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

Philippe Sultanik, Caroline Klotz, Philippe Brault, Stanislas Pol and Vincent Mallet

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).

Figure 1

Representative pictures from the positron emission tomography scanner before and after interferon-free anti-HCV treatment. Left panels: photos before antiviral treatment of (A) infiltrated cervical lymph node, (B) left humeral shaft lesion, and (C) right breast lesion. Right panels: photos after sustained virologic response of (D) same cervical area, (E) left humeral shaft, and (F) right breast. White stars indicate the localization of the lymphoma.

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.


Contribution: P.S. and C.K. collected patient data and wrote the manuscript; P.B. and S.P. reviewed the manuscript; and V.M. reviewed and edited the manuscript.

Conflict-of-interest disclosure: S.P. is a speaker for GlaxoSmithKline (GSK), Bristol-Myers Squibb (BMS), Boehringer Ingelheim, Janssen, Gilead, Roche, Merck (MSD), Sanofi, Novartis, Vertex, and AbbVie; received grants from BMS, Gilead, Roche, and MSD; and is a board member for GSK, BMS, Boehringer Ingelheim, Janssen, Gilead, Roche, MSD, Sanofi, Novartis, Vertex, and AbbVie. V.M. is a scientific advisor or consultant for Gilead, AbbVie, MSD, Johnson & Johnson (JJ)/Janssen-Cilag, BMS, and Pfizer and received payment for lectures, including service on speakers' bureaus, from AbbVie, BMS, Gilead, JJ/Janssen-Cilag, Novartis, Roche, and Astellas. The remaining authors declare no competing financial interests.

Correspondence: Philippe Sultanik, Département d'Hépatologie, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Université Paris Descartes, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; e-mail: philippe.sultanik{at}