Non-Hodgkin's Lymphomas Associated With Positive Hepatitis-C Virus Infection: A Prospective Multicentric Observational Study On Behalf Of The “Rete Ematologica Lombarda/Hematology Network Of Lombardia Region”
Authors: Rattotti Sara , Arcaini Luca , Ferretti Virginia Valeria , Rossi Andrea , Fogazzi Stefano , Greco Antonino , Baldini Luca , Balzarotti Monica , Pioltelli Pietro , Bonfichi Maurizio , Varettoni Marzia , Gotti Manuel , Farina Lucia , Ferreri Andrés J.M. , Laszlo Daniele , Morra Enrica 
Published: October 2019

Abstract

Introduction
The association between hepatitis-C virus (HCV) infection and non-Hodgkin’s lymphomas (NHL) has been demonstrated in epidemiological studies. In Lombardia, a densely populated region of northern Italy with around 10 millions of inhabitants, the prevalence of infected people is around 5%. In 2008, the “Rete Ematologica Lombarda” (Hematology Network of Lombardia region) started a prospective multicentric observational study, with the aim to collect data on virological and hematological features, on treatment and outcome of HCV-related NHL. Herein, we present the final results of this study.

Methods
Between January 2008 and December 2012, 241 consecutive adult patients (pts) with first diagnosis of NHL associated with HCV-positivity were enrolled in this prospective observational study (“Registro Lombardo dei Linfomi HCV-positivi”), approved by the Regional Administration and by IRBs of 10 Hematology Centres of Lombardia region. All pts signed a written informed consent. HIV-positive pts were excluded.

Results
Median age at lymphoma diagnosis was 69 years (yrs) (range 32-90); females were 60%. Histotypes were classified as follows: diffuse large B-cell lymphoma (DLBCL) (44%), marginal zone lymphoma (MZL) (28%), follicular lymphoma (10%), low-grade B-cell lymphoma NOS (10%), small lymphocytic lymphoma (SLL) (3%), lymphoplasmacytic lymphoma (3%), mantle cell lymphoma (1%), peripheral T-cell lymphoma NOS (1%). Ann Arbor stage was III-IV in 79% of pts, with bone marrow involvement in 47%. ECOG score was ≥ 2 in 16% of pts; 63% of pts showed at least one extranodal localization (spleen in 22%, skin in 11%, liver in 10%, Waldeyer’s ring in 5%, ocular adnexa in 3%). Virological features and treatment details are summarized in Table 1. HCV-positivity was detected before the diagnosis of NHL in 166 pts (69%) and median time between HCV detection and NHL diagnosis was 11 yrs. Serum monoclonal component (p=0.003), autoimmunity manifestations (p<0.001) and cryoglobulinemia (p=0.002) resulted more frequent in indolent NHL respect to aggressive subtypes. A shorter overall survival (OS) was observed in pts with ECOG ≥ 2 (p<0.001), hemoglobin < 12 g/dl (p=0.008), albumin < 3.5 g/dl (p=0.005), platelets < 100 x 109/L (p<0.001) and lactate dehydrogenase ≥ UNL (p=0.031). Data on first line treatment for NHL were available in 231 pts: 178 pts (77%) received chemotherapy (CHT) [plus Rituximab (R) in 122]; anthracycline contain-regimens (+/- R) were used in 121 pts (52%). Forty pts (17%) developed liver toxicity of any grade (grade III-IV in 19 pts) and 22 pts (10%) interrupted early the treatment. Fifty-three pts were treated with antiviral therapy (AT) for active HCV infection and among them 12 pts (8 MZL, 3 low-grade B-cell lymphoma NOS, 1 SLL) were treated with AT as first anti-lymphoma therapy; 8 pts obtained a virological response and a complete lymphoma response, 2 pts had a partial response (HCV-RNA negative in 1), 1 pt had neither hematological nor virological response and 1 pt is still on therapy. After a median follow-up of 32 months, 47 pts (20%) died (24 with aggressive NHL, 23 with indolent NHL): 23 due to lymphoma, 10 due to cirrhosis/hepatocarcinoma, 7 due to other solid neoplasms, 7 due to other causes.

Conclusions
In this prospective study conducted in Lombardia, a northern region of Italy, the most common histologies of HCV-associated NHL are DLBCL and MZL. In nearly 70% of pts, first detection of HCV positivity preceded the lymphoma diagnosis. A proportion of pts developed meaningful liver toxicity and/or were not able to complete the therapeutic program. In the indolent lymphomas treated with AT as first anti-lymphoma approach, virological and hematological responses are achieved in about two thirds of pts.

Disclosures:
No relevant conflicts of interest to declare.