taiwan, a proportion of these patients receive no prophylaxis. In addition, late HBV reactivation has emerged as a new issue in recent reports, and no consensus has been reached for the optimal duration of antiviral prophylaxis. Thus, the aim of our study was to investigate the incidence and outcomes of HBV reactivation in NHL patients in a real-world setting and to study the frequency of late HBV reactivation. Materials Non-Hodgkin lymphoma patients who received rituximab and/or chemotherapy at our institute between January 2011 and December 2015 and who were hepatitis B surface antigen (HBsAg)- or hepatitis B core antibody (HBcAb)-positive were reviewed retrospectively. Results A total of 388 patients were screened between January 2011 and December 2015. In total, 196 patients were excluded because HBsAg was not assessed, HBcAb was negative or not assessed, or they were not treated with immunosuppressive therapy. Finally, the retrospective study included 62 HBsAg-positive NHL patients and 130 NHL patients with resolved HBV infection (HBsAg-negative and HBcAb-positive). During a median 30.5-month follow-up period, seven patients experienced HBV reactivation, five of whom had a hepatitis flare. The incidence of HBV reactivation did not significantly differ between the HBsAg-positive patients and the resolved HBV infection population without anti-HBV prophylaxis (4.8% vs. 3.1%, P = 0.683). All patients with HBV reactivation were exposed to rituximab. Notably, late HBV reactivation was not uncommon (two of seven patients with HBV reactivation events, 28.6%). Hepatitis B virus reactivation did not influence the patients’ overall survival. An age ≥65 years and an advanced disease stage were independent risk factors for poorer overall survival. Conclusion The incidence of HBV reactivation was similar between the HBsAg-positive patients with antiviral prophylaxis and the resolved HBV infection population without anti-HBV prophylaxis. All HBV reactivation events occurred in NHL patients exposed to rituximab. Late reactivation was not uncommon. The duration of regular liver function monitoring for more than 1 year after immunosuppressive therapy or after withdrawal of prophylactic antiviral therapy should be prolonged. Determining the exact optimal duration of anti-HBV prophylaxis is warranted in a future prospective study for NHL patients treated with rituximab-containing therapy.

scholarly journals Prophylaxis of hepatitis B virus (HBV) infection reactivation – recommendations of the Working Group for prevention of HBV reactivation

2019 ◽  
Vol 5 (3) ◽  
pp. 195-202 ◽  
Author(s):  
Małgorzata Pawłowska ◽  
Robert Flisiak ◽  
Lidia Gil ◽  
Andrzej Horban ◽  
Iwona Hus ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Working Group ◽  
Hbv Infection ◽  
Hbv Reactivation ◽  
B Virus

Hepatitis B Virus (HBV) Screening in Hematology/Oncology Patients Who Receive Rituximab: Continued Need for Evidence-Based Standardized Recommendations and Effective Implementation Into Clinical Practice

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 970-970
Author(s):  
Jayde Bednarik ◽  
Karen Smethers ◽  
Delila Katz ◽  
Jennifer S Daly ◽  
Roy Guharoy ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Single Agent ◽  
Hbv Infection ◽  
Evidence Based ◽  
Hbv Reactivation ◽  
B Virus ◽  
Initiation Of Therapy ◽  
Hbv Screening

Abstract Abstract 970 Background: The CD20 monoclonal antibody, rituximab, has been implicated in the reactivation of hepatitis B virus (HBV) when given either combined with chemotherapy or as a single-agent. This potentially fatal complication has been documented in patients (pts) with high risk of HBV reactivation (i.e., HBV surface antigen (HBSAg) positive), and in lower risk populations (i.e., HBsAg negative, HBV core antibody (HBcAb) positive), the latter where the risk of reactivation with rituximab-based therapy is approximately 15–20% (Yeo W, et al. J Clin Oncol 2009; Evens AM et al, Ann Onc 2011). Published recommendations on HBV screening and anti-viral prophylaxis related to rituximab vary considerably, leaving practicing clinicians without clear consensus. In addition, HBV screening and prophylaxis have not been universally implemented into clinical practice. We sought to determine our institutional frequency of HBV screening and rates of HBV reactivation in Hematology/Oncology pts treated with rituximab-based therapy who underwent appropriate screening and prophylaxis. METHODS: We completed a single center, retrospective analysis at a large academic center to examine pts >17 years of age who received rituximab for a hematologic or oncologic disorder from January 1, 2005 through August 1, 2011. We reviewed drug administration records to identify pts who received rituximab for a malignancy or other hematological disorder. Pts were evaluated for documented HBV screening, HBV diagnosis, number of doses of rituximab received, vaccination status, baseline characteristics, and relevant past medical history and laboratory values. A ‘cycle’ of rituximab was defined as 1 dose given in combination with chemotherapy, 4 consecutive weeks given as a single agent, or 1 dose given q2-4 months as part of maintenance therapy. Data regarding use of prophylactic therapy for HBV were also collected. RESULTS: 212 pts were identified as having received rituximab; 109 were excluded as they received rituximab for other indications (n=86 multiple sclerosis, n=11 rheumatoid arthritis, and n=17 other), leaving a total of 103 pts who met study inclusion criteria. The median age was 63 years (19-90), median number of rituximab ‘cycles’ received was 3 (1-9); 45% of pts had diffuse large B-cell lymphoma (DLBCL), 15% other high-grade lymphoma, 14% follicular lymphoma (FL), and 26% other hematologic malignancy. Among the 103 pts, a total of 53 (51.4%) were screened for HBV at some point before or after initiation of therapy. Only 6.8% of pts were screened (within 9 months) prior to initiation of treatment, while 18.4% had HBV screening within 30 days of the 1st rituximab dose. Of the pts screened for HBV after 30 days, the median time to screening was 196 days (32-2660) after rituximab initiation. Notably, there were no differences in rates of HBV screening based on the year of therapy. Among the 53 pts screened for HBV prior to or within 30 days of rituximab initiation, eight (15.1%) were positive for HBV infection. Three pts were positive for HBsAg, all of whom received HBV anti-viral prophylaxis. Five pts were negative for HBsAg, but positive for HBcAb (1/5 also with positive HBV surface antibody); one HBcAb+ pt received anti-viral prophylaxis. These four pts received anti-viral prophylaxis for a median time of 17.1 months, which included a median of 7.9 months after the last rituximab dose. Among the 53 pts who underwent HBV screening, there were no cases of HBV reactivation observed with a median follow-up time of 15.6 months (5.9-16.5). CONCLUSION: At our academic institution, we identified an occult HBV infection rate of 15% in Hematology/Oncology pts who received rituximab treatment. A relatively low rate of pre-treatment HBV screening was performed, while approximately 45% of pts had screening after initiation of therapy. Among pts who were screened, appropriate anti-viral prophylaxis was instituted, and there were no cases of HBV reactivation. Altogether, there remains a critical need for standardized recommendations and consensus for screening and prophylaxis of HBV infection in pts who receive rituximab therapy. This is particularly evident given recent data regarding cost effectiveness of this approach (Zurawaska U, et al, J Clin Oncol 2012). In addition, continued efforts are needed to implement evidence-based HBV screening and prophylaxis guidelines in clinical practice. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Transcriptional Elongation Control of Hepatitis B Virus Covalently Closed Circular DNA Transcription by Super Elongation Complex and BRD4

2017 ◽  
Vol 37 (19) ◽  
Author(s):  
Joel Celio Francisco ◽  
Qian Dai ◽  
Zhuojuan Luo ◽  
Yan Wang ◽  
Roxanne Hui-Heng Chong ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hbv Infection ◽  
Intermediate Step ◽  
Hbv Reactivation ◽  
Transcriptional Elongation ◽  
Elongation Complex ◽  
Super Elongation Complex ◽  
Chronic Hepatitis B Virus ◽  
B Virus

ABSTRACT Chronic hepatitis B virus (HBV) infection can lead to liver cirrhosis and hepatocellular carcinoma. HBV reactivation during or after chemotherapy is a potentially fatal complication for cancer patients with chronic HBV infection. Transcription of HBV is a critical intermediate step of the HBV life cycle. However, factors controlling HBV transcription remain largely unknown. Here, we found that different P-TEFb complexes are involved in the transcription of the HBV viral genome. Both BRD4 and the super elongation complex (SEC) bind to the HBV genome. The treatment of bromodomain inhibitor JQ1 stimulates HBV transcription and increases the occupancy of BRD4 on the HBV genome, suggesting the bromodomain-independent recruitment of BRD4 to the HBV genome. JQ1 also leads to the increased binding of SEC to the HBV genome, and SEC is required for JQ1-induced HBV transcription. These findings reveal a novel mechanism by which the HBV genome hijacks the host P-TEFb-containing complexes to promote its own transcription. Our findings also point out an important clinical implication, that is, the potential risk of HBV reactivation during therapy with a BRD4 inhibitor, such as JQ1 or its analogues, which are a potential treatment for acute myeloid leukemia.

scholarly journals Low Risk of Hepatitis B Virus Reactivation in HBsAg-negative/Anti-HBc–positive Carriers Receiving Rituximab for Rheumatoid Arthritis: A Retrospective Multicenter Italian Study

2016 ◽  
Vol 43 (5) ◽  
pp. 869-874 ◽  
Author(s):  
Valentina Varisco ◽  
Mauro Viganò ◽  
Alberto Batticciotto ◽  
Pietro Lampertico ◽  
Antonio Marchesoni ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hepatitis B Surface Antigen ◽  
Hbv Dna ◽  
Hbv Infection ◽  
Core Antigen ◽  
Hbv Reactivation ◽  
Serum Hbsag ◽  
B Virus

Objective.Patients with resolved hepatitis B virus (HBV) infection, i.e., hepatitis B surface antigen (HBsAg)-negative/antihepatitis B core antigen (anti-HBc)-positive, undergoing rituximab (RTX)-based chemotherapy for hematological malignancies without anti-HBV prophylaxis are at risk of HBV reactivation, but the risk in such patients receiving RTX for rheumatological disorders is not clear. We evaluated this risk in HBsAg-negative/anti-HBc–positive patients with rheumatoid arthritis (RA) undergoing RTX without prophylaxis.Methods.Thirty-three HBsAg-negative/anti-HBc–positive outpatients with RA with undetectable HBV DNA by sensitive PCR assay [73% women, median age 60 years, 85% with HBsAg antibodies (anti-HBs), 37% with antihepatitis B envelope antigen] received a median of 3 cycles of RTX (range 1–8) over 34 months (range 0–80) combined with disease-modifying antirheumatic drugs (DMARD) without prophylaxis. All underwent clinical and laboratory monitoring during and after RTX administration, including serum HBsAg and HBV DNA measurements every 6 months or whenever clinically indicated.Results.None of the patients seroreverted to HBsAg during RTX treatment, but 6/28 (21%) showed a > 50% decrease in protective anti-HBs levels, including 2 who became anti-HBs–negative. One patient (3%) who became HBV DNA-positive (44 IU/ml) after 6 months of RTX treatment was effectively rescued with lamivudine before any hepatitis flare occurred. Among the 14 patients monitored for 18 months (range 0–70) after RTX discontinuation, no HBV reactivation was observed.Conclusion.The administration of RTX + DMARD in patients with RA with resolved HBV infection leads to a negligible risk of HBV reactivation, thus suggesting that serum HBsAg and/or HBV DNA monitoring but not universal anti-HBV prophylaxis is justified.

scholarly journals New Markers in Monitoring the Reactivation of Hepatitis B Virus Infection in Immunocompromised Hosts

Viruses ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 783 ◽  
Author(s):  
Valentina Svicher ◽  
Romina Salpini ◽  
Vincenzo Malagnino ◽  
Lorenzo Piermatteo ◽  
Mohammad Alkhatib ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Immunosuppressive Treatment ◽  
Hbv Infection ◽  
Viral Reactivation ◽  
Hbv Reactivation ◽  
Therapeutic Implications ◽  
B Virus ◽  
New Biomarkers ◽  
Immunocompromised Hosts

Hepatitis B virus (HBV) persistence is at the basis of HBV reactivation as a consequence of chemotherapy and immunosuppressive treatments. The identification of early viral replication indicators and markers of effective HBV immunological control would be useful in monitoring patients who are at risk of potential viral reactivation during the course of immunosuppressive treatment. Currently, international guidelines have shared some criteria to identify patients with a low, medium or high risk of HBV reactivation; however, permanently placing a patient in a definitive category is not always easy. More often, patients move from one category to another during the course of their immunosuppressive treatment; therefore, in many cases, there are no precise indicators or tools for monitoring possible reactivation and establishing the duration and suspension of antiviral prophylaxis. Historically, the sequence of HBV antigens and antibodies and HBV DNA levels has been used to evaluate the different stages of the acute and chronic phases of an HBV infection. In the last few years, new biomarkers, such as anti-HBs and anti-HBc titres, HBV core-related antigen (HBcrAg), ultra-sensitive HBsAg evaluation and HBV RNA, have been used in patients with an HBV infection to evaluate their diagnostic and prognostic potential. The aim of this review is to evaluate the published results on the use of new infection markers in the diagnosis and monitoring of HBV reactivation over the course of immunosuppressive treatments. Moreover, the importance of viral genotypic studies was emphasized, given the diagnostic and therapeutic implications of the mutational profiles of HBsAg during the HBV reactivation phase.

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