Antiviral Agent HARVONI® for the Treatment of HCV-associated Indolent B-Cell Lymphoma

Phase 2

• Conditions: Indolent Lymphoma
• Interventions: Drug: Ledipasvir and sofosbuvir

• Registration Number: NCT03261349
• Lead Sponsor: National Taiwan University Hospital

Brief Summary

We and other investigators have revealed an association between Hepatitis C virus (HCV) seropositivity and an increased risk of developing marginal zone B-cell lymphoma (MZ), lymphoplasmacytic lymphoma (LPL, also known as Waldenström's macroglobulinemia), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). The sustained virologic response (SVR) to treatment with interferon or pegylated (Peg)IFN with ribavirin was closely associated with the regression of HCV-associated B-cell NHL (mainly MZL, and LPL).

Currently, the second-generation direct-acting antiviral agents (DAAs), such as sofosbuvir, have been shown to have a higher cure rate, less side effects, and a shorter duration of therapy for chronic HCV infection. After the approval of DAA for HCV therapy, several recent anecdotal case reports showed that indolent low-grade B-cell NHLs regressed after HCV clearance by DAAs. It is noted that the time to complete remission of these lymphomas was around 20 to 24 weeks after starting DAAs. These findings indicate that DAAs can eradicate the trigger of lymphomagenesis by curing chronic HCV infection.

Because DAAs are more potent and efficient than pegylated (Peg) interferon plus ribavirin and well-tolerated for the treatment of HCV infection, it is reasonable to use DAAs as the frontline treatment for HCV-positive patients with indolent B-cell NHL, such as MZL, LPL, and low-grade FL, who do not require immediate cytoreductive therapy. The aim of this proposal is to assess whether Harvoni® (ledipasvir and sofosbuvir) could eradicate HCV and lead to durable complete remission of these lymphomas..

Detailed Description

Although several epidemiological studies, including our study have been demonstrated the link between HCV and B-cell non-Hodgkin's lymphoma (NHL), the direct evidence of the HCV-associated-NHL remains uncertain. Direct antiviral agents (DAA) have been shown to have a higher cure rate, less side effects, and a shorter duration of therapy for chronic HCV infection. Whether DAA treatment can cure HCV-associated indolent B-cell NHL remains unclear? If yes, a direct evidence of HCV-associated lymphomagenesis will be approved. Because DAAs are more potent and efficient than pegylated (Peg) interferon plus ribavirin and well-tolerated for the treatment of HCV infection, it is reasonable to use DAAs as the frontline treatment for HCV-positive patients with indolent B-cell NHL, such as MZL, LPL, and low-grade FL, who do not require immediate cytoreductive therapy. The aim of this proposal is to assess whether Harvoni® (ledipasvir and sofosbuvir) could eradicate HCV and lead to durable complete remission of HCV-associated indolent B-cell NHL.

In the translational part, we will assess the expression pattern of BAFF-related canonical and non-canonical NF-κB signaling molecules by immunohistochemical (IHC) staining, and t(11;18)(q21;q21), and t(14;18)(q32;q21) by fluorescence in situ hybridization (FISH) in pre-treatment tumors samples of patients in prospectively predicting the antiviral responsiveness of HCV-positive indolent B-cell NHLs. The serum cytokines and chemokines, IFN-gamma, TNF-alpha, IL-4, IL-5, IL-6, IL-13 and CXCL13, BAFF level, and HCV RNA load before and after DAA treatment in HCV-associated indolent B-cell NHLs will be examined. The genotype of the HLA class II, and cloning followed by sequences of the VH region of the immunoglobulin gene derived from pre-treatment tumor samples will be assessed.

Study Timeline

• Status Verified: 2017-08
• Study First Submitted: 2017-08-09
• Study First Submitted QC: 2017-08-23
• Last Update Submitted: 2017-08-23
• Study First Posted: 2017-08-25
• Last Update Posted: 2017-08-25
• Study Start: 2017-09-01
• Primary Completion: 2020-12-31
• Study Completion: 2021-08-15

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 21

Inclusion Criteria

1. Patients older than 18 years with histologically proven diagnoses of indolent B-cell NHLs and with positive genotype 1 or 2 HCV (non-cirrhotic status) were eligible.

2. Indolent B-cell NHLs includes:

   • Low-grade marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type: known as MALT lymphoma.
   • Splenic marginal zone lymphomas (SMZL)
   • Waldenström's macroglobulinemia (WM, known as lymphoplasmacytic lymphoma) .
   • Grade 1, 2 follicular lymphoma (FL). 3 Stage I to III (modified Ann Arbor stage), and non-life threatening IV lymphoma. 4 Patients had not previously been treated with chemotherapy or immunotherapy, were eligible. 5 Patients with clinical, echographical, or radiological suspicion of lymphoma lesions were eligible.

Exclusion Criteria

1. Evidence of histologic transformation to a high-grade lymphoma (such as grade 3 and 4 follicular lymphoma, and high-grade MALT lymphoma).
2. Life-threatening disseminated lymphoma.
3. Primary gastric lesions were not eligible.
4. Prior diagnosis of neoplasm within 5 years, except cervical intraepithelial neoplasia type 1 (CIN1) or localized non-melanomatous skin cancer.
5. Evidence of clinically significant cardiac disease, as defined by history of symptomatic ventricular arrhythmias, congestive heart failure or myocardial infarction within 12 months before study entry.
6. Evidence of symptomatic central nervous system (CNS) disease.
7. Evidence of active opportunistic infections.
8. Liver cirrhosis B and C (Child-Pugh score)
9. Known HIV infection.
10. Pregnant or lactating status.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Anti-HCV (Ledipasvir and sofosbuvir)	Ledipasvir and sofosbuvir	Harvoni® (90 mg ledipasvir and 400 mg sofosbuvir) one tablet daily for 12 weeks

Primary Outcome Measures

Name	Time	Method
The complete remission rate	During the first-year, every 3 months to evaluate	The complete remission rate by using Harvoni® (ledipasvir and sofosbuvir) as the first-line line therapy.

Secondary Outcome Measures

Name	Time	Method
The durability of complete remission (disease-free interval)	Follow-up every 3 motnhs for 3 years	The lymphoma-free
The overall response rate	During the first-year, every 3 months to evaluate	Complete remission and partial remission rate
The association between HCV RNA load and response of lymphoma.	During the first-year, every 3 months to evaluate	The assessment of HCV RNA load
The toxicity of Harvoni®.	3 months	The assessment of toxicity during the first 3 months
Potential biomarkers predicting the response of Harvoni®.	3 years	Translational study