Abstract: 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

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.

Abstract: A new method of graft manipulation based on physical removal of αβ+ T cells and CD19+ B cells, leaving mature NK cells and γδ T cells in the graft, has been recently developed for HLA-haploidentical HSCT. We demonstrated that γδ T cells collected from transplanted patients are endowed with capacity of killing leukemia cells after ex vivo treatment with zoledronic acid (ZOL). Thus, we hypothesized that infusion of ZOL in patients receiving this type of graft, may boost γδ T cell cytotoxic activity against leukemia cells. Thirty-three patients were treated with ZOL every 28 days at least twice. γδ T cells before and after ZOL treatments were studied till at least 7 months after HSCT by high-resolution mass spectrometry, flow-cytometry, and degranulation assay. Proteomic analysis of γd T cells purified from patients showed that, starting from the first infusion, ZOL caused up-regulation of proteins involved in activation processes and immune response, paralleled by down-regulation of proteins involved in proliferation. These findings are consistent with an induction of Vδ2 cell differentiation, paralleled by increased cytotoxicity of both Vδ1 and Vδ2 cells against primary leukemia blasts. Furthermore, a proteomic signature was identified for each individual ZOL treatment. Patients given 3 or more ZOL infusions had a better probability of survival in comparison to those given 1 or 2 treatments. In conclusion,ZOL influences Vδ2 cell activity, determines a specific proteomic signature and enhances anti-leukemia activity, this potentially resulting into an increased anti-tumor effect. Disclosures No relevant conflicts of interest to declare.

Abstract: Abstract 2651 Background and objectives [18F]fluorodeoxyglucose - Positron Emission Tomography (FDG-PET) is confirmed as a useful functional imaging tool for staging and response assessment in Hodgkin lymphoma and Diffuse Large B-Cell Lymphoma. Despite FL is accounted among FDG-avid lymphomas few studies have been performed to investigate how FDG-PET can be used in initial staging of FL patients. We conducted a retrospective analysis to investigate the role of FDG-PET in the initial staging of FL. Patients and methods The study was designed as a retrospective unplanned analysis of patients with newly diagnosed FL enrolled in the FOLL05 phase III trial (NCT00774826) and randomized to one of the three study arms (R-CVP. R-CHOP, R-FM). To be included in the study patients should have confirmed eligibility for the FOLL05 trial, have available data on clinical presentation, treatment details and results, and on follow-up. Baseline staging had to be performed with contrast-enhanced Computed Tomography (CT), with CT-PET, and with Bone Marrow (BM) biopsy. For study purposes disease extension at baseline was defined independently for both CT and PET using on local report and interpretation; only for difficult cases images were centralized and reviewed. For each exam nodal sites (NS) were counted according to the FLIPI schema. NS were considered as positive if greater than 1.5 cm in their maximum transverse diameter at CT or, using PET, if FDG avid or if they had disappeared at the end of treatment. Extranodal sites (ENS) were counted on an organ basis and were considered positive at CT in case of nodular involvement or in case of organ enlargement not otherwise justified. Extranodal involvement at PET was considered for sites showing avidity for FDG not justified by conditions other than FL. Conventional Ann Arbor (AA) staging was based on CT scan assessment only. PET and CT scan results were compared using the kappa-statistic measure of interrater agreement (IR), and the level of agreement was defined by the Koch Landis scale. Results Among 534 patients enrolled in the FOLL05 trial, 122 cases fulfilled eligibility criteria for this study. All but 2 cases were confirmed as FDG avid at PET scan; these two cases were not used for staging comparison. Median age of patients was 57 years (range 33–74), 33% were older than 60 years, 48% were males. Bone marrow biopsy was positive in 52%. Using CT, AA stage was III-IV in 77% of cases. Fifty-two percent, 36%, and 12% of cases had less 0–4, 5–8, and 〉 8 NS, at CT, respectively. Overall CT scan allowed the identification of 48 ENS in 36 patients (30%); 2 or more ENS were described in 8 patients (6%); most frequent ENS were spleen (52%), liver (10%), skin/soft tissue (8%) and GI tract (6%). Using PET 38%, 37%, and 25% of cases had 0–4, 5–8, 〉 8 NS, respectively. PET allowed the identification of 88 ENS in 55 patients (46%) and 2 or more ENS were found in 17 patients (14%). Most frequent ENS at PET were bone (35%), spleen (30%), GI tract (10%), and skin/soft tissue (7%). Classifying patients according to the number of NS (0–4, 5–8, 〉 8) agreement between CT and PET was fair (IR= 61%, Kappa=0.39). Agreement between CT and PET for ENS (grouped as 0, 1, and 〉 1) was also fair (IR= 63%, Kappa=0.31) and improved to moderate when also details on BM histology were considered (IR 82% K=0.4). When PET was used independently of CT to define AA stage a moderate agreement was achieved with CT (IR=76%, kappa= 0.58): in particular 22 cases (18%) were upstaged with PET while only 6 (5%) were downstaged; seventeen out of 25 (68%) patients were reclassified by PET as stage III-IV from a previous localized stage. Looking at FLIPI, 22%, 41%, and 37% were classified by CT as having score of 0–1, 2, and 3–5, respectively. The use of PET modified CT based FLIPI index in 26% of cases, with a substantial agreement between PET and CT (IR=74%, kappa=0.61). FLIPI2 index is not affected by the use of PET. Conclusions The results of this study confirm FL as a FDG-avid disease. The use of PET for the initial staging of patients with FL seems to provide a more accurate definition of disease extent compared with CT. The clinical usefulness of adding PET to the initial staging of FL needs to be further investigated. Disclosures: Di Raimondo: Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau.

Abstract: Diagnosis of non-CLL B Cell Chronic Lymphoproliferative Disorders (BCLPD), defined by the detection of peripheral blood (PB) B-Cell clone with flow cytometry (FC) Matutesscore≤3, is not an infrequent event in clinical daily practice. Only a portion of these cases may be actually classified according to the 2016 revision of WHO classification of lymphoid neoplasms, as in these cases a non-bone marrow (BM) tissue biopsy is rarely available due to "liquid-only disease" (BM, PB, splenomegaly) or difficult accessible sites. The two most likely diagnosis of BCLPD according to WHO 2016 are splenic marginal-zone lymphoma (SMZL) and monoclonal B Cell lymphocytosis (MBL) with non-CLL phenotype (CD19+, CD20+, SIg+, CD5-), sometimes reported as MZL-like, defined by monotypic clonal B lymphocytes (CBL) 〈 5 x 109/l. A recent study pointed out a similar outcome regardless CBL value exceeding or not this arbitrary cut-off in strictly defined cases (absence of cytopenias, splenomegaly and adenopathy) of clonal B cell lymphocytosis with marginal-zone features (CBL-MZ) and confirmed the really indolent behaviour of this entity (Xochelli, Blood 2014). On these bases we decided to retrospectively collect clinical, immunophenotypic, molecular features and outcome of all consecutive patients (pts) with CD5- CBL-MZ owing to the Department of Hematology of University of Insubria (Varese, Italy) from 2011 to 2019 and to compare them with overt SMZL cases. Excluding 5 SMZL pts who were splenectomized, all cases were diagnosed by means of non-BM tissue biopsy, namely BM histology and PB/BM FC, FISH and molecular studies, when appropriate, and complete laboratory and imaging staging procedures (CT scan or US). The primary objective of the study was time to progression (TTP) for CBL-MZ group. Secondary objectives were overall survival (OS), progression-free survival (PFS) for treated pts and evaluation of early progression 〈 24 months (Early POD) (Luminari, Blood 2019). Overall we collected complete data of 33 pts with CD5- CBL-MZ, and 44 with SMZL (Table 1). Focusing on CBL-MZ, FC immunophenotypic findings showed a B-Cell population with Matutes score 0 to 2 in all cases, uniform expression of B Cell antigens, namely CD19, CD20 strong, FMC7 (93%), SIg (intermediate/bright in 71%), while CD10 and CD5 were consistently negative. CD23 was expressed in 18%, CD38 in 9% and CD49b in 95%. BM sinusoidal infiltration pattern was detected in 50% of cases. TP53 mutation/deletion was detected in 4/16 pts (25%) while trisomy 12 and del13q in 1 pt each. Twenty pts presented with 〈 5000/mmc CBL (MBL-MZ) and 13 with ≥5000/mmc CBL. With a median follow-up of 1.8 years, 6 pts (18%) progressed (4 in SMZL, 1 NMZL and 1 SLL; Fig 2) with a median TTP of 1.7 yrs (range 0.3- 12.3), while the remaining 27 remained completely stable. Among 4 pts treated, 2 received Rituximab-based regimen, both achieving CR and 2 with Chlorambucil both experiencing progression. Overall, 5 pts died (2 for progressive lymphoma), with an estimated 5-yrs of 80%. Concerning prognostic factors, after adjusting by competing risk method, at univariate analysis age 〉 60 yrs, CBL 〉 5000/mmc and albumin 〈 3.5 g/dl, were associated to shorter TTP, while age 〉 60 yrs, Hb 〈 11 g/dl, ECOG PS ≥2 and albumin 〈 3.5 g/dl resulted predictive of worse OS (Table 2). By applying multivariate Cox regression model, only age 〉 60 yrs and CBL 〉 5000/mmc retained prognostic significance for TTP (p 〈 0.0001), while ECOG PS ≥2 and albumin 〈 3.5 g/dl remained independently associated with inferior OS (p 〈 0.0001). Considering the SMZL group, 34 pts underwent systemic treatment (rituximab-based in 32, including R-Bendamustine in 17). With a median follow-up time of 2.8 yrs, 9 pts progressed (4 of whom within 24 months from treatment initiation), with a median PFS 2.9 yrs, and 8 died (7 due to progression, including 3 DLBCL transformations) with an estimated 5-yrs OS of 79%. Notably, Early POD SMZL pts exhibited a significant increased risk of death (p 〈 0.0001, fig.2), while in CBL-MZ did not (p=0.4). In conclusion, CBL-MZ confirmed to be associated with indolent course and preferential evolution toward SMZL, of which it can be viewed as an initial phase or a precursor entity. In contrast with previous findings, the WHO 16 CBL cut-off defining MBL (5 x 109/l), together with advanced age, retained prognostic relevance for TTP. Finally, we confirmed for the first time in an independent series of SMZL the highly prognostic impact of Early POD24. Disclosures Passamonti: Roche: Consultancy; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

Abstract: Hodgkin’s lymphoma (HL) is generally treated according to stage and risk profile. A tailored therapy decrease the risk of secondary malignancies which exceeds 10% in several historical series in patients with early stage disease. Anatomic imaging modalities, particularly computed tomography (CT), allow to good morphological imaging but lack sensitivity and specificity because the definition of lymph node involvement is based on size criteria. During the last decade FDG-PET has been introduced for noninvasive staging of lymphoma. Herein we propose a prospective multicentric study with the aim to assess the impact of FDG-PET on the staging of pts with diagnosis of HL. A total of 135 consecutive pts coming from five Italian hematological Institutions underwent a FDG-PET scan in addition to conventional staging procedures, which include physical examination, laboratory data, bone marrow biopsy and imaging of the neck, thorax and abdomen using CT scan. All pts with disconcordant results were carefully evaluated with CT or NMR or ultrasound before starting, during and at the end of therapy. Pts characteristics: 70 male and 65 female, 106 (78.5%) with diagnosis of nodular sclerosis classical HL, 16 (12%) mixed cellularity classical HL, 8 (6%) lymphocyte-rich classical HL, 1 (0.5%) lymphocyte-depleted classical HL and 4 (3%) non specified HL. Standard staging procedures led to: 12 (9%) pts were stage I, 82 (61%) stage II, 26 (19%) stage III and 15 (11%) stage IV. FDG-PET and CT were concordant in 114 out 135 pts (84%). FDG-PET allowed to identify in 30 out 114 concordant stage more nodal (27 pts) or extranodal (3 pts: two spleen and one liver) involvement in comparison with CT imaging. In five out 114 concordant stage CT showed one more involved site in comparison with FDG-PET. FDG-PET results suggested an upstage in 17 pts (12,5%) and a downstage in 4 pts (3%). In these four pts FDG-PET did not confirm one nodal involvement and 3 extranodal involvement identified by CT (1 in the spleen, 1 in the liver and 1 in the lung). All these abnormal uptake sites were confirmed with other instrumental tests, we check after two or three cycles of chemotherapy and, after an accurate re-evaluation, they disappeared. Eleven pts (7%) with localized disease (I–II) at standard staging changed in an advanced stage as a result of the FDG-PET scan: four pts shifted from II to IV stage and seven pts from II to III stage. All pts with an upstaging PET were carefully analysed to confirm or not the PET positivity and in five out 17 of these pts the information provided by FDG-PET led to a change in the therapeutic options in particular for the extent of the radiation fields. In conclusion our data confirm that conventional staging system has an high sensibility nevertheless in this large cohort of pts FDG-PET is a relevant noninvasive method that supplements conventional procedures and therefore should be used in combination with conventional diagnostics to stage HL particularly in pts with early stage, where a change in staging could modify disease management.

Abstract: Abstract 2876 Background: HCV infection has been demonstrated to be involved in clonal B cell proliferation and in the subsequent development of non-Hodgkin's lymphoma (NHL). The regression of NHL after antiviral treatment is considered an indirect evidence of this pathogenetic relationship. Aim: to evaluate clinical course of patients affected by HCV infection (serology and HCV RNA positive) and low grade B-cell NHL (LG-NHL), not needing immediate treatment (absence of B symptoms, bulky disease or symptomatic tumor mass and lymphocyte doubling time less than 6 months) and treated upfront with antiviral therapy alone. Method: From 2006 to 2010, 13 patients, affected by LG- NHL at diagnosis have been treated with pegylated interferon (PegIFNa2a, 100–180 mcg weekly) and ribavirin (Rbv, 800–1200 mg daily) for a median treatment period of 6 months (6-18 months). Two patients are still in treatment. M/F ratio was 1.6 and median age was 59 years (range 51–73). The study included 9 marginal zone lymphomas (MZL: 2 splenic MZL, 7 extranodal non gastric MZL), 3 LG-NHL NOS and 1 lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia (LPL). Cryoglobulin were present in five patients. 7 pts had genotype 2, 5 pts genotype 1b, one not assessed; HCV infection was detected before lymphoma diagnosis in 9 pts and at lymphoma onset in 4 pts. Only 2 patients have previously received other combinations of antiviral therapy. Virologic response was assessed monthly by HCV-RNA polymerase chain reaction (PCR) and hematologic response was evaluated according to International Working Group response criteria (Cheson et al. J Clin Oncol. 2007) at the end of antiviral therapy. Results: Eleven patients completed the planned treatment course. Sustained virologic response (SVR) was achieved in 9 patients (6 with genotype 2); viremia clearance was achieved in a median period of 2 months (1-6). Among patients that gained a SVR, 5 achieved a complete response (CR) (3 genotype 2, 1 1b, one not assessed), one (genotype 2) partial response (PR), and 3 (2 genotype 2 and one genotype 1b) presented stable disease (SD). The remaining patients obtained only a reduction of viremia: one presented a SD and one was in PR. The treatment was well tolerated without any WHO grade III-IV toxicity. Among patients that completed treatment program, more frequent toxicity was haematological (one patient developed a WHO grade 1 anemia and one patients developed WHO grade 1 anemia and grade 2 neutropenia). After a median follow up of 17 months from the end of therapy (range 3–44), considering the 9 patients in SVR, only 2 (1 CR and 1 PR) progressed, maintaining SVR and one lost SVR maintaining SD. Patients that obtained only a reduction of viremia, maintained their hematologic status. Conclusion: We described a high CR rate in patients that obtained SVR after antiviral therapy (55%); the relationship between hematologic and viral response during follow up is not always stringent. We confirm that antiviral therapy could be considered as frontline therapeutic option in cases of HCV-related LG-NHL not requiring immediately immunochemotherapy. Disclosures: No relevant conflicts of interest to declare.

Abstract: Introduction. Although rabbit anti-thymocyte globulin (ATG) is largely used for preventing immune-mediated complications in patients given allogeneic hematopoietic stem cell transplantation (HSCT) from a matched unrelated donor (MUD), the optimal dosage of this drug in children is still undefined. We conducted an academic open-label, multicenter, randomized trial comparing two different dosages of rATG in children with hematological malignancies transplanted with either bone marrow (BM) or peripheral blood stem cell (PBSC) from a MUD selected using high-resolution typing for HLA class I/II (i.e. A, B, C, DRB1) loci. The study aimed at testing whether a higher dose of rATG (30 mg/Kg over 3 days, from day -4 to day -2) was superior to a lower dose (15 mg/Kg over 3 days, from day -4 to day -2) in terms of grade II-IV acute graft-versus-host disease (GvHD) prevention. Secondary end-points included cumulative incidence (CI) of chronic GvHD, non-relapse mortality (NRM), disease recurrence and event-free survival (EFS). The drug was kindly provided by Fresenius/Neovii. Patients and methods. Inclusion criteria were: diagnosis of acute or chronic leukemia in remission/chronic phase, non-Hodgkin lymphoma or myelodysplasia; age at HSCT 0-19 years; availability of an unrelated donor selected using high-resolution molecular typing of HLA-A, B, C and DRB1 loci, completely matched or with a single allelic disparity at one of the HLA loci or with 2 allelic disparities, or with one antigenic disparity; use of G-CSF-mobilized PBSC or BM-derived hematopoietic stem cells. From January 2008 to September 2012, 180 patients were enrolled in the study. Eight patients, 5 randomized to the rATG 30 mg/kg group and 3 to the 15 mg/kg group, did not proceed to transplant due to further relapse before HSCT. The remaining 172 patients, 84 belonging to the 30 mg/kg group and 88 belonging to the 15 mg/kg group, were transplanted and included in this analysis; 94 children had acute lymphoblastic and 42 acute myeloid leukemia. The 2 randomization groups were comparable for all demographic and transplant-related variables evaluated (see Table 1). Patients were stratified according to the stem cell source (BM vs. PBSC), degree of HLA compatibility with the donor (unrelated donor perfectly matched or with 1 allelic disparity vs. unrelated donor with 2 allelic disparities or with 1 antigenic disparity) and disease risk group (standard- vs. high-risk, SR and HR). All patients received a fully myeloablative preparative regimen. All patients received cyclosporine-A and short-term methotrexate as post-transplant GvHD prophylaxis. The trial was registered at ClinicalTrials.gov (NCT00934557). Data were analyzed as of January 31st, 2016. Results. With a median follow-up of 4.5 years (range 3.3-7.6 years), the 100-day CI of grade II-IV acute GvHD in the high and low rATG group was 29% and 36%, respectively (P=NS, Figure 1A); the CI of extensive chronic GvHD in the two groups was 6% and 10%, respectively (P=NS, Figure 1B). The CI of NRM was 19% and 9% in the high and low rATG group, respectively (P=0.09). Children receiving the higher rATG dosage had a greater incidence of viral reactivations as compared to those who received the lower dosage. The difference was statistically significant for EBV reactivation (37% vs. 23%; P = 0.038) and for Adenovirus reactivation (12% vs. 1%; P = 0.004). The overall CI of disease recurrence was 17% and did not differ between high and low dose rATG. The 5-year EFS for the whole cohort of patients was 69%; it was 61% and 77% for children given high and low dose rATG, respectively (P=0.028, Figure 1C). EFS was 78% and 55% in the SR and HR groups, respectively (P=0.001, Figure 1D). EFS of the 136 children with acute leukemia given either high or low dose rATG was 60% and 77%, respectively (P=0.049). In multivariate analysis on EFS, the following variables were associated with an unfavorable outcome: rATG dose of 30 mg/kg (relative risk 1.90; P=0.026), HLA mismatch 〉 1 allele (relative risk 2.08; P=0.01) and HR disease (relative risk 2.46; P=0.0015). Conclusions. Our data indicate that, in children with hematological malignancies transplanted from a MUD selected through high-resolution HLA typing, the use of low dose rATG results into decreased incidence of NRM and better EFS. Low dose rATG is able to spare life-threatening viral infections, without significantly increasing the incidence of acute and chronic GvHD. Table 1 Table 1. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract: INTRODUCTION: The availability of novel monoclonal antibodies (moAbs) including the anti-CD30 Brentuximab Vedotin (BV) and the anti-programmed cell death-1 (anti-PD-1) Nivolumab and Pembrolizumab has introduced innovative options in the process of therapeutic decision making for relapsed/refractory classical Hodgkin lymphoma (R/R cHL). However, multiagent chemotherapy followed by autologous stem cell transplantation (auto-SCT) in chemosensitive patients still remains the standard-of-care treatment of R/R cHL. In a multicenter phase 2 study, the BEGEV (Bendamustine, Gemcitabine, Vinorelbine) regimen was previously reported as a highly effective treatment in the second-line salvage setting (Santoro et al., J Clin Oncol, 2016). Here, we report a retrospective analysis of efficacy and toxicity of the BEGEV regimen administered as second- or subsequent-line therapy to R/R cHL in a real-world setting. PATIENTS AND METHODS: From January 2013 to March 2018, 73 cHL patients (median age, 31 years; range, 16 - 69) were candidate to receive 4 courses of BEGEV as second-line (n= 50) or beyond second-line (n= 23) salvage therapy. Refractory patients were 56% in the second-line group and 78% in the group treated beyond second-line. This latter group received a median of 3 (range, 2-8) lines of therapy prior to BEGEV, including Brentuximab Vedotin (BV) (83%) and auto-SCT (43%). RESULTS: In keeping with the phase 2 study, hematological and non-hematological side effects were acceptable. In fact, 64 (88%) patients completed the planned treatment whereas only 9 (12%) patients experienced early therapy discontinuation due to progressive disease (n= 8) and sepsis (n= 1). Of 72 patients evaluable for response, 50 (69.4%) achieved complete remission (CR) and 7 partial remission (PR) with an overall response rate (ORR) of 79%; 1 patient experienced stable disease (SD) and 14 (19%) progressive disease (PD). All but one patient experiencing PD/SD were chemorefractory (14/15). The probability of achieving response (CR+PR) to BEGEV was significantly higher in chemosensitive vs chemorefractory patients (96% vs 70%, P=0.007) whereas no difference could be detected for patients receiving BEGEV as second-line vs those treated beyond second-line (84% vs 70%, P=0.217). All BEGEV responders (n=57) were offered SCT: 44 received auto-SCT, 9 allo-SCT and 1 tandem auto/allo-SCT; 1 patient is waiting for SCT, and 2 refused. With a median follow-up of 14 months, the 1-yr overall survival (OS) and progression-free survival (PFS) are 93% and 69%, respectively. Disease status (sensitive vsrefractory) at BEGEV had no impact on survival (1-yr OD: 94% vs 92%, P=0.57) likely due post-BEGEV consolidation therapy, whereas timing of BEGEV administraton (second-line vs subsequent-lines) significantly affected survival (1-yr OS: 97% vs 78%, P=0.018). CONCLUSION: Data from this real-world analysis further confirm that BEGEV is an effective and safe salvage treament in R/R cHL even when administered to heavily pre-treated patients, thus representing an optimal therapeutic platform prior to consolidation with SCT or immunotherapy. Disclosures Carlo-Stella: Sanofi: Consultancy; Genenta Science: Speakers Bureau; AstraZeneca: Speakers Bureau; Rhizen Pharmaceuticals: Research Funding; Amgen: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; MSD Italia: Speakers Bureau; Boehringher Ingelheim Italia: Consultancy; Janssen: Speakers Bureau; ADC Therapeutics: Research Funding, Speakers Bureau.

Abstract: Abstract 2686 Poster Board II-662 Introduction: Fludarabine in combination with cyclophosphamide (FC) plus rituximab (R) is an effective treatment for newly diagnosed as well as relapsed low-grade non-Hodgin's lymphoma (NHL). The role of maintenance treatment with R has been demonstrated in relapsed/resistant follicular NHL improving overall and progression-free survival. We investigated efficacy and safety of the chemo-immunotherapy FCR followed by rituximab maintenance treatment in patients with advanced untreated indolent B-cell non follicular lymphomas (INFL). Patients and methods: from July 2005 to May 2007, 47 pts whit untreated advanced stage INFL (23 lymphocytic, 20 limphoplasmacytic and 4 nodal marginal zone NHL) were enrolled by 10 IIL centres, in an open label, single arm, multicenter phase II study. Treatment plan was: 6 courses of FC (Fludarabine, 25 mg/m2 i.v. plus Cyclophosphamide, 250 mg/m2, days 2–4) every 28 days plus 8 doses of R (375 mg/m2 , day 1 every FC cycle and day 14 of cycles 4 and 5) followed by R maintenance (375 mg/m2 every two months for 4 doses). Prophylactic antibiotic treatment with cotrimoxazole (two tablets three times a week) and antifungal profilaxis with itraconazole was planned from the beginning of chemotherapy to three months later or until normalization of CD4 count. The primary endpoint of this study is the percentage of failure free patients after two years from the treatment start. Results: all the patients were evaluable for safety analysis and 46/47 pts were evaluable in terms of intention to treat analysis. Median age was 59 years (31–68) and M/F ratio was 28/18; stages II/III/IV were 2/2/44; B symptoms and splenomegaly were observed in 11 and 14 pts respectively; FLIPI scores were: 0–1 in 16 pts (34.8%), score 2 in 19 pts (41.3%) and score ≥ 3 in 11 pts (23.9%). Forty-one patients (87.2%) completed the planned therapeutic program; the remaining 6 patients stopped the treatment for SAE (4 pts) or for other reasons (2 pts) after 9 courses (1 pt), 8 (1 pt), 6 (2 pts), 3 (1 pt) and 1 (1 pt). Overall response at the end of treatment was 80.4% with 60.9% CR and 19.5% PR. One patient relapsed during maintenance phase. All the patients are still alive. A total of 279 courses of FC were given to 47 patients. All the patients presented at least one toxic/adverse events (AE); 11 pts developed 12 serious AEs, but only 6 were related to therapy. Seventeen pts had to interrupt (4 pts), delay or reduce therapy. Three hundred twenty related AEs were registered: grade 1–2: 228 events; grade 3–4: 92 events. Among these last the most frequent was neutropenia: 30 pts presented 83 episodes whose grade 3–4 related to the therapy were 58. During maintenance phase, 4 episodes of neutropenia occurred (2 of grade 3–4). Sixteen pts presented 31 infective episodes; the most frequent were: 5 Herpes zoster infections, 5 pneumonia (1 mycotic) and 4 urinary tract infections. Conclusions: in a series of INFL at diagnosis, FCR regimen is effective with a very high CR rate. The toxicity was acceptable and the schedule can be considered safe although the frequence of neutropenia and infective events require a close surveillance. The next year of follow-up will allow us to establish the failure free survival after two years from the treatment start. Disclosures: Vitolo: Roche: Lecture fees. Morra:Roche: Lecture fees.