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Central nervous system (CNS) relapse of mantle cell lymphoma (MCL) is a rare phenomenon with dismal prognosis, where no standard therapy exists. Since the covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in relapsed/refractory MCL and penetrates the blood–brain barrier (BBB), on behalf of Fondazione Italiana Linfomi and European Mantle Cell Lymphoma Network we performed a multicenter retrospective international study to investigate the outcomes of patients treated with ibrutinib or chemoimmunotherapy. In this observational study, we recruited patients with MCL with CNS involvement at relapse who received CNS-directed therapy between 2000 and 2019. The primary objective was to compare the overall survival (OS) of patients treated with ibrutinib or BBB crossing chemotherapy. A propensity score based on a multivariable binary regression model was applied to balance treatment cohorts. Eighty-eight patients were included. The median age at study entry was 65 years (range, 39-87), 76% were males, and the median time from lymphoma diagnosis to CNS relapse was 16 months (range, 1-122). Patients were treated with ibrutinib (n = 29, ibrutinib cohort), BBB crossing chemotherapy (ie, high-dose methotrexate ± cytarabine; n = 29, BBB cohort), or miscellaneous treatments (n = 30, other therapy cohort). Both median OS (16.8 vs 4.4 months; P = .007) and median progression-free survival (PFS) (13.1 vs 3.0 months; P = .009) were superior in the ibrutinib cohort compared with the BBB cohort. Multivariable Cox regression model revealed that ibrutinib therapeutic choice was the strongest independent favorable predictive factor for both OS (hazard ratio [HR], 6.8; 95% confidence interval [CI], 2.2-21.3; P < .001) and PFS (HR, 4.6; 95% CI, 1.7-12.5; P = .002), followed by CNS progression of disease (POD) >24 months from first MCL diagnosis (HR for death, 2.4; 95% CI, 1.1-5.3; P = .026; HR for death or progression, 2.3; 95% CI, 1.1-4.6; P = .023). The addition of intrathecal (IT) chemotherapy to systemic CNS-directed therapy was not associated with superior OS (P = .502) as the morphological variant (classical vs others, P = .118). Ibrutinib was associated with superior survival compared with BBB-penetrating chemotherapy in patients with CNS relapse of MCL and should be considered as a therapeutic option.

The combination of rituximab, bendamustine, and low dose cytarabine (R-BAC) has been studied in a phase 2 prospective multicenter study from the Fondazione Italiana Linfomi (FIL RBAC500). In 57 previously untreated elderly patients with mantle cell lymphoma (MCL), R-BAC was associated with complete remission rate of 91%, and 2-years progression free survival (PFS) of 81% (95%CI 68-89). Here, we report the long-term survival outcome, late toxicities, and results of minimal residual disease (MRD) evaluation. After a median follow-up of 86 months (57-107), the median overall survival (OS) and progression-free survival (PFS) were not reached. The 7-years PFS and OS rates were 55% (95%CI 41-67), and 63% (95%CI 49-74), respectively. Responding patients (n=53) had a 7-years PFS of 59% (95%CI 44-71), with no relapse or progression registered after the 6th year. At multivariate analysis blastoid/pleomorphic morphology was the strongest adverse predictive factor for PFS (p=0.04). Patients with an end of treatment negative minimal residual disease (MRD) had better, but not significant, outcomes for both PFS and OS than MRD positive patients (p=0,148 and p=0,162, respectively). There was no signal of late toxicity or increase of secondary malignancies during the prolonged follow-up. In conclusion, R-BAC, which was not followed by maintenance therapy, showed sustained efficacy over time in elderly patients with MCL. Survival outcomes compare favorably with other immuno-chemotherapy regimens (with or without maintenance), including combinations of BTK-inhibitors upfront.

Letermovir (LTV), recently approved for the prophylaxis of human cytomegalovirus (HCMV) reactivation after hematopoietic stem cell transplantation (HSCT), has been shown to decrease the rate of infection in the first months post-transplantation. The aim of this study was to evaluate the impact of LTV prophylaxis on immune reconstitution and late-onset infection. We studied HCMV infection and HCMV-specific T cell reconstitution in 2 matched groups of HSCT recipients, those treated with LTV prophylaxis (n = 30; LTV group) and those receiving preemptive therapy (n = 31; PET group). We analyzed the rates of graft-versus-host disease (GVHD), neutropenia, baseline disease recurrence, and overall survival in the 2 groups. Clinically significant infections necessitating preemptive therapy showed a similar rate in the 2 groups (PET: 21 of 31 [68%]; LTV: 17 of 30 [57%]; P = .434) but occurred significantly later (after prophylaxis discontinuation) in the LTV group. There was no between-group difference in peak HCMV DNAemia level (P = .232). HCMV-specific T cell recovery was delayed by approximately 100 days in the LTV group. HCMV-specific CD4 and CD8 T cell counts were significantly lower in the LTV group at days 120 to 360 and days 90 to 120, respectively. A lower rate of chronic GVHD (P = .024) was seen in the LTV group. Time to engraftment, rate of disease relapse, and 1-year survival were not different between the 2 groups, whereas trends toward a lower rate of neutropenia (P = .124) and a higher rate of acute GVHD grade III-IV (P = .103) were observed in the LTV group. Because LTV prophylaxis delays HCMV infection and HCMV-specific immune reconstitution, immunologic and virologic monitoring should be implemented after discontinuation of prophylaxis. The potential effect of LTV prophylaxis in reducing chronic GVHD should be evaluated in prospective studies.

Patients with mantle cell lymphoma (MCL) that fail induction treatment represent a difficult-to-treat population, where no standard therapy exists. We evaluated outcomes in patients with first relapsed-refractory (r/r) MCL after upfront high dose cytarabine including standard regimens. Overall survival (OS-2) and progression-free survival (PFS-2) were estimated from the time of salvage therapy. The previously described threshold of 24 months was used to define patients as early- or late-progressors (POD). Overall, 261 r/r MCL patients were included. Second-line regimens consisted of rituximab-bendamustine (R-B, 21%), R-B and cytarabine (R-BAC, 29%), ibrutinib (19%), and others (31%). The four groups were balanced in terms of clinicopathological features. Adjusting for age and early/late-POD, patients treated with R-BAC had significantly higher complete remission (63%) than comparators. Overall, Ibrutinib and R-BAC were associated with improved median PFS-2 [24 and 25 months, respectively], compared to R-B (13) or others (7). In patients with early-POD (n = 127), ibrutinib was associated with inferior risk of death than comparators (HR 2.41 for R-B, 2.17 for others, 2.78 for R-BAC). In patients with late-POD (n = 134), no significant differences were observed between ibrutinib and bendamustine-based treatments. Ibrutinib was associated with improved outcome in early-POD patients.

The role of allogeneic stem cell transplantation (allo-SCT) in mantle cell lymphoma (MCL) is uncertain, even more in the era of bruton's tyrosine kinase inhibitors (BTKi) and chimeric antigen receptor T-cells. We retrospectively analyzed 55 patients who underwent allo-SCT for MCL relapsed or refractory (r/r) after rituximab and high-dose cytarabine within the MANTLE-FIRST project. With a median follow-up of 3.7 years, non-relapse mortality (NRM), progression-free survival, and overall survival were 23%, 53%, and 56%, respectively. NRM was significantly higher in the case of acute graft-versus-host disease, > 2 prior lines of therapy, age > 60 years. The outcome was similar for patients with early (≤24 months) and late progression of disease. The use of BTKi as a bridge to allo-SCT did not increase the toxicity and allowed a good control of disease. Our real-life experience confirms that allo-SCT still represents an option in MCL patients, especially if young and early-relapsed.

The R-BAC regimen is considered among standard first-line treatment for elderly fit patients with mantle cell lymphoma (MCL). In the previous R-BAC500 FIL trial, patients with the blastoid variant and/or high Ki67 proliferative index (High Risk - HR-) had a significantly higher risk of progression (2-years PFS of 40%), as compared to classical histologies and low proliferative index (Low Risk -LR-). When treated with R-BAC, LR patients had excellent outcome (median PFS not reached after 7 years), although no maintenance therapy was delivered. For this reason we designed a phase 2 trial that enrolled patients from 35 centers of the Fondazione Italiana Linfomi (FIL). At study entry, patients were centrally reviewed and stratified as "low risk (LR)", or "high risk (HR)", depending on morphology (blastoid versus others), Ki67 expression (≥30% versus others), TP53 mutation/TP53 deletions (present versus not). Patients with any of the three risk factors were classified as HR. The primary endpoint was 2-years progression-free survival (PFS) for the HR patients. Patients had to be aged ≥65 years and fit according to the geriatric CGA assessment, or age ≤64 years if not eliglible to high-dose chemotherapy plus transplantation. Asymptomatic patients with non-nodal disease were excluded. Treatment consisted of 6 cycles of R-BAC (rituximab 375 mg/m2 d 1; bendamustine 70 mg/m2 d 1,2; cytarabine 500 mg/m2 d 1,2,3) for LR patients. HR patients received abbreviated induction with a maximum of 4 R-BAC followed by consolidation (4 months, 800 mg/d), and maintenance (20 months, 400 mg/d) with venetoclax. First patient was included on the 3rd of september, 2018, and last patient on the 20th of july, 2021. Overall, 140 patients were enrolled, of whom 52 were HR (37%). Median age was 72 (range 57-79), and 75% were males. The prevalence of TP53 mutations and deletions in the whole series was 21%, and 13%, respectively; Ki67 was ≥30% in 24%, and the blastoid variant was diagnosed in 9%. Demographic characteristics of HR versus LR patients (127 patients with available data at the present time) are reported in Table 1A. Median follow-up was 9 months (range 0-34). The two groups (HR and LR) had similar age, gender, and MIPI, but differed for LDH, and SUVmax at diagnosis, both being significantly more elevated in the HR group. The VR-BAC trial represents the first prospective study that stratified patients with MCL to different frontline treatments according to centralized on-time evaluation of the risk profile. We have shown that almost 40% of elderly patients with MCL in need of treatment have HR features. Data on tolerance, and tumor response will be presented at the meeting. Figure 1 Figure 1. Disclosures Tisi: GILEAD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BWS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Zilioli: Roche, Italfarmaco: Consultancy, Honoraria; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Takeda: Other: travel expenses, accommodation; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau. Corradini: AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Honoraria; BMS: Other: Travel and accommodation; Novartis; Gilead; Celgene: Consultancy, Other: Travel and accommodations; Amgen; Takeda; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations; KiowaKirin; Incyte; Daiichi Sankyo; Janssen; F. Hoffman-La Roche; Kite; Servier: Consultancy; Sanofi: Consultancy, Honoraria; Incyte: Consultancy; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Consultancy; Novartis, Janssen, Celgene, BMS, Takeda, Gilead/Kite, Amgen, AbbVie: Other: travel and accomodations. Musuraca: janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Puccini: Takeda: Membership on an entity's Board of Directors or advisory committees. Cavallo: Servier: Speakers Bureau; ROCHE: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau. Merli: EUSA Pharma: Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; MSD: Membership on an entity's Board of Directors or advisory committees; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Celgene: Other: Travel, Accomodations, Expenses. Ferreri: PletixaPharm: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Beigene: Research Funding; Hutchison Medipharma: Research Funding; ADC Therapeutics: Research Funding; Adienne: Membership on an entity's Board of Directors or advisory committees; Genmab: Research Funding; Amgen: Research Funding; x Incyte: Membership on an entity's Board of Directors or advisory committees; Ospedale San Raffaele srl: Patents & Royalties; Pfizer: Research Funding. Santoro: AstraZeneca: Speakers Bureau; AbbVie: Speakers Bureau; Amgen: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; Sandoz: Speakers Bureau; Eli-Lilly: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; Sanofi: Consultancy; Arqule: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zinzani: KYOWA KIRIN: Other, Speakers Bureau; SERVIER: Other: Advisory board, Speakers Bureau; SANDOZ: Other: Advisory board; TG Therapeutics: Other: Advisory board, Speakers Bureau; ROCHE: Other, Speakers Bureau; BMS: Other: Advisory board, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; MSD: Consultancy, Other: Advisory board, Speakers Bureau; NOVARTIS: Consultancy, Other, Speakers Bureau; EUSAPHARMA: Consultancy, Other, Speakers Bureau; Beigene: Other, Speakers Bureau; ADC Therap.: Other; Incyte: Other, Speakers Bureau; JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau. OffLabel Disclosure: Venetoclax is off-label in Italy in mantle cell lymphoma

The activity of the combination of rituximab, bendamustine, and low dose cytarabine (R-BAC) was evaluated in a phase 2 multicentre trial from the Fondazione Italiana Linfomi (FIL RBAC500) in previously untreated patients with mantle cell lymphoma (MCL) who were not eligible to stem cell transplant. Maintenance treatment was not planned after induction therapy, and no patient in the study received rituximab maintenance. Fifty-seven patients (median age 71 years, range 61-79) were recruited and treated with 4 to 6 cycles between 2012 and 2014. Despite some concern in terms of hematological toxicity, the R-BAC regimen was associated with high complete remission (CR) rate (91%), 2-years overall survival (OS) of 86% (74-93), and 2-years progression free survival (PFS) of 81% (68-89). Here, we present long-term survival outcomes. After 7 years of median follow-up (86 months, range 57-107), the median OS and PFS for all patients were not reached (Figure 1A and 1B). The 7-years PFS and OS rates were 56% (95%CI 41-67) and 63% (95%CI 46-72), respectively. Patients who achieved CR (n=53) had a 7 years PFS of 59% (95% CI 44-71), with the curve that appears to plateau after 6 years. Adverse predictive factors affecting PFS were blastoid morphology (p 30% (p Eight patients (14%) developed a secondary neoplasia: 1 parotid heteroplasia, 1 parotid nodular hyperplasia, 1 prostate cancer, 1 bladder cancer, 1 larynx, 1 thyroid cancer, 1 lung cancer and 1 secondary acute myeloid leukemia. Among the 25 relapsed patients, 8 did not receive any other treatment. Six had Ibrutinib monotherapy as second line, of whom 4 responded (3 are still in CR), 4 had CHOP or CHOP-like regimens with only partial responses. As per protocol, 31 patients with molecular marker at diagnosis and available samples were followed-up for minimal residual disease (MRD) with ASO-droplet digital polymerase chain reaction (D-PCR). Patients with MRD persistence at the end of induction, either in peripheral blood or bone marrow, had significantly worse 7 years-PFS (p In conclusion, in elderly patients with newly diagnosed MCL, R-BAC showed sustained efficacy over time, which compared favorably with any other reported immuno-chemotherapy regimen (with or without maintenance) in similar populations. With a median OS exceeding 60% after 7-years this regimen has significantly impacted on the life-expectancy of elderly patients with MCL. Figure 1 Figure 1. Disclosures Tisi: Incyte: Membership on an entity's Board of Directors or advisory committees; BWS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nassi: Takeda: Consultancy; Incyte: Consultancy; Kyowa Kirin: Consultancy; Roche: Consultancy. Ferrero: Gilead: Research Funding, Speakers Bureau; Morphosys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Clinigen: Membership on an entity's Board of Directors or advisory committees. Zilioli: Takeda: Other: travel expenses, accommodation; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Roche, Italfarmaco: Consultancy, Honoraria; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau. Merli: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; MSD: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; EUSA Pharma: Other: Travel, Accomodations, Expenses; Celgene: Other: Travel, Accomodations, Expenses.

Background: Hepatitis C virus (HCV) chronic infection has been associated with increased risk of non-Hodgkin lymphoma (NHL) in people living with human immunodeficiency virus (HIV) as well as with a trend of inferior overall survival (OS) in HIV-associated NHL in the modern antiretroviral therapy (ART) era (Besson 2020). The recent introduction of interferon (IFN)-free direct-acting antivirals (DAAs) led to the achievement of sustained virologic response (SVR) in nearly all treated patients (pts) with negligible toxicity in all settings, including HIV/HCV coinfected pts, in which, however, careful attention to interactions with ART is required. We recently showed that DAAs' administration after immuno-chemotherapy (I-CT) may improve long-term outcome in HIV-negative HCV-associated diffuse large B-cell lymphomas (DLBCL) pts (Merli 2019), however, only scant data have been reported so far about the use of DAAs in HIV/HCV coinfected NHL pts. METHODS: We retrospectively collected clinical and virological features, treatments and outcome data of all consecutive pts with NHL and HIV/HCV co-infection, diagnosed and treated at 13 Italian centers between 2005 and 2021, with a special focus on pts affected by DLBCL and treated with DAAs. Only pts who received ART were included. The primary endpoints were SVR rate after DAAs and 2-year OS in HIV/HCV-positive NHL pts. RESULTS: Overall, we collected data of 74 HIV/HCV coinfected pts with NHL (69 males, 93%), including 52 DLBCL, 13 Burkitt lymphoma (BL), 5 plasmablastic lymphoma (PL), 1 anaplastic large-cell ALK negative, 1 T lymphoblastic, 1 gastric MALT and 1 lymphoplasmacytic lymphoma (Table 1). Median age was 51 years (22-57). Previous AIDS defining event was recorded in 16 cases (22%). The main HIV transmission group was represented by intravenous drug users (69%). Stage was III-IV in 63 pts (85%) and aaIPI was ≥2 in 57 pts (77%). At NHL diagnosis 38% of pts had CD4+ DAAs use was associated with improved OS in all pts (p=0.01) and in DLBCL (p=0.04) and with better PFS (p=0.01) in all pts. Similarly, the achievement of SVR after either DAAs or IFN predicted a better OS (Fig.2) and PFS in all pts (p=0.005 and p=0.008, respectively) and in DLBCL (p=0.018 and p=0.047, respectively). The impact of DAAs and SVR on OS remained significant also if considering only pts who achieved CR or PR after I-CT (p At univariate analysis, age >60 years (p=0.02), ARL-IPI (p=0.013), PS ECOG ≥2 (p=0.018) were associated with inferior OS. By applying multivariate Cox regression analysis, age >60 years (HR 67.9, 95% CI 7.2- 643.3, p CONCLUSIONS: In this very high risk series of HIV/HCV coinfected pts with NHL, mainly represented by DLBCL, the administration of DAAs after I-CT resulted feasible and effective (SVR 95%), and displayed an independent favourable influence on OS. These results strongly support DAAs' use in this hard to treat population. Figure 1 Figure 1. Disclosures Tisi: Incyte: Membership on an entity's Board of Directors or advisory committees; BWS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zilioli: Roche, Italfarmaco: Consultancy, Honoraria; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Takeda: Other: travel expenses, accommodation; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau. Passamonti: AbbVie: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Arcaini: Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Gilead Sciences: Research Funding; Celgene: Speakers Bureau.

BACKGROUND. HCV-positive DLBCL has distinct clinical and pathologic characteristics compared to its negative counterpart: patients (pts) are usually older with more frequent splenic and extranodal involvement and elevated LDH. Differently from its clinical hallmarks, the molecular landscape of this pathological entity has been scarcely outlined. METHODS. In this bicentric study, we investigated the clinical and molecular features and outcome of 54 pts with HCV-positive DLBCL. Targeted next generation sequencing (NGS) was performed on DNA extracted from formalin-fixed paraffin-embedded tissue biopsies. A core panel probes covering coding exons from 184 genes frequently mutated in mature B cell neoplasms was designed using IDT tool and libraries were prepared using Illumina DNA-prep-with enrichment. Sequencing was performed on Illumina HiSeq 2500. Cluster analysis was performed using LymphGen tool. We also applied fluorescence in situ hybridization (FISH) for MYC, BCL2 and BCL6. RESULTS. Median age was 71 (33-84; IQR: 61.9-77). Stage was III/IV in 34 pts (63%). Extranodal sites were involved in 21 pts (38%), spleen in 20 pts (37%). LDH was higher than the upper limit in 40 pts (74%). R-IPI was good for 2 pts (4%), intermediate for 24 pts (44%), poor for 28 pts (52%). HPS score was intermediate or high in 33 of 44 assessed pts (75%). A histological low-grade component was identified in 15 pts (27%). Hans algorithm differentiated pts almost equally in GCB (26/50, 52%) and non-GCB (24/50, 48%) subtype. HCV-RNA was detectable in 52 pts (96%) and quantifiable in 43 pts (79%). Of 29 pts assessed, genotype was 1 in 9 (31%), 2 in 16 (55%), 3 in 4 pts (14%). Among 37 pts whose data were available, 11 pts (30%) received direct antiviral agents, 7 pts (19%) received interferon-containing regimen, 19 pts (51%) were not treated for HCV. Twenty-seven pts (50%) received rituximab-enriched protocols, 23 pts (43%) were treated with chemotherapy alone, 1 pt (2%) with surgery alone, 3 pts (5%) were lost to follow up. With a median follow up of 7.7 years (yrs) (IQR: 4.6-10.6), 5-yrs overall survival (OS) (95%CI) was 49.3% (34.1-62.8%) and 5-yrs progression free survival (PFS) (95%CI) was 39.5% (25.5-53.3%). Median OS and PFS were 4.9 and 3.1 yrs, respectively. FISH analysis showed lack of BCL2 (0/19) and MYC translocations (0/15). BCL6 fusions were found in 76% of pts (16/21). NGS showed mutations in 154 of the 184 analyzed genes. The informativity of the panel was 100% with all pts presenting at least one oncogenic variant. Gene mutation frequencies are presented in Fig. 1. The median mutation load (MML) was 13 mutated genes per case (2-32; IQR: 9-16). Most frequently mutated genes were the epigenetic regulators KMT2D, mutated in 23 pts (42.6%), and SETD1B, mutated in 17 pts (31.5%). FAS, PM1 and RERE were mutated in 15 pts each (27.8%). TBL1XR1, BCL11A and SGK1 were mutated in 14 (26%), 13 (24%) and 12 pts (22%), respectively. Considering genes in their specific pathway, 94% of pts harbored mutations in genes involved in epigenetic regulation (MML: 3; range 1-7; IQR: 1.25-4), 90% of pts in apoptosis-related genes (MML: 2; 1-7; IQR: 1-3) and 77% of pts in genes belonging to BCR/NFkB signaling pathway (MML: 2; 1-7; IQR: 1-3). Of note, 56% of pts carried mutations in genes related to immune regulation (MML: 1.7; 1-5; IQR: 1-2) and 25% of pts had mutations within the NOTCH pathway (MML: 1.2; range 1-2). Via the LymphGen 1.0 tool, we classified 26 pts (48%) into 4 genetic clusters: BN2 (11/26, 42%), ST2 (8/26, 31%), MCD (4/26, 15%), EZB (3/26, 12%). Twenty-eight pts (52%) were classified as "others". Among those belonging to BN2 cluster, 7 pts (64%) had a histologically confirmed transformed DLBCL. No significant differences in terms of OS and PFS were identified according to cluster subgroups. CONCLUSIONS. The prevalence of the BN2 cluster and enrichment of mutations of genes involved in NOTCH pathway seem to indicate a preferential marginal-zone origin in HCV-positive DLBCL. In addition, our data confirm the absence of BCL2 translocation in this subset of DLBCL and show a high prevalence of mutated genes within the epigenetic and immune regulation pathways in HCV-positive DLBCL, pointing out their compelling role in the pathogenesis and suggesting potential implications for molecularly targeted therapies. Figure 1 Figure 1. Disclosures Passamonti: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Arcaini: Celgene: Speakers Bureau; Gilead Sciences: Research Funding; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses.

International audience; Background: International guidelines suggest hepatitis C virus (HCV) eradication by direct-acting antivirals (DAAs) after first-line immunochemotherapy (I-CT) in patients with HCV-positive diffuse large B-cell lymphoma (DLBCL), although limited experiences substantiate this recommendation. Moreover, only a few data concerning concurrent administration of DAAs with I-CT have been reported.Subjects, materials, and methods: We analyzed hematological and virological outcome and survival of 47 consecutive patients with HCV-positive DLBCL treated at 23 Italian and French centers with DAAs either concurrently (concurrent cohort [ConC]: n = 9) or subsequently (sequential cohort [SeqC]: n = 38) to first-line I-CT (mainly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone [R-CHOP]-like).Results: Median age was 61 years, 89% of patients had stage III/IV, and 25% presented evidence of cirrhosis. Genotype was 1 in 56% and 2 in 34% of cases. Overall, 46 of 47 patients obtained complete response to I-CT. All patients received appropriate DAAs according to genotype, mainly sofosbuvir-based regimens (n = 45). Overall, 45 patients (96%) achieved sustained virological response, 8 of 9 in ConC and 37 of 38 in SeqC. DAAs were well tolerated, with only 11 patients experiencing grade 1-2 adverse events. Twenty-three patients experienced hepatic toxicity (grade 3-4 in seven) following I-CT in SeqC, compared to only one patient in ConC. At a median follow-up of 2.8 years, two patients died (2-year overall survival, 97.4%) and three progressed (2-year progression-free survival, 93.1%).Conclusion: Excellent outcome of this cohort of HCV-positive DLBCL suggests benefit of HCV eradication by DAAs either after or during I-CT. Moreover, concurrent DAAs and R-CHOP administration appeared feasible, effective, and ideally preferable to deferred administration of DAAs for the prevention of hepatic toxicity.Implications for practice: Hepatitis C virus (HCV)-associated diffuse large B-cell lymphomas (DLBCLs) represent a great therapeutic challenge, especially in terms of hepatic toxicity during immune-chemotherapy (I-CT) and long-term hepatic complications. The advent of highly effective and toxicity-free direct-acting antivirals (DAAs) created an exciting opportunity to easily eradicate HCV shortly after or in concomitance with first-line immunochemotherapy (usually R-CHOP). This retrospective international study reports the real-life use of the combination of these two therapeutic modalities either in the concurrent or sequential approach (DAAs after I-CT) in 47 patients. The favorable reported results on long-term outcome seem to support the eradication of HCV with DAAs in all patients with HCV-positive DLBCL. Moreover, the results from the concurrent approach were effective and safe and displayed an advantage in preventing hepatic toxicity during I-CT.

Although patients with early-stage Hodgkin's lymphoma have a high rate of cure, a portion of these are resistant to or relapse after standard treatment. Current prognostic criteria based on clinical and laboratory parameters at diagnosis do not allow to accurately identify the subset of patients with less favourable clinical outcome. An increased number of tumour-infiltrating macrophages was found to be associated with shortened survival in patients with classic Hodgkin's Lymphoma. The aim of this study was to assess the clinical significance of the proportion of CD68-positive infiltrating macrophages in patients with early-stage classic Hodgkin's lymphoma. By using immunohistochemistry technique, we evaluated for CD68 expression diagnostic biopsies of 106 patients affected by supradiaphragmatic early-stage classic Hodgkin's lymphoma treated at our institution since 2000 to 2010. All patients were treated with adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy followed by radiotherapy in the majority. The 2-year overall survival and progression-free survival (PFS) in the entire cohort were 97% and 83% respectively. The 2-year PFS was statistically different between patients with favourable and those with unfavourable prognosis according to the European Organisation for Research and Treatment of Cancer (EORTC) risk criteria (96% vs 79%, p = 0.039) and between patients having less than 25% of CD68-positive infiltrating macrophages and those with more than 25% (85% vs 67%, p = 0.012). All patients with favourable EORTC criteria had CD68 expression lower than 25%. Within those with unfavourable EORTC criteria, patients with a CD68+ count greater than 25% had a worse 2-year PFS than patients having values lower than 25% (64% vs 82%, p = 0.03). Moreover, in multivariate analysis, after adjusting for CD68+ macrophages count and EORTC score, only CD68+ macrophages count higher than 25% retained a prognostic effect on PFS (hazard ratio = 2.8, 95%CI: 1.1-7.6, p = 0.038). Our data show that a proportion of tumour-infiltrating macrophages greater than 25% is associated with unfavourable clinical outcome in patients with early-stage Hodgkin's lymphoma Copyright © 2016 John Wiley & Sons, Ltd.

Chronic hepatitis C virus (HCV) infection is related with an increased risk of non-Hodgkin lymphomas (NHL). In indolent subtypes, regression of NHL was reported after HCV eradication with antiviral therapy (AT). In 2008 in Lombardy, a region of Northern Italy, the "Rete Ematologica Lombarda" (REL, Hematology Network of Lombardy-Lymphoma Workgroup) started a prospective multicenter observational cohort study on NHL associated with HCV infection, named "Registro Lombardo dei Linfomi HCV-positivi" ("Lombardy Registry of HCV-associated non-Hodgkin lymphomas"). Two hundred fifty patients with a first diagnosis of NHL associated with HCV infection were enrolled; also in our cohort, diffuse large B cell lymphoma (DLBCL) and marginal zone lymphoma (MZL) are the two most frequent HCV-associated lymphomas. Two thirds of patients had HCV-positivity detection before NHL; overall, NHL was diagnosed after a median time of 11 years since HCV survey. Our data on eradication of HCV infection were collected prior the recent introduction of the direct-acting antivirals (DAAs) therapy. Sixteen patients with indolent NHL treated with interferon-based AT as first line anti-lymphoma therapy, because of the absence of criteria for an immediate conventional treatment for lymphoma, had an overall response rate of 90%. After a median follow-up of 7 years, the overall survival (OS) was significantly longer in indolent NHL treated with AT as first line (P = 0.048); this confirms a favorable outcome in this subset. Liver toxicity was an important adverse event after a conventional treatment in 20% of all patients, in particular among DLBCL, in which it is more frequent the coexistence of a more advanced liver disease. Overall, HCV infection should be consider as an important co-pathology in the treatment of lymphomas and an interdisciplinary approach should be always considered, in particular to evaluate the presence of fibrosis or necroinflammatory liver disease.

High-dose chemotherapy with autologous stem cell transplantation (ASCT) has been shown effective in the control of relapsed/refractory follicular lymphoma. We evaluate the long-term outcome of patients with relapsed or refractory follicular lymphoma treated with ASCT with in vivo purged progenitors cells. We report the long-term results of a prospective multicenter phase 2 trial on 124 relapsed/refractory follicular lymphoma patients treated with a program of anthracycline-based debulking chemotherapy, immunochemotherapy, mobilization of in vivo purged PBSC followed by ASCT. Median age was 52 years; 14% of patients had grade 3A histology. Debulking chemotherapy produced CR in 16% and PR in 71%, while 13% of patients progressed. After rituximab, cyclophosphamide, vincristine, prednisone (R-COP), CR was obtained in 60% and PR in 35%; 118 patients successfully mobilized PBSC and 117 proceeded to ASCT. The harvest in all the 32 molecularly informative patients was bcl-2 negative. TRM was 0%. The 5-year PFS was 54% and the 5-year OS was 83%. After a median f-up of 6.7 years (range 1.5-13.6), 54% are still in CR. These data show that prolonged PFS is achievable in relapsed/refractory patients with high dose autologous transplantation of in vivo purged progenitor cells.

Introduction HCMV infection is a significant viral complication in HSCTR, causing either a subclinical infection or a severe disease (systemic syndrome and localized tissue invasive disease (TID)). Pre-emptive therapy used for the management of HCMV infection and prevention of disease requires the monitoring of HCMV load in blood to start antiviral therapy after detection of a viral load threshold associated to the risk for HCMV severe infection and disease. In previous studies we observed that patients reconstituting both CD4+ and CD8+ HCMV-specific T cells are generally protected from HCMV disease. Thus, determination of specific T cells may discriminate patients lacking immunity and requiring stricter virological monitoring (negative T-cell response) from those early recovering T-cell immunity and thus not requiring antiviral interventions (positive T-cell response). Aims The aim of our work is to assess the possibility to manage HCMV infection by combined virological and immunological monitoring. The primary endpoint of this study is to compare the frequency of HCMV disease between two groups of HSCTR: in the first one, pre-emptive therapy was started according to combined virological/immunological methods; the second group consisted of an historical cohort of patients monitored with HCMV-DNA as the only guiding parameter for pre-emptive therapy. Methods We analyzed adult patients receiving allogeneic HSCT: the recipients, the donor or both had to be HCMV seropositive. Virological follow-up (HCMV-DNA determination in whole blood) was performed weekly for the first 3 months, then monthly during the first year. Immunological follow-up was performed at 1, 2, 3, 4, 6, 8, 10 and 12 months. Peripheral blood HCMV-specific T cells were determined by two assays: i) iCL (infected Cell Lysate)-ELISPOT, considering as "protective" immunity a blood count of specific T-cell ≥ 0.1/µL ii) iDC-CFC (infected Dendritic Cells-Cytokine Flow Cytometry), considering as "protective" immunity a blood count of CD4+ T-cell ≥ 1/µL and CD8+ T cells ≥ 3/µL. According to study, within the first 3 months following transplantation pre-emptive antiviral therapy was given to all patients presenting a viral load ≥30.000 copies/mL blood (severe infection). Beyond 3 months following transplantation, patients with negative T-cell response continued receiving a pre-emptive antiviral therapy as reported above. In patients with positive T-cell response confirmed by both assays ("protected" patients), antiviral therapy was deferred even if viral load would reach ≥30.000 copies/mL blood. Results We performed an analysis of 36 patients with a follow-up ≥4 months from HSCT (median follow-up 245 days, 120-397; see Table 1 for patients' characteristics). Among them, 32 HCMV-seropositive HSCTR developed HCMV infection whereas 4 HCMV-seronegative patient receiving HSCT from seropositive donors did not (nor developed specific immunity). Among the 32 HSCTR with HCMV reactivation, 13 (41%) resolved spontaneously HCMV reactivation, whereas 19 (59%) had a severe infection (11 [34%] controlled the infection after a single course of Valganciclovir therapy and the remaining 8 [25%] required multiple courses for relapsing episodes). Thirty days after HSCT, levels of total and HCMV-specific CD4+ and CD8+ T cells were significantly higher in the 13 patients spontaneously resolving the infection than in the 19 patients with severe infection. The two immunological assays were concordant in detecting time to protective immune reconstitution (median time: 177 vs 183 days for iDC and iCL-ELISPOT, respectively). HCMV-specific immune reconstitution was significantly delayed in patients with multiple infection episodes (median time: 250 days post-transplantation) vs patients with a single episode of severe infection (187 days) and patients with self-resolving infection (89 days). No patient developed HCMV severe infection after HCMV-specific immune reconstitution. Currently, no patient developed HCMV disease. Conclusion These results suggest that combined virological/immunological monitoring can be useful to identify patients not requiring strict virological controls and antiviral interventions. Disclosures No relevant conflicts of interest to declare.

Although patients with early-stage Hodgkin's lymphoma have a high rate of cure, a portion of these are resistant to or relapse after standard treatment. Current prognostic criteria based on clinical and laboratory parameters at diagnosis do not allow to accurately identify the subset of patients with less favourable clinical outcome. An increased number of tumour-infiltrating macrophages was found to be associated with shortened survival in patients with classic Hodgkin's Lymphoma. The aim of this study was to assess the clinical significance of the proportion of CD68-positive infiltrating macrophages in patients with early-stage classic Hodgkin's lymphoma. By using immunohistochemistry technique, we evaluated for CD68 expression diagnostic biopsies of 106 patients affected by supradiaphragmatic early-stage classic Hodgkin's lymphoma treated at our institution since 2000 to 2010. All patients were treated with adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy followed by radiotherapy in the majority. The 2-year overall survival and progression-free survival (PFS) in the entire cohort were 97% and 83% respectively. The 2-year PFS was statistically different between patients with favourable and those with unfavourable prognosis according to the European Organisation for Research and Treatment of Cancer (EORTC) risk criteria (96% vs 79%, p = 0.039) and between patients having less than 25% of CD68-positive infiltrating macrophages and those with more than 25% (85% vs 67%, p = 0.012). All patients with favourable EORTC criteria had CD68 expression lower than 25%. Within those with unfavourable EORTC criteria, patients with a CD68+ count greater than 25% had a worse 2-year PFS than patients having values lower than 25% (64% vs 82%, p = 0.03). Moreover, in multivariate analysis, after adjusting for CD68+ macrophages count and EORTC score, only CD68+ macrophages count higher than 25% retained a prognostic effect on PFS (hazard ratio = 2.8, 95%CI: 1.1-7.6, p = 0.038). Our data show that a proportion of tumour-infiltrating macrophages greater than 25% is associated with unfavourable clinical outcome in patients with early-stage Hodgkin's lymphoma Copyright © 2016 John WileySons, Ltd.

Introduction: Transformation of Marginal Zone Lymphoma (MZL) into an aggressive histology is uncommon phenomenon that can occur at any time after diagnosis and is expected to have a detrimental impact on prognosis. Biological and clinical knowledge on transformed Marginal Zone Lymphoma (tMZL) is poor and no standard treatment is established in the Rituximab era for these patients (pts). We retrospectively analyzed all consecutive biopsy proven tMZL in two Italian Hematological Divisions from 2002 to 2014 and we focused on post-transformation treatment and outcome. Methods: The dataset included 378 MZL pts diagnosed between 2002 and 2014 at Division of Hematology in Pavia and in Milan (Niguarda Hospital): 204 pts (53.9%) by extranodal MALT lymphomas, 113 pts (29.8%) by splenic MZL, and 61 pts (16.3%) by nodal MZL. Histological transformation (HT) was defined as transformation into an aggressive lymphoma at any time from previous MZL diagnosis; only cases with biopsy confirmed HT were comprised in the present analysis, while cases with only clinical suspicion of transformation were not counted as tMZL. Results: HT was documented in 18 of the 378 pts (4.8%), 6.5% in nodal MZL, 7.0% in splenic MZL and 2.9% in MALT. Histology at transformation was Diffuse Large B-Cell lymphoma in all but one case; the remaining pt was diagnosed as high-grade B-cell lymphoma, unclassifiable. CD20 was negative only in one Rituximab-naïve pt. Median time from first diagnosis to HT was 31 months (range: 10-124) and median number of previous therapies was 1 (range 0-1); pts received first line therapy listed in table 1. Median age at transformation was 68 years (range: 46-85), M/F ratio was 0.8. In the tMZL population, first diagnosis was nodal MZL in 4 pts (22%), splenic MZL in 8 pts (45%) and MALT in 6 pts (33%). At first diagnosis of MZL, 72% of t-MZL pts had stage IV disease, 17% had B symptoms, 11% had elevated LDH and ECOG performance status was lower than 2 in all the cases. HCV serology was positive in 5/17 cases; HCV status was not available for one pt. At HT disease stage was III or IV in 14 pts (78%), B symptoms were present in 7 pts (39%), LDH and beta2microglobulin were both elevated in 7 pts (39%) and ECOG performance status was lower than 2 in all the cases. Pts received post-HT treatment listed in table 2. At time of analysis 6 pts died (33%), and the main cause of death was progressive disease. With a median post-transformation follow-up of 16.6 months (range: 2-98), the 2-years Progression-Free Survival (PFS) was 45,4 % and the 2-years Overall Survival (OS) was 56.75%. No correlation was found between the following characteristics and survival: MZL type at first diagnosis, stage, symptoms, LDH and ECOG at HT, number and types of pre-HT therapies. Conclusions: This large cohort confirms that HT is a relatively rare and early event in MZL. At present time, we did not identify any feature predictive of outcome for transformed MZL. Chemotherapy in combination with Rituximab showed to be an effective treatment for tMZL. Table 1 First line treatment N. of patients % Therapy strategy CVP 7 39 Anthracycline-containing regimen 2 11 Chlorambucil monotherapy 5 28 Splenectomy 1 5.5 H.pylori eradication 1 5.5 Watch and wait strategy 2 11 Rituximab incorporation Included in first line therapy 6 33 Maintenance 0 0 Response ORR (%) 67 CRR (%) 33 Table 2. Post-HT treatment N. of patients % Therapy strategy CHOP regimen 16 89 Platinum-containing regimen 1 5.5 Missing 1 5.5 Rituximab incorporation Included in first line therapy 17 94 Maintenance 0 0 ASCT consolidation 3 17 Response ORR (%) 61 CRR (%) 59 Disclosures Rusconi: Roche: Honoraria.

Hepatitis C virus has been found to be associated with B-cell non-Hodgkin lymphomas, mostly marginal zone lymphomas and diffuse large B-cell lymphoma. Deregulation of signaling pathways involved in normal marginal zone development (NOTCH pathway, NF-κB, and BCR signaling) has been demonstrated in splenic marginal zone lymphoma. We studied mutations of NOTCH pathway signaling in 46 patients with hepatitis C virus-positive diffuse large B-cell lymphoma and in 64 patients with diffuse large B-cell lymphoma unrelated to HCV. NOTCH2 mutations were detected in 9 of 46 (20%) hepatitis C virus-positive patients, and NOTCH1 mutations in 2 of 46 (4%). By contrast, only one of 64 HCV-negative patients had a NOTCH1 or NOTCH2 mutation. The frequency of the NOTCH pathway lesions was significantly higher in hepatitis C virus-positive patients (P=0.002). The 5-year overall survival was 27% (95%CI: 5%–56%) for hepatitis C virus-positive diffuse large B-cell lymphoma patients carrying a NOTCH pathway mutation versus 62% (95%CI: 42%–77%) for those without these genetic lesions. By univariate analysis, age over 60 years, NOTCH2 mutation, and any mutation of the NOTCH pathway (NOTCH2, NOTCH1, SPEN) were associated with shorter overall survival. Mutation of the NOTCH pathway retained an independent significance (P=0.029). In conclusion, a subset of patients with hepatitis C virus-positive diffuse large B-cell lymphoma displays a molecular signature of splenic marginal zone and has a worse clinical outcome.