Incidence of Hepatitis B Reactivation in Non-Hodgkin's Lymphoma Patients

Study Description

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Brief Summary:

This is a single-arm study. Key eligibility criteria include (1) newly diagnosed, diffuse large B-cell or follicular cell non-Hodgkin's lymphoma; (2) negative test for hepatitis B surface antigen (HBsAg) and positive for antibody to hepatitis B core antigen (anti-HBc); (3) adequate bone marrow, liver, and kidney function. All eligible patients will receive rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy according to current treatment guidelines. The primary endpoint of this study is the incidence of hepatitis B virus (HBV) reactivation, defined by a greater than 10-fold increase, compared with previous nadir levels, of HBV DNA during rituximab-CHOP chemotherapy and within 1 year after completion of the last course of rituximab-CHOP chemotherapy. Patients who have HBV reactivation during the study period will receive free entecavir treatment, one of the standard treatment for chronic hepatitis B, for 48 weeks. The secondary endpoints include the incidence of hepatitis flare, defined as a greater than 3 fold increase of serum alanine aminotransferase (ALT) level that exceeded 100 IU/L, and the efficacy and safety of rituximab-CHOP chemotherapy.

In the T1408 study we enrolled patients with newly diagnosed lymphoma who were HBsAg (-) and anti-HBc (+) and were to receive rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-based chemotherapy. Key findings of this study included (1) HBV reactivation, defined as a greater than 10-fold increase in HBV DNA compared with previous nadir levels, occurred to 10-20% of patients, depending on the sensitivity of the HBV DNA tests; (2) no HBV-related death with the prompt anti-viral therapy upon HBV reactivation; (3) patients with HBV reactivation were associated with poorer progression-free survival and overall survival; (4) serological breakthrough (i.e., re-appearance of HBsAg) is an important predictor of HBV-related hepatitis flare.

In this amendment we will enroll more patients to clarify the above findings: (1) the association between HBV reactivation and survival; (2) diagnostic value of quantitative HBsAg and anti HBc tests on HBV reactivation; (3) whether host factors (DNA polymorphism) may help predict HBV reactivation. A larger patient cohort is needed to identify (1) baseline features that may help predict HBV reactivation, and (2) on-treatment features that may help timely anti-viral therapy.

Condition or disease	Intervention/treatment	Phase
Non-Hodgkin's Lymphoma	Drug: entecavir	Not Applicable

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Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	202 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Prevention
Official Title:	Incidence of Hepatitis B Reactivation in Non-Hodgkin's Lymphoma Patients Who Receive Rituximab-containing Chemotherapy and Are Previously Infected With Hepatitis B Virus
Study Start Date :	June 2009
Estimated Primary Completion Date :	December 2017
Estimated Study Completion Date :	December 2017

Arms and Interventions

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Arm

Intervention/treatment

Experimental: entecavir; All eligible patients will receive rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy according to current treatment guidelines.

Drug: entecavir; All eligible patients will receive rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy according to current treatment guidelines. The primary endpoint of this study is the incidence of HBV reactivation, defined by a greater than 10-fold increase, compared with previous nadir levels, of HBV DNA during rituximab-CHOP chemotherapy and within 1 year after completion of the last course of rituximab-CHOP chemotherapy. Patients who have HBV reactivation during the study period will receive free entecavir treatment, one of the standard treatment for chronic hepatitis B, for 48 weeks.

Outcome Measures

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Primary Outcome Measures :

1. enroll 150 patients [ Time Frame: 3 years ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 75 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Histologically proven diffuse large B-cell or follicular B-cell non-Hodgkin's lymphoma, for which chemotherapy with rituximab-CHOP chemotherapy is considered treatment-of-choice.
2. Evidence of 'resolved' HBV infection. Eligible subjects must be negative for serum HBV surface antigen (HBsAg) and positive for anti-core antibody (anti-HBc).
3. Age >18 years.
4. Performance status with ECOG score 0-2.
5. No previous chemotherapy and radiotherapy, no concurrent glucocorticoid use.
6. Absolute neutrophil count (ANC) > 1,500/mm3, platelet > 100,000/mm3 in the peripheral blood.
7. Total bilirubin ＜ 2.5 mg/dl. Alanine aminotransferase (ALT) ＜ 3 times UNL (upper limits of normal range).
8. Serum creatinine ＜ 1.5 mg/dl. 9.10.Life expectancy 3 months.

11.Signed informed consent.

Exclusion Criteria:

1. Pregnant or breast-feeding women.
2. Patients with history of brain metastasis or CNS involvement.
3. Child's class B or C in patients with liver cirrhosis.
4. Impaired cardiac function with NYHA (New York Heart Association) classification Gr II.
5. History of other liver diseases such as hepatitis C, D, autoimmune hepatitis, primary biliary cirrhosis, Wilsons' disease.
6. Other major systemic disease, such as active infection, significant cardiac disease, neurological deficit or psychiatric disorder, that the investigators consider to be significant risk.
7. Any concomitant cancer treatment.
8. Known hypersensitivity of any of the study drugs (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone).
9. Known human immunodeficiency virus (HIV) infection.

Contacts and Locations

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Locations

Taiwan
National Taiwan University Hospital
Taipei, Taiwan

Sponsors and Collaborators

National Health Research Institutes, Taiwan

National Taiwan University Hospital

Mackay Memorial Hospital

China Medical University Hospital

Chi Mei Medical Hospital

Taichung Veterans General Hospital

Kaohsiung Veterans General Hospital.

Kaohsiung Medical University

Investigators

Study Director:	Tsang-Wu Liu, Ph.D	National Health Research Institutes, Taiwan

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	National Health Research Institutes, Taiwan
ClinicalTrials.gov Identifier:	NCT00931229 History of Changes
Other Study ID Numbers:	T1408
First Posted:	July 2, 2009
Last Update Posted:	November 9, 2016
Last Verified:	December 2011
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by National Health Research Institutes, Taiwan:

hepatitis B reactivation

Additional relevant MeSH terms:

Lymphoma; Hepatitis; Lymphoma, Non-Hodgkin; Hepatitis B; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Liver Diseases; Digestive System Diseases	Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Rituximab; Entecavir; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antiviral Agents; Anti-Infective Agents