Hepatitis C Virus and Hepatitis B Virus in Indolent Lymphomas: Prospective Data from the International Observational NF10 Study

Background: Hepatitis C virus (HCV) chronic infection has been unequivocally associated with a wide spectrum of B-cell lymphoproliferative disorders, ranging from mixed cryoglobulinemia to overt B-cell non-Hodgkin's lymphomas (B-NHL), including both indolent, especially marginal zone lymphomas (MZL), and diffuse large B-cell lymphomas (DLBCL). HCV has been estimated as associated with up to 20% of B-NHL cases in Italy, 14% in Japan and 11% in United States, with suggested decrease of the actual incidence in last decades. Hepatitis B virus (HBV) infection accounts for chronic hepatitis and cirrhosis. HBV is also recognized as oncogenic, leading to increased risks of B-NHL (Odds ratio around 2) in addition to hepatocellular carcinoma. Moreover, although the role for antivirals to prevent HBV reactivation is well known in HBV+ patients (pts) receiving chemo-immunotherapy, their influence on outcome is undetermined. Data on HCV and HBV role in lymphomas are based on retrospective epidemiological studies; here we present the HCV and HBV data in the NF10 observational multicentric prospective international study promoted by Fondazione Italiana Linfomi (FIL). Methods: The NF10 Project was started in 2010 as a prospective registry specifically conceived to investigate the prognosis of Indolent Non-Follicular B-Cell Lymphomas (INFL). All pts with a histologic confirmed diagnosis of INFL were eligible with no exclusion criteria. Pts were followed based on local institution guidelines, and progression-free survival (PFS) was defined as the time from the date of diagnosis to progression, re-treatment, or death due to any cause. Results: Between July 2010 and July 2018, 1340 INFL cases had been registered by 65 centres in Europe and South America. HCV serology was available for 1267 (MZLs 768, 327 ENMZL, 255 SMZL, 81 NMZL, 105 disseminated MZL) and was positive in 6.6% ranging from 2% in SLL to 12% in in NMZL and disseminated MZL. Age > 70 years (yrs), female sex, absolute lymphocyte count (ALC) < 1 x 109/L, MZL histology and early yrs of registration (2010-2016) were associated with higher rates of positive HCV serology; in multivariate analysis, age, female sex, were independently correlated with HCV infection, while MZL subtypes had only a trend towards higher positivity rate vs non MZLs. 5-y PFS was 71% for the entire series and was 71% for HCV- and 66% for HCV+ (HR 1). No difference in OS was observed. HBV status was available in 1232 cases and was considered positive if HBsAg+ or HBcAb+; MZLs were 752 (320 ENMZL, 250 SMZL, 81 NMZL, 101 disseminated MZL). Overall, HBV positivity was detected in 16.4% (2.2% HbsAg+ and 14.2% HBcAb+) ranging from 10% in CD5- NHL NOS to 21% in SMZL. LDH > Upper Normal Limiti (UNL), hemoglobin (Hb) < 12 g/dl, need of treatment and early years of registration (2010-16) were associated with higher HBV+ rates; MZL histology was of borderline significance. Considering HbsAg+, in multivariable multinomial logistic regression analysis, the Relative Risk Ratio (RRR) was higher for age < 70 yrs, males, LDH > UNL and MZL histology (borderline significance). Considering HBcAb+, in multivariable analysis RRR was significant only for Hb < 12 g/dl. 5-y PFS was 71% for entire series and was 73% for HBV-, and 61% for HBV+ (p = 0.01) (59% for HBsAg+ and 62% for HBcAb+ cases). In multivariate analysis, considering the entire series, PFS was negatively associated with HBV+, age > 70 yrs, B symptoms, LDH > UNL, PS > 1, Hb < 12 g/dl, platelets < 100.000/mmc, and non-MZL histology. 5-y OS was 86% for the entire series and was 87% for HBV- and 83% for HBV+ (p = 0.013) (79% for HBsAg+ and 84% for HBcAb+ cases). Conclusions: With this NF10 sub-study we provide prospective data about HCV and HBV positivity in INFL. Regarding HCV, we observed higher prevalence of HCV+ in nodal and disseminated MZL without any effect on survival. Conversely, HBV positivity was associated with poorer outcomes. Finally, the observation of higher positivity rates among pts registered in the earlier phase of enrollment, suggests a declining role of the two