Lymphocyte/monocyte ratio and cycles of rituximab-containing therapy are risk factors for hepatitis B virus reactivation in patients with diffuse large B-cell lymphoma and resolved hepatitis B

Reactivation of hepatitis B virus (HBV) following rituximab (R)-containing chemotherapy for lymphoma is a major concern, and risk factors remain to be defined. We enrolled 190 patients diagnosed with diffuse large B-cell lymphoma (DLBCL) and resolved hepatitis B, receiving first-line R-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone)-based regimens. Twenty-seven patients (14.2%) developed HBV reactivation during a median follow-up of 23.6 months. Two independent risk factors were identified: cycles of rituximab > 8 (hazard ratio [HR], 2.797; 95% confidence interval [CI], 1.184–6.612) and lymphocyte/monocyte ratio (LMR) < 2.50 (HR, 2.733; 95% CI, 1.122–6.657). Two-year overall survival in patients with or without HBV reactivation was 53.8% vs. 77.6% (p = 0.025). Regarding the negative impact on clinical outcome, patients at “super high risk” of HBV reactivation, including those receiving more than eight cycles of R and having low LMR at diagnosis, may warrant first priority for antiviral prophylaxis.

[1]  A. Lok,et al.  Hepatitis B virus infection , 2014, The Lancet.

[2]  Pei-Jer Chen,et al.  Chemotherapy‐induced hepatitis B reactivation in lymphoma patients with resolved HBV infection: A prospective study , 2014, Hepatology.

[3]  A. Lok,et al.  Management of patients with hepatitis B who require immunosuppressive therapy , 2014, Nature Reviews Gastroenterology &Hepatology.

[4]  Y. Ishigatsubo,et al.  Peripheral blood absolute lymphocyte/monocyte ratio as a useful prognostic factor in diffuse large B‐cell lymphoma in the rituximab era , 2014, European journal of haematology.

[5]  Shou-Dong Lee,et al.  Reply to S. Kusumoto et al. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  Chiun Hsu,et al.  Hepatitis B virus reactivation in B-cell lymphoma patients treated with rituximab: analysis from the Asia Lymphoma Study Group. , 2013, European journal of cancer.

[7]  M. Nojima,et al.  Reactivation of hepatitis B virus in patients with undetectable HBsAg undergoing chemotherapy for malignant lymphoma or multiple myeloma , 2013, Journal of medical virology.

[8]  Shou-Dong Lee,et al.  Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  Jianmin Yang,et al.  Concurrent Infection of Hepatitis B Virus Negatively Affects the Clinical Outcome and Prognosis of Patients with Non-Hodgkin’s Lymphoma after Chemotherapy , 2013, PloS one.

[10]  C. Tzeng,et al.  Comparison of prognostic models for patients with diffuse large B-cell lymphoma in the rituximab era , 2013, Annals of Hematology.

[11]  C. Tzeng,et al.  Diminishing prognostic role of preexisting diabetes mellitus for patients with diffuse large B-cell lymphoma in the rituximab era , 2013, Annals of Hematology.

[12]  David Cunningham,et al.  Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles , 2013, The Lancet.

[13]  C. Tzeng,et al.  Absolute lymphocyte count predicts response to rituximab‐containing salvage treatment for relapsed/refractory B‐cell non‐Hodgkin's lymphoma with prior rituximab exposure , 2013, Journal of the Chinese Medical Association : JCMA.

[14]  C. Tzeng,et al.  Patients with diffuse large B cell lymphoma in partial response or stable disease after first-line R-CHOP: the prognostic value of the absolute lymphocyte count and impact of autologous stem cell transplantation , 2012, Annals of Hematology.

[15]  Wen-Qi Jiang,et al.  Blood Lymphocyte-to-Monocyte Ratio Identifies High-Risk Patients in Diffuse Large B-Cell Lymphoma Treated with R-CHOP , 2012, PloS one.

[16]  Y. Xie,et al.  Comparison of entecavir and lamivudine in preventing hepatitis B reactivation in lymphoma patients during chemotherapy , 2011, Journal of viral hepatitis.

[17]  Z. Xia,et al.  Genomewide microRNA down‐regulation as a negative feedback mechanism in the early phases of liver regeneration , 2011, Hepatology.

[18]  C. Tzeng,et al.  Low absolute lymphocyte count and addition of rituximab confer high risk for interstitial pneumonia in patients with diffuse large B-cell lymphoma , 2011, Annals of Hematology.

[19]  S. Belknap,et al.  Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[20]  S. Kimura,et al.  Reactivation of hepatitis B virus after rituximab‐containing treatment in patients with CD20‐positive B‐cell lymphoma , 2010, Cancer.

[21]  J. Gea-Banacloche.  Rituximab-associated infections. , 2010, Seminars in hematology.

[22]  J. Byrd,et al.  NCCN Clinical Practice Guidelines in Oncology: non-Hodgkin's lymphomas. , 2010, Journal of the National Comprehensive Cancer Network : JNCCN.

[23]  Chien-Hung Chen,et al.  Reactivation of hepatitis B virus following rituximab-based regimens: a serious complication in both HBsAg-positive and HBsAg-negative patients , 2010, Annals of Hematology.

[24]  G. Salles,et al.  Retreatment with rituximab in 178 patients with relapsed and refractory B-cell lymphomas: a single institution case control study , 2010, Leukemia & lymphoma.

[25]  N. Tsuneyoshi,et al.  Retrospective and prospective studies of hepatitis B virus reactivation in malignant lymphoma with occult HBV carrier. , 2009, Annals of oncology : official journal of the European Society for Medical Oncology.

[26]  S. Lim,et al.  Hepatitis B virus reactivation and role of antiviral prophylaxis in lymphoma patients with past hepatitis B virus infection who are receiving chemoimmunotherapy , 2009, Cancer.

[27]  Dong Wang,et al.  Relationship between serum HBV DNA level and HBV-specific, nonspecific cytotoxic T lymphocytes and natural killer cells in patients with chronic hepatitis B. , 2009, Chinese medical journal.

[28]  Shou-Dong Lee,et al.  Fatal reactivation of hepatitis B virus in a patient who was hepatitis B surface antigen negative and core antibody positive before receiving chemotherapy for non-Hodgkin lymphoma. , 2009, Journal of clinical gastroenterology.

[29]  Edwin P Hui,et al.  Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  Alejandro Martín,et al.  R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study , 2008, Haematologica.

[31]  E. Angelucci,et al.  Hepatitis B virus-related liver disease in isolated anti-hepatitis B-core positive lymphoma patients receiving chemo- or chemo-immune therapy , 2008, Haematologica.

[32]  Y. Liaw,et al.  Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update , 2008, Hepatology international.

[33]  Markus Loeffler,et al.  Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). , 2008, The Lancet. Oncology.

[34]  R. Gascoyne,et al.  Clinical Trials and Observations , 2007 .

[35]  Randy D Gascoyne,et al.  Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  J. Luk,et al.  Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy. , 2006, Gastroenterology.

[37]  Antonio Bertoletti,et al.  The immune response during hepatitis B virus infection. , 2006, The Journal of general virology.

[38]  A. Zelenetz,et al.  Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. , 2004, Blood.

[39]  B. E. C. Oiffier,et al.  CHOP Chemotherapy plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma , 2002 .

[40]  R. Levy,et al.  Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  Ding‐Shinn Chen,et al.  Hepatitis B Virus Infection , 2007 .

[42]  Reactivation of Hepatitis-B Virus , 1977, The Lancet.

[43]  R. Ueda,et al.  Reactivation of hepatitis B virus following rituximab-plus-steroid combination chemotherapy , 2010, Journal of Gastroenterology.

[44]  P. Pumpens,et al.  Priming of cytotoxic T cell responses to exogenous hepatitis B virus core antigen is B cell dependent. , 2003, The Journal of general virology.