Abstract: There is a lack of evidence regarding the benefits of β-blocker treatment after invasively managed acute myocardial infarction (MI) without reduced left ventricular ejection fraction (LVEF). Methods and results The tREatment with Beta-blockers after myOcardial infarction withOut reduced ejection fracTion (REBOOT) trial is a pragmatic, controlled, prospective, randomized, open-label blinded endpoint (PROBE design) clinical trial testing the benefits of β-blocker maintenance therapy in patients discharged after MI with or without ST-segment elevation. Patients eligible for participation are those managed invasively during index hospitalization (coronary angiography), with LVEF & gt;40%, and no history of heart failure (HF). At discharge, patients will be randomized 1:1 to β-blocker therapy (agent and dose according to treating physician) or no β-blocker therapy. The primary endpoint is a composite of all-cause death, non-fatal reinfarction, or HF hospitalization over a median follow-up period of 2.75 years (minimum 2 years, maximum 3 years). Key secondary endpoints include the incidence of the individual components of the primary composite endpoint, the incidence of cardiac death, and incidence of malignant ventricular arrhythmias or resuscitated cardiac arrest. The primary endpoint will be analysed according to the intention-to-treat principle. Conclusion The REBOOT trial will provide robust evidence to guide the prescription of β-blockers to patients discharged after MI without reduced LVEF.

Abstract: 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. Am. J. Hematol. 90:230–234, 2015. © 2014 Wiley Periodicals, Inc.

Abstract: The complete remission (CR) rate achieved with induction chemotherapy prior to autologous stem cell transplantation (ASCT) represents the strongest prognostic factor in relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL). By inducing a CR rate of 75%, the bendamustine, gemcitabine, vinorelbine (BEGEV) regimen represents an optimal chemotherapy regimen prior to ASCT. Presented here are the 5-year results of BEGEV followed by ASCT in R/R cHL. With a median follow-up of 5 years, progression-free survival (PFS) and overall survival (OS) for the whole series (n = 59) were 59% and 78%, respectively. ASCT was performed in 43 of 49 responding patients (73% by intention to treat [ITT] ; 88% by response to BEGEV) and resulted in 33 with continuous CR (56% by ITT; 77% of transplanted patients), 7 with disease relapse, and 3 with nonrelapse mortality. For patients who received transplants, the 5-year PFS and OS were 77% and 91%, respectively, with no significant difference between relapsed and refractory patients. No patient experienced secondary leukemia or myelodysplasia. In summary, the long-term efficacy data, the benefits for both relapsed and refractory patients, and the excellent safety profile provide a strong rationale for further development of the BEGEV regimen. This trial was registered at EudraCT as #2010-022169-91 and at www.clinicaltrials.gov as #NCT01884441.

Abstract: INTRODUCTION: High-dose salvage chemotherapy followed by autologous stem cell transplantation (Auto-SCT) in chemosensitive patients still remains the standard-of-care treatment for relapsed/refractory classic Hodgkin lymphoma (R/R CHL). As previously reported in a multicenter phase 2 study (Santoro et al., J Clin Oncol, 2016), the BEGEVregimen induces an objective response rate (ORR) 〉 80% in the second-line salvage setting of R/R cHL, thereby resulting a highly effective treatment. Here, we assess efficacy and safety of the BEGEV regimen after extended follow-up (registered at www.clinicaltrials.gov as #NCT01884441). PATIENTS AND METHODS: cHL patients who were refractory to, or have relapsed after first-line chemotherapy were eligible. The primary endpoint was CR rate after 4 cycles of therapy. Secondary endpoints were: ORR, stem cell mobilization activity, and toxicity. Progression free survival (PFS) and overall survival (OS) were also evaluated. The BEGEV regimen consisted of: Bendamustine (90 mg/sqm, days 2-3), Gemcitabine (800 mg/sqm, day 1 and 4) and Vinorelbine (25 mg/sqm, day 1) every 3 weeks for a total of 4 courses. RESULTS: Between September 2011 and March 2014, 59 consecutive patients with relapsed (46%) or refractory (54%) cHL were enrolled. The median age was 33 years (range 18-68). By intention to treat (ITT), after 4 cycles of therapy, 44 (75%) achieved a CR and 5 (8%) a partial response (PR) for an ORR of 83%. One case (2%) showed stable disease (SD), while 8 patients (14%) progressed, and 1 (2%) was not evaluable for response. In univariate analysis, the only factor which resulted associated with a different probability to reach CR was disease status at study entry, with CR being achieved by 84% of relapsed patients and 59% of refractory patients (P=0.031). With a median follow-up of 56 months (range, 3.4-79), the overall patient population (n=59) has an OS of 78% and a PFS of 61%, respectively, without significant difference between relapsed and refractory patients. Fifty-seven out of 59 patients were evaluable for CD34+ cell mobilization. Two of 57 patients (3.5%) experienced CD34+ cell mobilization failure, whereas the planned target dose of CD34+ cells (3×10^6 CD34+ cells/Kg body weight) was successfully harvested in the remaining 55 patients (96.5%). After AutoSCT, engraftment of neutrophils and platelets was recorded on day 11 (range 9-21) and day 12 (range 9 - 26), respectively. Of the 49 responding patients, 43 (73% by intention to treat) proceeded to Auto-SCT (39/43 in CR, 4/5 in PR); the remaining 6 patients did not proceed to Auto-SCT due to mobilization failure (n=2), physician decision (n=2), early relapse (n=1), patient refusal (n=1).After transplant, 4 patients died [pneumonia (n=1), infection (n=1), multi-organ failure (n=1), PD (n=1)] and 7 patients relapsed. No patient has developed secondary leukemia or myelodysplasia. For transplanted patients, the 5-yr OS and PFS are 91% and 77%, respectively. CONCLUSIONS: These 5-year follow-up data demonstrate that BEGEV is a highly effective and safe salvage regimen. Nearly 80% of BEGEV-treated R/R cHL patients who experience an objective response and are addressed to Auto-SCT achieve long-term disease control and may potentially be cured. These data provide a strong rationale for further development of the BEGEV regimen. Disclosures Luminari: Roche: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Servier: Consultancy; Sandoz: Consultancy. Carlo-Stella:ADC Therapeutics: Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Janssen: Speakers Bureau; Boehringher Ingelheim Italia: Consultancy; AstraZeneca: Speakers Bureau; Rhizen Pharmaceuticals: Research Funding; Sanofi: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Genenta Science: Speakers Bureau; MSD Italia: Speakers Bureau.

Abstract: Background. Ara-c based chemo-immunotherapy followed by autologous stem cell transplantation (ASCT) is the most effective approach in young mantle cell lymphoma (MCL) patients, though few if any patients are cured. Recent data indicate that subsequent Rituximab maintenance (RM) prolongs PFS and OS (Le Gouill NEJM 2017). Lenalidomide is an oral agent effective in MCL, considered suitable for prolonged maintenance programs, but has never been tested in this setting. The FIL MCL0208 trial (NCT02354313) is a prospective, international randomized, phase III trial, comparing Lenalidomide maintenance (LM) vs observation (OBS) after an intensive Ara-c containing chemo-immunotherapy (R-HDS) program, followed by ASCT in previously untreated MCL patients. Patients and Methods. Adult patients aged 18-65 years, with advanced stage MCL without clinically significant comorbidities were enrolled. Patients received 3 R-CHOP-21, followed by R-HDS i.e. R-high-dose Cyclophosphamide (R-HD-CTX) (4g/m2), 2 cycles of R-high-dose Ara-C (R-HDAC) (2g/m2 q12x3 d). CD34+ cells were collected after the first course of R-HDAC. The conditioning regimen for ASCT was BEAM. After ASCT, responding patients were randomized between LM (15 mg days 1-21 every 28 days) for 24 months or observation. Primary endpoint analysis was scheduled at the occurrence of the 60th PFS event in the randomized population, which occurred on June 20th, 2017 and data were analyzed for the present abstract on March 3rd 2018. Results. Three-hundred three patients were enrolled from May 2008 to August 2015 by 48 Italian and 1 Portuguese Center. Three patients were excluded after central histological review. Median age was 57 years (IQR 51-62), M/F ratio 3.6/1. Ninety-two percent of patients had stage IV, 33% bulky disease ( 〉 5 cm), 33% elevated LDH, and 75% BM infiltration. Ki67 ≥30% was observed in 32%, MIPI was low (L) in 54%, intermediate in 31% and high (H) in 15% of patients. MIPI-c was L in 49%, low-intermediate (LI) in 29%, high-intermediate (HI) in 14%, H in 9%. Nine percent had blastoid variant. Fifty-two (17%) patients interrupted treatment before randomization (8 toxic deaths, 1 death for car accident, 24 progressions and 19 toxicity/refusals). On an ITT basis, the R-HDS + ASCT program induced 78% of CR, 7% of PRs, 10% of PD, 3% of toxic deaths (TRM) and 2% NA. Median follow-up (mFU) from inclusion was 51 months. Three years PFS and OS for the enrolled population were 67% and 84%, respectively. Of 248 patients who received ASCT, 205 were randomized either to LM (n=104) or OBS (n=101) and 43 (17%) were not because of: lack of response (8), refusal/PI decision/delay (8), unresolved infections (3) and inadequate hematopoietic recovery (24). Feasibility and efficacy were assessed on an ITT basis while toxicity was analyzed on subjects receiving at least one Lenalidomide dose. In the LM arm, 53 out of 104 patients did not start or complete the planned maintenance because of death (2), AE (26), PD (7), still ongoing (2), other causes (16). In the OBS arm 32 patients did not complete the observation phase because of death (1), AE (1), PD (20), still ongoing (10), other causes (1). Overall 28% of patients received less than 25% of the planned Lenalidomide dose. Despite suboptimal exposure to study drug, with a mFU from randomization of 35 months, 22 PFS events were recorded in the LM cohort vs 38 in the OBS arm, resulting in a 3y-PFS of 80% (95% CI; 70%-87%) in the LM arm vs. 64% in the OBS arm (95% CI; 53%-73%), stratified HR 0.51; 95% CI 0.30-0.87; p=0.013 (Fig 1A). OS was superimposable in the two arms: 93% vs 86%, stratified HR 0.96, 95% CI 0.44-2.11, p= 0.91 (Fig1B). Two deaths were observed in the LM arm due to pneumonia and thrombotic thrombocytopenic purpura and one in the OBS arm due to pneumonia. Grade 3-4 hematological toxicity was seen in 63% of patients in LM vs 11% in the OBS arm with 59% vs 10% of patients experiencing granulocytopenia. Non-hematological grade 3 toxicity was comparable in the two arms except grade 3-4 infections (11% vs. 4%; Fisher's p=0.10). Second cancers occurred in 7 patients in the LM and 3 in the OBS arm (Fisher's p=0.20). Conclusions. Results from the MCL0208 trial indicate that LM has a clinically meaningful anti-lymphoma activity in MCL. However, the applicability of LM has some limitations in the context of patients undergoing intensified chemoimmunotherapy. Overall these data support the use of a maintenance regimen after ASCT in young MCL patients. Disclosures Ladetto: Roche: Honoraria; Celgene: Honoraria; Acerta: Honoraria; Jannsen: Honoraria; Abbvie: Honoraria; Sandoz: Honoraria. Di Rocco:Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Rossi:Novartis: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Janssen: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Mundipharma: Honoraria; Sandoz: Honoraria; Seattle Genetics: Research Funding; Alexion: Other: Travel expenses. Chiappella:Janssen: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Roche: Other: lecture fees; Teva: Other: lecture fees; Nanostring: Other: lecture fees; Amgen: Other: lecture fees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees. Rusconi:Celgene: Research Funding. Gomes da Silva:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Institution's payment for consultancy, Travelling support; Celgene: Other: Travelling support; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Roche: Other: Institution's payment for consultancy, Travelling support; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Research Funding. Vitolo:Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau. Martelli:Sandoz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; F. Hoffman-La Roche: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Mundipharma: 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.

Abstract: The association between hepatitis-C virus (HCV) infection and non-Hodgkin’s lymphomas (NHL) has been demonstrated in epidemiological studies. In Lombardia, a densely populated region of northern Italy with around 10 millions of inhabitants, the prevalence of infected people is around 5%. In 2008, the “Rete Ematologica Lombarda” (Hematology Network of Lombardia region) started a prospective multicentric observational study, with the aim to collect data on virological and hematological features, on treatment and outcome of HCV-related NHL. Herein, we present the final results of this study. Methods Between January 2008 and December 2012, 241 consecutive adult patients (pts) with first diagnosis of NHL associated with HCV-positivity were enrolled in this prospective observational study (“Registro Lombardo dei Linfomi HCV-positivi”), approved by the Regional Administration and by IRBs of 10 Hematology Centres of Lombardia region. All pts signed a written informed consent. HIV-positive pts were excluded. Results Median age at lymphoma diagnosis was 69 years (yrs) (range 32-90); females were 60%. Histotypes were classified as follows: diffuse large B-cell lymphoma (DLBCL) (44%), marginal zone lymphoma (MZL) (28%), follicular lymphoma (10%), low-grade B-cell lymphoma NOS (10%), small lymphocytic lymphoma (SLL) (3%), lymphoplasmacytic lymphoma (3%), mantle cell lymphoma (1%), peripheral T-cell lymphoma NOS (1%). Ann Arbor stage was III-IV in 79% of pts, with bone marrow involvement in 47%. ECOG score was ≥ 2 in 16% of pts; 63% of pts showed at least one extranodal localization (spleen in 22%, skin in 11%, liver in 10%, Waldeyer’s ring in 5%, ocular adnexa in 3%). Virological features and treatment details are summarized in Table 1. HCV-positivity was detected before the diagnosis of NHL in 166 pts (69%) and median time between HCV detection and NHL diagnosis was 11 yrs. Serum monoclonal component (p=0.003), autoimmunity manifestations (p 〈 0.001) and cryoglobulinemia (p=0.002) resulted more frequent in indolent NHL respect to aggressive subtypes. A shorter overall survival (OS) was observed in pts with ECOG ≥ 2 (p 〈 0.001), hemoglobin 〈 12 g/dl (p=0.008), albumin 〈 3.5 g/dl (p=0.005), platelets 〈 100 x 109/L (p 〈 0.001) and lactate dehydrogenase ≥ UNL (p=0.031). Data on first line treatment for NHL were available in 231 pts: 178 pts (77%) received chemotherapy (CHT) [plus Rituximab (R) in 122]; anthracycline contain-regimens (+/- R) were used in 121 pts (52%). Forty pts (17%) developed liver toxicity of any grade (grade III-IV in 19 pts) and 22 pts (10%) interrupted early the treatment. Fifty-three pts were treated with antiviral therapy (AT) for active HCV infection and among them 12 pts (8 MZL, 3 low-grade B-cell lymphoma NOS, 1 SLL) were treated with AT as first anti-lymphoma therapy; 8 pts obtained a virological response and a complete lymphoma response, 2 pts had a partial response (HCV-RNA negative in 1) , 1 pt had neither hematological nor virological response and 1 pt is still on therapy. After a median follow-up of 32 months, 47 pts (20%) died (24 with aggressive NHL, 23 with indolent NHL): 23 due to lymphoma, 10 due to cirrhosis/hepatocarcinoma, 7 due to other solid neoplasms, 7 due to other causes. Conclusions In this prospective study conducted in Lombardia, a northern region of Italy, the most common histologies of HCV-associated NHL are DLBCL and MZL. In nearly 70% of pts, first detection of HCV positivity preceded the lymphoma diagnosis. A proportion of pts developed meaningful liver toxicity and/or were not able to complete the therapeutic program. In the indolent lymphomas treated with AT as first anti-lymphoma approach, virological and hematological responses are achieved in about two thirds of pts. Disclosures: No relevant conflicts of interest to declare.

Abstract: The aim of this study was to describe individual training strategies in preparation to Giro d'Italia of three world class road cyclists who achieved a top 5 in the general classification. Day‐to‐day power meter training and racing data of three road cyclists (age: 26, 27, 25 years; relative maximum oxygen consumption: 81, 82, 80 ml·min −1 ·kg −1 ; relative 20‐min record power output: 6.6, 6.6, 6.4 W kg −1 ) of the 22 weeks (December–May) leading up to the top 5 in Giro d'Italia general classification were retrospectively analyzed. Weekly volume and intensity distribution were considered. Cyclists completed 17, 22, 29 races, trained averagely for 19.7 (7.9), 16.2 (7.0), 14.7 (6.2) hours per week, with a training intensity distribution of 91.3–6.5‐2.2, 83.6–10.6‐5.8, 86.7–8.9‐4.4 in zone 1‐zone 2‐zone 3 before the Giro d'Italia. Two cyclists spent 55 and 39 days at altitude, one did not attend any altitude camp. Cyclists adopted an overall pyramidal intensity distribution with a relevant increase in high‐intensity volume and polarization index in races weeks. Tapering phases seem to be dictated by race schedule instead of literature prescription, with no strength training performed by the three cyclists throughout the entire periodization.