Prognostic Models to Predict Survival In Indolent and Aggressive Non-Hodgkin's Lymphomas Associated with Hepatitis C Virus Infection: a Multicenter Italian Study on 1,043 Patients.
Authors: Merli Michele , Spina Michele , Luminari Stefano , Basilico Claudia , Targhetta Clara , Visco Carlo , Levis Alessandro , Rossi Davide , D'Arco Alfonso Maria , Rigacci Luigi , Ambrosetti Achille , Musto Pellegrino , Tucci Alessandra , Chiappella Annalisa , Ferrario Andrea , Rattotti Sara , Ferretti Virginia Valeria , Pascutto Cristiana , Arcaini Luca 
Published: October 2019

Abstract
Abstract 2821
Epidemiological studies demonstrated that HCV is associated with B-cell NHL. A precise prognostication of HCV+ NHL is not available; in particular, the impact of liver toxicity on the outcome of pts treated with (immuno)-chemotherapy is not fully clarified. Aim of the present study was to analyse clinical and virological characteristics, toxicity and prognosis of a large series of indolent and aggressive HCV+ NHL. We studied 1,043 pts with HCV+ NHL diagnosed and treated from January 1993 to December 2009 in 15 italian hematologic institutions; 539 cases were aggressive NHL (522 DLBCL) and 504 indolent NHL (265 MZL). All pts were HIV negative, 3% carried HBsAg and 91% were HCV-RNA+. Thirteen out of 56 HCV-RNA negative pts cleared HCV by means of antiviral therapy before NHL diagnosis. An (immuno)-chemotherapy regimen was administered as first-line treatment in 859 pts: 537 received CHOP-like regimen (+ Rituximab 243), 66 III generation regimen, 174 alkylators, 30 purine analogues, 31 other regimens, 21 R alone. Doses of chemotherapy since first cycle were reduced in 31% of pts. A watch-and-wait policy was adopted in 82 pts, other treatments in 68 pts and anti-HCV antiviral therapy in 34 pts with indolent NHL (12 of whom obtained both a complete virologic and hematologic response). Hepatic toxicity was evaluable in 597 patients: among 347 pts with normal ALT at NHL diagnosis, 52 (15%) developed WHO hepatic toxicity ≥ grade 2; among 250 pts (42%) with abnormal ALT, 26 (11%) experienced ALT increase >3.5 times baseline value. Overall, a significant liver toxicity developed in 78 pts (13%) (15% of aggressive NHL and 10% of indolent NHL). Use of Rituximab was not associated with significant liver toxicity (p=0.4); particularly, in DLBCL, R-CHOP and CHOP showed the same rate of significant hepatic toxicity (15%, p=ns), although maximum grade of liver toxicity was registered earlier in patients treated with R-CHOP than in those treated with CHOP (before 3rd cycle respectively in 57% vs 41%, p=0.006). Planned treatment was not completed in 134 pts (29 for liver toxicity). After a median F-UP of 2.6 years, 321 pts died (24 for liver failure). 5-yrs OS was 76% for indolent NHL and 62% for DLBCL. In indolent NHL, the parameters associated with a shorter OS in univariate analysis were: elevated LDH (p<0.001), ECOG ≥2 (p<0.001), AA stage III-IV (p=0.04), age > 60 yrs (p<0.001), B symptoms (p<0.001), serum albumin <3.5 g/dl (p<0.001), Child score (p=0.003), HCV-RNA >106 UI/ml (p<0.02), no antiviral therapy at any time (p<0.001). According to a forward stepwise multivariate Cox regression analysis on OS the following parameters retained statistical significance: ECOG ≥2 (HR 2.82, p=0.005), age > 60 yrs (HR 2.11, p=0.02), AA stage III-IV (HR 2.0, p=0.04), no antiviral therapy at any time (HR 2.56, p=0.01). In DLBCL, the parameters associated with a shorter OS in univariate analysis were: elevated LDH (p<0.001), ECOG ≥2 (p<0.001), AA stage III-IV (p<0.001), age > 60 yrs (p=0.003), liver involvement by lymphoma (p=0.02), B symptoms (p<0.001), serum albumin <3.5 g/dl (p<0.001), INR >1.7 (p=0.01), Child score (p<0.001), HCV-RNA >106 UI/ml (p<0.001), HBsAg+ (p=0.01), HAI grade >9 and/or fibrosis stage >2 at liver biopsy (p=0.03). Moreover IPI, aaIPI and R-IPI were predictive for OS (p<0.001). According to a forward stepwise multivariate Cox regression analysis on OS the following parameters retained statistical significance: ECOG ≥2 (HR 3.12, p=0.001), HCV-RNA >106 UI/ml (HR 3.59, p=0.001), serum albumin <3.5 g/dl (HR 2.53, p=0.01), while other IPI factors (age, AA stage, LDH, extranodal sites) were excluded from the final model. We combined the 3 factors significantly associated to a worse OS (ECOG, albumin, HCV-RNA load) in a new HCV Prognostic Score (HPS) able to discriminate 3 categories of risk (low=0; intermediate=1; high risk ≥2 factors) (p<0.001) (Fig. 1). After adjusting by IPI in multivariate Cox regression analysis, the HPS retained prognostic effect (p<0.001), while IPI itself did not. In conclusion, a significant proportion of pts with HCV+ NHL, when treated with conventional (immuno)-chemotherapy, develops severe liver toxicity. In indolent NHL, employment of antiviral therapy at any time during lymphoma history ameliorates OS. In HCV+ DLBCL, addition of rituximab to CHOP scheme does not increase hepatic toxicity; moreover, the new score HPS performs better than IPI in discriminating different risk categories.

Disclosures:
No relevant conflicts of interest to declare.