Abstract: Many measurements at the LHC require efficient identification of heavy-flavour jets, i.e. jets originating from bottom (b) or charm (c) quarks. An overview of the algorithms used to identify c jets is described and a novel method to calibrate them is presented. This new method adjusts the entire distributions of the outputs obtained when the algorithms are applied to jets of different flavours. It is based on an iterative approach exploiting three distinct control regions that are enriched with either b jets, c jets, or light-flavour and gluon jets. Results are presented in the form of correction factors evaluated using proton-proton collision data with an integrated luminosity of 41.5 fb -1 at  √s = 13 TeV, collected by the CMS experiment in 2017. The closure of the method is tested by applying the measured correction factors on simulated data sets and checking the agreement between the adjusted simulation and collision data. Furthermore, a validation is performed by testing the method on pseudodata, which emulate various mismodelling conditions. The calibrated results enable the use of the full distributions of heavy-flavour identification algorithm outputs, e.g. as inputs to machine-learning models. Thus, they are expected to increase the sensitivity of future physics analyses.

Abstract: Background. The PI3Kδ inhibitor idelalisib given in combination with rituximab in relapsed/refractory chronic lymphocytic leukemia (R/R CLL) has been associated with an objective response in 81% of cases with a median PFS of 20.3 months in a phase-3 clinical trial (Sharman et al, JCO 2019). Because the efficacy of new drugs reported in clinical trials may not translate into similar results in the day-to-day practice, we performed an observational retrospective-prospective study on the efficacy and safety of idelalisib and rituximab (IR) in R/R CLL patients treated outside of clinical trials in Italian centers belonging to the GIMEMA group. Methods. R/R CLL patients treated with IR outside of clinical trials between July 2014 and May 2017 were enrolled. Treatment was initiated at symptomatic progression; treatment response and disease progression were assessed according to the NCI criteria. The data were extracted from the medical files and entered into case record forms (CRF) by each treating physician. Computerized and manual consistency checks were performed by the GIMEMA data center on newly entered forms and queries were issued in case of inconsistencies. The primary endpoint was progression-free survival (PFS), secondary endpoints were overall response rate (ORR), the percentage of patients on treatment at 12, 24 and 36 months, overall survival (OS) and response to the subsequent anti-leukemic treatment. Results. 149 R/R CLL patients from 35 Italian centers were included in the study. The baseline characteristics are shown in Table 1. At a median follow-up of 39.4 months, the median PFS was 22.9 months (95% CI 20.5-28.8). In univariate analysis, a shorter PFS was associated with ≥3 lines of therapy (p=0.0175) (Fig. 1a). The ORR (CR + PR) was 72.5%. Age ≤70 yrs (p=0.037) and a PS & lt;1 (p=0.014) were associated with a higher ORR. The median OS was 44.5 months (95% CI 32.5-NR). In univariate analysis, a shorter OS was associated with advanced stage (p=0.016) and ≥3 lines of therapy (p=0.0009) (Fig. 1b). Forty-eight%, 24.3% and 11.8% of patients were still receiving the study drug at 12, 24 and 36 months, respectively. Discontinuation at 12 months was due to toxicity in 60.8% of cases. Variables associated with a treatment duration & lt;12 months were advanced clinical stage (p=0.029) and a poor ECOG performance status (p & lt;0.001). Overall, 59 patients received a subsequent treatment, with an ORR of 64.4%. Median follow-up for these patients was 11 months (range 0.1-45.6). The 12-month OS were 85.5% (95% CI 74.6-98.1) for patients who discontinued RI for toxicity and 61.5% (95% CI 43.8-86.5) for those who discontinued for progression (p=0.0031) (Fig. 2). The only predictor for response to the new treatment was having received & lt;2 lines of therapy before RI (p=0.0153). Adverse events & gt;grade 3 during RI treatment were neutropenia (35% of cases), gastrointestinal disorders (17%), infections (17%) and transaminitis (6%). Conclusions. The results hereby observed show that the efficacy of IR in a cohort in a real-life RR/CLL with a long follow-up is superimposable to those reported in the pivotal clinical trial, suggesting that the patient population who received IR in the day-to-day clinical practice mirrored that enrolled in the trial. Advanced clinical stage and 3 or more previous lines of therapy were associated with shorter PFS and OS. Interestingly, PFS and objective measures of efficacy such as the proportion of patients still on treatment at 12, 24 and 36 months, as well as OS, were not influenced by the TP53 status. Furthermore, the majority of patents responded to the subsequent anti-leukemic treatment and relatively durable responses were observed in patients who discontinued IR due to toxicity. Disclosures Rigolin: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: 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, Research Funding, Speakers Bureau. Visentin:Janssen: Honoraria; Gilead: Honoraria; Abbvie: Honoraria. Coscia:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Farina:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Gaidano:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Sunesys: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Murru:Janssen: 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; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Varettoni:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Travel/accommodations/expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses. Sportoletti:Janssen: Honoraria; AbbVie: Honoraria. Laurenti:Janssen: Honoraria; Gilead: Honoraria; AbbVie: Honoraria; Roche: Honoraria. Marasca:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria. Marchetti:Takeda: Other: Sponsored meetings; Gilead: Consultancy; Novartis: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Other: Sponsored meetings; Pfeizer: Other: Sponsored meetings. Mauro:Jannsen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Octopharma: Consultancy; Astrazeneca: Membership on an entity's Board of Directors or advisory committees. Molica:Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pane:Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Other: Travel Expenses; Bristol Myers Squibb: 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, Speakers Bureau. Gozzetti:Janssen: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Galieni:Celgene: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Krampera:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Trentin:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria. Montillo:AbbVie: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding; Janssen: Honoraria, Speakers Bureau; Verastem: Honoraria; Gilead: Honoraria, Speakers Bureau; Astra Zeneca: Honoraria. Foà:Incyte: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees. Cuneo:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract: The GIMEMA group investigated the efficacy, safety, and rates of discontinuations of the ibrutinib and rituximab regimen in previously untreated and unfit patients with chronic lymphocytic leukemia (CLL). Treatment consisted of ibrutinib, 420 mg daily, and until disease progression, and rituximab (375 mg/sqm, given weekly on week 1–4 of month 1 and day 1 of months 2–6). This study included 146 patients with a median age of 73 years, with IGHV unmutated in 56.9% and TP53 disrupted in 22.2%. The OR, CR, and 48-month PFS rates were 87%, 22.6%, and 77%, respectively. Responses with undetectable MRD were observed in 6.2% of all patients and 27% of CR patients. TP53 disruption (HR 2.47; p = 0.03) and B-symptoms (HR 2.91; p = 0.02) showed a significant and independent impact on PFS. The 48-month cumulative rates of treatment discontinuations due to disease progression (DP) or adverse events (AEs) were 5.6% and 29.1%, respectively. AEs leading more frequently to treatment discontinuation were atrial fibrillation in 8% of patients, infections in 8%, and non-skin cancers in 6%. Discontinuation rates due to AEs were higher in male patients (HR: 0.46; p = 0.05), patients aged ≥70 years (HR 5.43, p = 0.0017), and were managed at centers that enrolled 〈 5 patients (HR 5.1, p = 0.04). Patients who discontinued ibrutinib due to an AE showed a 24-month next treatment-free survival rate of 63%. In conclusion, ibrutinib and rituximab combination was an effective front-line treatment with sustained disease control in more than half of unfit patients with CLL. Careful monitoring is recommended to prevent and manage AEs in this patient population.

Abstract: As a reliable scoring system to detect the risk of symptomatic intracerebral hemorrhage after thrombectomy for ischemic stroke is not yet available, we developed a nomogram for predicting symptomatic intracerebral hemorrhage in patients with large vessel occlusion in the anterior circulation who received bridging of thrombectomy with intravenous thrombolysis (training set), and to validate the model by using a cohort of patients treated with direct thrombectomy (test set). Methods— We conducted a cohort study on prospectively collected data from 3714 patients enrolled in the IER (Italian Registry of Endovascular Stroke Treatment in Acute Stroke). Symptomatic intracerebral hemorrhage was defined as any type of intracerebral hemorrhage with increase of ≥4 National Institutes of Health Stroke Scale score points from baseline ≤24 hours or death. Based on multivariate logistic models, the nomogram was generated. We assessed the discriminative performance by using the area under the receiver operating characteristic curve. Results— National Institutes of Health Stroke Scale score, onset-to-end procedure time, age, unsuccessful recanalization, and Careggi collateral score composed the IER-SICH nomogram. After removing Careggi collateral score from the first model, a second model including Alberta Stroke Program Early CT Score was developed. The area under the receiver operating characteristic curve of the IER-SICH nomogram was 0.778 in the training set (n=492) and 0.709 in the test set (n=399). The area under the receiver operating characteristic curve of the second model was 0.733 in the training set (n=988) and 0.685 in the test set (n=779). Conclusions— The IER-SICH nomogram is the first model developed and validated for predicting symptomatic intracerebral hemorrhage after thrombectomy. It may provide indications on early identification of patients for more or less postprocedural intensive management.

Abstract: In chronic lymphocytic leukemia (CLL) the distribution and prognostic impact of genetic and molecular markers has been assessed on retrospective series of patients in different phases of the disease. Our aim was to assess the distribution and clinical significance of a comprehensive panel of clinical and biologic parameters prospectively evaluated at presentation in all young patients diagnosed with CLL at our Institution, taking advantage of the fact that in Italy individuals with a lymphocytosis are referred to the hematologist for the diagnostic work-up. From November 2002 to June 2008, 105 young CLL patients ( & lt;60 years-old) were diagnosed with CLL and included in this study. There were 56 males and 49 females, with a median age of 52 years-old. 81% were in Binet stage A, 19% in stages B/C. Rai stage 0 was recorded in 63% of patients, I/II in 31%, III/IV in 6%. The median white blood cell (WBC) count was 18.8 × 109/L (range 5.8–236.6). Prognosis was evaluated as the time from diagnosis to first treatment (TFI, treatment-free interval), since only 3 patients died after a median follow-up of 32.4 months (range 1 to 88). The median TFI was 43.9 months. Clinical features included: gender, WBC count, Binet and Rai stage. Serological and biologic parameters included: beta2-microglobulin, LDH, IgG immunoglobulin levels, lymphocyte morphology, T-cell subsets, IgVH mutational status, CD38 and ZAP-70 expression, cytogenetic abnormalities evaluated by FISH, p53 protein expression and p53 gene sequencing (exon 5 to 8). The distribution of the prognostic markers is summarized in the table. Raised beta2-microglobulin and LDH were present only in 5% and 15% of cases, respectively. The CD4/CD8 ratio was normal in almost all cases. The proportion of unmutated IgVH, CD38 and ZAP-70 positive cases was about one third of the cohort of CLL patients at diagnosis. The incidence of del(17p) (cut off & gt;20% cells) and del(11q) (cut off & gt;10% cells) was 2% and 7%, respectively. Patients with del(17p) or del(11q) exclusively showed unmutated IgVH and ZAP-70+, and were mostly CD38+. p53 mutations were present in 4 cases, 3 with unmutated IgVH and del(17p) and 1 with mutated IgVH and no del(17p). In univariate analysis, the following variables resulted associated to a short TFI: advanced stage Binet B/C and Rai I/IV ( & lt;0.0001), WBC count ( & lt;0.0001), proportion of CD3+ cells & lt;16% (0.0002), raised beta2-microglobulin ( & lt;0.0001) and LDH ( & lt;0.0001), unmutated IgVH ( & lt;0.0001), CD38+ ( & lt;0.0001), ZAP-70+ ( & lt;0.0018), adverse cytogenetic abnormalities (del(17p), del(11q), +12) ( & lt;0.0001). Atypical CLL morphology showed a trend for significance (0.06). Multivariate analysis on TFI - including WBC count (as continuous variable), CD3 %, LDH, IgVH mutation status, ZAP-70 and CD38 expression and corrected with interaction between WBC and IgVH status - was focused on the 84 patients with Binet stage A. High WBC count, raised LDH, unmutated IgVH resulted as unfavorable prognostic factors, whilst the proportion of CD3+ cells was associated with a better outcome. Neither ZAP-70 or CD38 showed an independent prognostic value. In CLL cases with discordant expression of ZAP-70 and IgVH mutation status (25% of cases), the latter appeared to be more relevant than ZAP-70 in determining the TFI. In conclusion, unmutated IgVH, raised LDH, WBC count and a low proportion of CD3+ cells at diagnosis are significant predictors of TFI in early stage CLL. This group represents about one third of young patients at diagnosis. Adverse FISH abnormalities are present only in a small subgroup of cases in the early phases of the disease. Young CLL patients at diagnosis N° of cases % Raised beta2-microglobulin ( & gt;3400 ng/l) 5/102 5% Raised LDH 16/105 15% Hypo IgG 21/98 21% Atypical morphology 27/104 26% CD3+ cells ( & lt;16%) 60/105 57% CD4/CD8 ( & lt;1) 3/101 3% IgVH mutated (≥98%) 67/103 65% IgVH unmutated ( & lt;98%) 36/103 35% CD38 ≥7% 25/104 24% ZAP-70 ≥10% 39/100 39% Del(17p) & gt;20% 2/104 2% Del(11q) & gt;10% 7/104 7% +12 & gt;5% 7/104 7% Del(13q) & gt;5% isolated 59/104 57% Normal (none of the above) 29/104 28% p53 protein expression 3/100 3% p53 gene mutation 4/105 4%

Abstract: Abstract 1377 Targeting the CLL microenvironment with immunomodulatory agents like lenalidomide results in antileukemic activity. Addition of lenalidomide to an effective regimen such as fludarabine and cyclophosphamide (FC) could further increase therapeutic activity. On this basis, we designed a study aimed at evaluating the activity and safety profile of FC combined with lenalidomide (FCL) in previously treated CLL patients. Treatment consists of 6 monthly courses of FC (F, fudarabine: 30 mg/m2 iv and C, cyclophosphamide: 250 mg/m2, days 1–3) combined with 14 consecutive days of lenalidomide administration (days1-14). The first phase of this study was focused on defining the maximum tolerated dose (MTD) of lenalidomide given in combination with FC. In all patients, lenalidomide was given at the starting dose of 2.5 mg daily during the first course. For the subsequent courses the dose of lenalidomide was progressively escalated to reach a maximum daily dose of 5 mg, 10 mg and 15 mg, respectively, in each 3 cohorts of 3 patients, unless a dose limiting toxicity (DLT) was experienced. DLT was defined as persistent and severe hematologic toxicity, grade ≥2 tumor lysis syndrome (TLS), grade ≥3 tumor flare reaction (TFR) or other grade ≥3 toxicities. Supportive treatment included primary prophylaxis of granulocytopenia (G-CSF, days 6–11), PC and HVZ prophylaxis, thromboembolic prophylaxis with low molecular weight heparin (enoxaparin, 4000 units/sc/day) and TLS prophylaxis (oral hydration, allopurinol 300 mg/day, days -3 - 90). Strict contraceptive measures were required for all males and females with childbearing potential. At present, 9 relapsed CLL patients with advanced disease have been included in the first phase of the study focused on identifying the MTD for lenalidomide given in combination with FC. The median age was 63 years (range: 50–68); the median number of prior treatments was 2 (range: 1–2). All patients but 1 had been previously treated with the FC/FCR regimens; the majority showed a considerably high white blood count (range: 33–216 × 109/L) and 2 had a bulky nodal disease. Adverse cytogenetic abnormalities were detected by FISH in 5 cases (17p-, 2 cases; 6q-, 3 cases). While no DLT was observed in 3 patients who reached the 5 mg dose of lenalidomide given in combination with FC, a DLT was recorded in 2 of 3 patients who received 10 mg of lenalidomide (pneumonia; grade 3 hepatic toxicity). The 5 mg dose of lenalidomide was tested in 3 further patients with no DLT. Thus, 5 mg of lenalidomide was defined as the MTD of lenalidomide given in combination with FC. A marked reduction of white blood count was observed within the first 2 weeks of treatment in all cases but 1. A response was observed in 6 patients (67%; CR, 3; PR, 3), while a treatment-failure was recorded in 3 cases (SD, 2; Richter's syndrome,1). Despite G-CSF prophylaxis, the majority of patients experienced transient grade 3–4 neutropenia. Grade 1 fatigue and constipation were frequently observed during the first course of treatment. A transient grade 1 TFR was documented, while no episodes of TLS and thrombosis were recorded. Our findings indicate that 5 mg daily is the MTD of lenalidomide given in combination with FC. Initial responses suggest that FCL is a promising investigational regimen for patients with CLL who have failed prior treatment with fludarabine-based combinations. In the ongoing phase 2 of this study 32 patients are planned to receive 5 mg of lenalidomide in combination with FC. Disclosures: Foà: Celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract: Abstract 4373 In chronic lymphocytic leukemia (CLL), the distribution and prognostic impact of genetic and molecular markers have been mostly investigated in retrospective studies including patients in different phases of the disease. From November 2002 to May 2009, we prospectively assessed the clinical and biologic features of 219 young CLL patients ('65 years), distributed in three different cohorts: 124 cases at diagnosis, of which 99 in Binet stage A (group 1), 68 at first progression (group 2), 27 at progression after one or more therapies (group 3). Median age was 52 years for group 1, 57 years for group 2 and 61 years for group 3. Advanced disease defined as Rai stage III/IV was present in 6%, 19% and 48% patients and as Binet stages B/C in 19%, 68% and 78% patients in the 3 cohorts, respectively. The proportion of unmutated IgVH cases progressively and significantly increased, being 36% in group 1, 48.5% in group 2 and 75% in group 3 (p 0.001). The same trend was found for CD38 (p 0.01). The incidence of ZAP-70 expression and p53 mutations showed a trend towards a progressive increase among the three groups (41%, 55% and 56.5% for ZAP-70 and 4%, 7% and 12.5% for p53 mutations), without however reaching significance. The incidence of del(17p) ≥20% raised progressively from group 1, to groups 2 and 3 (2%, 4.5% and 18.5%, respectively; p 0.001). The incidence of del(11q) increased from group 1 to 2 (10% and 16%; p 0.18), though it was not higher in group 3 (7.5%). Focusing the comparison to groups 1 and 2 only, i.e. patients with CLL at diagnosis in all stages and patients at first progression of the disease requiring therapy, the distribution of prognostic markers did not differ significantly, except for a lower proportion of cases expressing CD38, although the proportion of del(17p) 〉 20% and 〉 10% and of +12 doubled. When the analysis was restricted to stage A CLL at diagnosis, there was a highly significant difference in the lower proportion of unmutated IgVH (0.003), CD38 expression (p 0.009), ZAP-70 expression (p 0.004), del(17p) (p 0.034) and in the higher proportion of del(13q) (p 0.028) in comparison with CLL at first progression. No patient with stage A CLL at diagnosis showed del(17p) ≥20%, whilst 2% showed del(17p) 〉 10% and 3% harbored p53 mutations. Of the 40 patients evaluated by FISH at multiple time points, 35% showed clonal evolution. Only previous treatment was significantly associated with the development of clonal evolution, whilst no correlation with the IgVH mutational status, ZAP-70 or CD38 expression was found. Patients of group 1 required treatment after a median time of 49.6 months from diagnosis. Treatment-free interval (TFI) was significantly shorter in cases with IgVH unmutated vs. mutated (at 48 months, 16.5% and 68.3%, respectively p 〈 0.0001), CD38 pos vs. neg (at 48 months 12.5% vs. 61.3%, p 〈 0.0001) and ZAP-70 pos vs neg (39.1% vs. 58.9%, p=0.0049). Cases with del(17p) or del(11q) had a TFI at 48 months of 0% versus 25% for cases with +12 and 61.7% for cases with del(13q) or no abnormalities (p 〈 0.0001). IgVH status and white blood cell count were the only independent predictors of TFI in multivariate analysis (p=0.0005 and p=0.012, respectively). The same prognostic impact was shown in the stage A subgroup. The variable incidence of the biologic factors with prognostic impact has to be considered when patients in different phases of the disease are investigated, both in terms of the timing of the assessment and of the design of clinical trials. Reassessment of genetic abnormalities during the course of CLL is warranted, especially after treatment. Disclosures: No relevant conflicts of interest to declare.

Abstract: Introduction. The fludarabine, cyclophosphamide, rituximab (FCR) regimen is associated with high complete response (CR) rates and a negative residual disease status in a significant proportion of cases and is considered the optimal front-line treatment for fit patients with chronic lymphocytic leukemia (CLL). In addition, long-term follow-up of patients treated with FCR at the MD Anderson Cancer Center, in the multicenter German CLL8 study and at Italian institutions indicate that a sizable fraction of patients characterized by a favorable biologic profile remains free from progression in excess of 10 years. FC combined with ofatumumab (FC-O), a human monoclonal antibody which targets an epitope of the CD20 molecule, has also been associated with a high CR rate. The aim of this study was to evaluate whether a double dose of ofatumumab (O2) combined with FC could improve the CR rate in young (≤65 yrs) and fit patients with CLL. Methods. Sixty-one fit CLL patients from 15 Italian institutions were enrolled in this front-line study and treated with the FC-O2 regimen based on the FC schedule (F 25 mg/sqm i.v. d1-3, C 250 mg/sqm i.v. d1-3) combined with 13 doses of O (300 mg i.v. d14; 1000 mg d21 at the first cycle; 1000 mg d1 and d15 at cycles 2-6 and d28 at cycle 6). As infection prophylaxis, patients received bactrim and peg-filgrastim in order to prevent granulocytopenia. CLL diagnosis, treatment requirement and response were assessed according to the 2008 iwCLL guidelines. Minimal residual disease (MRD) was evaluated by flow cytometry in the peripheral blood (PB) and bone marrow (BM), and also by RQ-PCR in flow negative cases. CT scan evaluation was included in the response assessment. Adverse events (AEs) were graded according to the NCI-CTCAE. Results. The median age of patients was 60 years (range 36-65), Binet stages B and C were recorded in 86% of cases, B-symptoms in 21%, increased β2M values in 74% and bulky nodes (≥5 cm) in 10%. An IGVH unmutated status was recorded in 60% of cases, deletion 13q in 37%, no aberrations in 33%, deletion 11q in 14%, trisomy 12 in 12%, 17p deletion and/or TP53 mutation were found in 10% of cases. At present, the median follow-up of patients is 7 months (range 1-20). Response to treatment has been assessed in 29 patients after a median number of 6 courses of treatment (range 2-6). The overall response rate is 90%, with a CR rate of 69% (20 patients). No evidence of MRD was observed by flow cytometry in both PB and BM in 15/20 CR patients (75%). To date, 11 patients with cytometric MRD negative CR have been evaluated by RQ-PCR and no residual disease was detected in 3. Grade 3-4 granulocytopenia was recorded in 4 patients (7%), a severe infection in 4 (7%) and 5 patients (8%) experienced a severe infusion-related reaction during ofatumumab administration. Treatment was discontinued in 8 patients as a result of toxicity (infection, 2 cases; FUO, 1; infusion-related toxicity, 1; autoimmune hemolytic anemia, 1; recurrent granulocytopenia, 1; tachyarrhythmia, 1; non-specified toxicity,1). A non-treatment-related death (traumatic aortic transaction due to a dislocated aortic endoprostheses) has been recorded in a patient after 2 months from treatment discontinuation and 1 showed a disease progression after 4 courses of FC-O2. Conclusions. Taken together, the first analysis of this ongoing front-line study suggests that the combination of FC with an increased dose of ofatumumab is well tolerated with acceptable and no unexpected toxicity. Our preliminary results show that the FC-O2 treatment is associated with a high rate of cytometric MRD-negative CR in young and fit patients with previously untreated CLL. Disclosures Carella: Seattle Genetics Inc.: Research Funding. Foà:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.