Anti-Lymphoma Activity of Interferon-Free Antiviral Treatment in Patients with Indolent B-Cell Lymphomas Associated with Hepatitis C Virus Infection

Background: The regression of hepatitis C virus (HCV)-associated lymphoma with antiviral treatment (AT) is the strongest argument in favour of an etiological link between lymphoma, especially marginal zone lymphoma (MZL), and HCV infection. In addition, the favourable impact of AT on overall survival of these patients has been reported (Arcaini 2014, Michot 2015). Although there is a clear association across the studies between the lymphoma regression and the clearance of HCV, the direct anti-lymphoma activity of interferon (IFN) cannot be ruled out. AT is undergoing a revolution: new antiviral drugs, including direct-acting antiviral (DAA) like sofosbuvir (SOF) cure more than 90% of infections. However, data on new IFN-free regimens in HCV-associated lymphoproliferative disorders are scanty and based on clinical reports (Rossotti 2015; Sultanik 2015; Carrier 2015).

Patients and Methods: We analyzed virological and hematological response of 26 patients (pts) with indolent B-cell non-Hodgkin lymphomas (NHL) or chronic lymphocytic leukemia (CLL) and HCV infection treated with an IFN-free AT. We included the 5 cases reported in literature (Rossotti 2015; Sultanik 2015; Carrier 2015) with updated follow up.

Results: Histological, virological and hematological features are summarized in Table 1. Histology distribution was as follows: 12 splenic MZL, 6 extranodal MZL of MALT, 2 leukemic MZL, 2 nodal MZL, 2 CLL/SLL, 1 lymphoplasmacytic lymphoma (LPL) and 1 low grade NHL NOS. Cryoglobulins were present in 13 (symptomatic cryoglobulinemia in 5). HCV genotype was 1 in 15 pts, 2 in 4 pts, 3 in 3 pts and 4 in 2 pts, NA in 2 pts. Three pts previously received chemotherapy and 4 underwent IFN-based therapy before. Twenty-four pts received a SOF-based regimens (SOF + simeprevir in 10, SOF + ribavirin in 5, SOF + daclatasvir in 8, SOF + ledipasvir in 1) and 2 pts other regimens (ombitasvir + paritaprevir + ritonavir + ribavirin and faldaprevir + deleobuvir + ribavirin). In one pt with renal MZL 4 rituximab (R) doses have been added to SOF + simeprevir. Median AT duration was 12 weeks (range: 6-24). At time of present analysis, virological response is available in 21 pts while hematological response has been assessed in 20 pts. A sustained virological response has been obtained in 20 pts; hematological response has been observed only in pts with HCV clearance: in particular 8 pts (all MZL) achieved a complete response and 4 (all MZL) a partial response (comprising one treated also with R) while 5 had stable disease (response by histology is summarized in Table 1). In 7 pts response duration is +1 mo (in 2 pts), +2 mo (in 1 pt), +6 mo (in 3 pts), and +22 mo (in 1 pt); 6 pts (60%) cleared cryoglobulins after AT. After a median follow-up of 6 mo (range: 1-28), 2 pts progressed: one pt shifted to DLBCL and one pt without virological response progressed and died of lymphoma; another pt with hematological CR died of metastatic hepatocellular carcinoma 8 mo after AT. Complete data for all pts will be presented at the meeting.

Conclusions: Our study shows that a significant rate of hematological response can be achieved in HCV-associated MZL also with IFN-free AT. These data are a strong rationale for planning prospective trials with DAA in this setting.

Table 1 - Features of 26 pts with NHL associated with HCV infection treated with IFN-free regimen

and lymphoma response by histology

	N	%
Age, median (range)	26	57 (40-78)
M/F	11/15	42/58
- Marginal-zone lymphoma       Splenic       Nodal       Extranodal of MALT       Leukemic MZL - CLL - Lymphoplasmacytic lymphoma - Low-grade B-cell NHL NOS	22       12        2        6        2 2 1 1	84.7       46.2        7.7       23.1        7.7 7.7 3.8 3.8
Ann Arbor stage III-IV	19	73
B symptoms	4	15
ECOG    0    1    2    3	11 10 0 1	50 45 0 5
BM involvement	14	54
Extranodal disease	17	65
Splenic involvement	13	50
Liver involvement	5	19
Nodal disease	15	58
Bulky disease	7	27
Leukemic disease	9	35
Elevated LDH	8/22	36
Elevated b2-microglobulin	8/10	80
Albumin <3.5 g/dl	3/21	14
Serum MC	9/22	41
HCV genotype - 1 - 2 - 3 - 4	15 4 3 2	63 17 12 8
Cryoglobulins	13	50
Symptomatic cryoglobulinemia	5/13	38
HBsAg	1/25	4
Anti-HBc	4/25	16
Lymphoma response by histology - Marginal-zone lymphoma (n=17)       Splenic (n=9)       Nodal (n=1)       Extranodal of MALT (n=5)       Leukemic MZL (n=2) - CLL (n=2) - Lymphoplasmacytic lymphoma (n=1)	CR/PR/SD/Progression 8/4/2/3 4/2/2/1 1/-/-/- 2/1/-/2 1/1/-/- -/-/2/- -/-/1/-