Regression of an HCV-associated disseminated marginal zone lymphoma under IFN-free antiviral treatment

To the editor:

Hepatitis C virus (HCV) is prevalent in B-cell–associated lymphomas, including marginal zone and diffuse large B-cell lymphomas.¹  A stepwise model of lymphomagenesis induced by chronic antigenic stimulation and/or a direct pro-oncogenic effect of intracellular HCV proteins is a possible mechanism.²  Interferon-based HCV treatment may induce remission and improve prognosis of HCV-associated lymphomas.³  Whether these effects are due to HCV clearance or to an anti-proliferative effect of interferon remains unknown. We describe a patient with a complete hematologic response of an HCV-associated disseminated marginal zone lymphoma (MZL) to an interferon-free anti-HCV treatment.

A 57-year-old woman presented in June 2013 with a right breast swelling. She had received anti-D immunoglobulins in 1984. Alanine and aspartate transaminase levels were 4 and 1.5 times above the normal range, respectively. Anti-HCV antibodies and HCV RNA (genotype 3a) were detected. The patient tested negative for hepatitis B surface antigen and anti-HIV antibodies. There were no direct or indirect signs of cirrhosis. Type III mixed cryoglobulinemia and rheumatoid factor were detected.

A biopsy specimen of the breast revealed an extranodal MZL. The staging evaluation revealed cervical lymphatic, breast, and left humeral shaft involvement without bone marrow infiltration with histologic infiltrate of small-size lymphoid cells with irregular nuclei and scattered lymphoid blasts. The lymphoma cells were CD20⁺, CD79a⁺, BCL2⁺, CD5^–, CD3^–, CD10^–, BCL6^–, and cyclin D1^–. Given the putative causal link with HCV infection and the indolent course of the lymphoma, we chose to initiate an antiviral treatment aiming for a possible hemato-oncologic improvement associated with HCV clearance. During March 2014, an interferon-free antiviral treatment combining sofosbuvir (400 mg per day) and ribavirin (1000 mg per day) was started. Radiotherapy on the humeral shaft was conducted for a biopsy-induced pathologic fracture.

Within 2 weeks of treatment, the liver tests returned to normal and HCV RNA was undetectable in the serum. We replaced ribavirin with daclatasvir at week 4 of treatment and conducted a 12-week therapy of sofosbuvir and daclatasvir. Twelve weeks after the end of treatment, HCV RNA remained undetectable in the serum, defining a sustained virologic response. During the course of treatment, we observed a complete clinical and radiologic regression of breast, cervical ganglionic, and humeral shaft lesions, and the patient remained in complete remission 6 months after the end of antiviral treatment (Figure 1).

This clinical case is the first report of the efficacy of direct-acting antivirals in inducing remission of an HCV-associated disseminated MZL, and it highlights the causal relationship between HCV and MZL, given the rapid regression of lymphoma that was observed in parallel with HCV clearance under an interferon-free anti-HCV treatment.

Chronic HCV infection is a risk factor for B-cell non-Hodgkin lymphomas.¹  HCV replication associated with rheumatoid factor and/or mixed cryoglobulinemia production is believed to drive B-cell proliferation either by chronic antigenic stimulation or by pro-oncogenic activation by intracellular replication and synthesis of viral proteins.²  The hematologic benefit of HCV clearance was first demonstrated with interferon-based antiviral treatments in villous splenic lymphoma.⁴  Moreover, interferon-based antiviral treatment has been shown to improve the prognosis of HCV patients with B-cell lymphomas.³  The underlying mechanism is still debated, with a potential antiviral and/or antiproliferative effect of interferon.

Our observation supports a direct HCV-mediated antigenic stimulation and/or a pro-oncogenic stimulation of B cells in the genesis of MZL. This is supported by a recent report of a splenic MZL regression after HCV clearance under interferon-free therapy.⁵  The hematologic effect of HCV treatment seems related to the exclusive benefit of the control of HCV replication.

Research should be conducted to better define the indications of an interferon-free regimen as first-line therapy for HCV-associated lymphomas.