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2871 Introduction. The addition of Rituximab to standard CHOP chemotherapy has improved outcome of DLBCL; however, 30–40% of patients do not response or relapse after induction treatment. The use of Lenalidomide, as single-agent in relapsed or refractory aggressive NHL has been encouraging, with an overall response rate (ORR) of 19% for DLBCL. Preclinical evidence suggests that Lenalidomide may be synergistic with Rituximab. However the safety and efficacy of Lenalidomide combined with R-CHOP is not yet fully evaluated. Aims. On these basis, the IIL is running a prospective multicenter dose finding phase I-II pilot trial to evaluate efficacy and safety of Lenalidomide treatment plus R-CHOP21 (LR-CHOP21) for elderly patients with untreated DLBCL (registered at http://www.clinicaltrials.gov, NCT00907348). The primary endpoint for the phase I part of the study was: definition of Dose Limiting Toxicity (DLT) considered as the maximum dose inducing any grade ≥3 non-hematologic toxicity, or a >15 days delay of planned cycle date. The primary endpoint for the phase II part of the study was: complete response (CR) and ORR. Herein we report the results of phase I. Patients and Methods. Inclusion Criteria were: age 60–80; histologically proven CD20+ DLBCL; no prior chemotherapy and no prior malignancies in the last 3 years; Ann Arbor stage II, III, IV; International Prognostic Index (IPI) at low-intermediate, intermediate-high or high risk score. Treatment consisted of 6 courses of R-CHOP21 in association with Lenalidomide for days 1–14 at the established dose level (5, 10, 15, 20 mg), with Peg-Filgrastim support and prophylactic sc. low-molecular weight heparin. Phase I of the study was planned to define the Maximum Tolerated Dose (MTD) that is the dose that achieves a DLT in 33% or less patients evaluated after the first three courses of LR-CHOP21. The study was designed with the Continual Reassessment Method, a Bayesian “memory design” that begins with a subjective prediction of the dose-response relationship and uses, as dose allocation rule of the sequentially incoming patients, the re-estimated probability of toxicity based on the results obtained for the patients already observed. Four doses of Lenalidomide were tested: 5, 10, 15 and 20 mg. By decision of the steering committee of the study, a dose of 10 mg was administered to the first cohort of 3 patients; in the light of the observed toxicity the probability model assigned the next cohort to the dose with the higher probability to met the required MTD. At the end of each cohort, the dose level associated with an updated DLT probability closest to 33% was recommended to be administered to the next patient cohort. Results. In phase I, from May 2008 to February 2010, 21 patients were enrolled. Median age was 69 years (61-78), stage II/III/IV were 4/4/13 respectively, B symptoms in 11, PS 2 in 8, bone marrow involvement in 6, abnormal LDH in 8, intermediate-high or high IPI score in 15. Patient allocation by Lenalidomide dose was: none patients received 5 mg/day, nine patients received 10 mg/day, nine patients 15 mg/day and three patients 20 mg/day on days 1–14 of each LR-CHOP21 courses. The flow of the dose allocation and the observed DLTs are shown in figure 1. DLTs in the first three courses were recorded in seven patients (see figure 1 for details). These data, according to the continual reassessment method, determined Lenalidomide 15 mg as MTD in association to R-CHOP21. One-hundred-fifteen courses of LR-CHOP21 were performed in the whole series of 21 patients. Overall hematological toxicity was moderate: grade III or IV thrombocytopenia occurred in 10%, anemia in 4% and neutropenia in 28% of the courses. Extra-hematological toxicities were mild: only one patient with grade IV (increase of CPK), two patients with grade III cardiac, three with grade III neurological toxicities, and three patients with grade III infections (two pneumonias and one febrile neutropenia with diarrhea). At the end of six LR-CHOP21 courses, 15/21 patients achieved CR, 1/21 partial remission and 5/21 were not responsive. Conclusions. Lenalidomide 15 mg on days 1–14 in association with R-CHOP21 is the MTD for LR-CHOP. This schedule is safe and well tolerated in a population of elderly DLBCL patients. Preliminary efficacy results are promising. The ongoing phase II part of the LR-CHOP21 trial aims at evaluating the efficacy of 15 mg of Lenalidomide in association with R-CHOP21. Disclosure: Vitolo: Roche Italy: advisory committee; Celgene Italy: advisory committee; Janssen-Cilag: lecture-fee. Off Label Use: The use of Lenalidomide is off-label in untreated DLBCL.

1606 Introduction. Diffuse Large B-cell Lymphoma (DLBCL) patients at high-risk (age-adjusted International Prognostic Index (aa-IPI) 2–3), had a dismal prognosis if treated with conventional chemotherapy. The introduction of intensive regimens and the addition of monoclonal antibody anti-CD20, improved prognosis, but some issues remain unresolved such as: the risk of central nervous system (CNS) relapses and the incidence of late toxicities. We analyzed a series of young DLBCL patients at high-risk consecutively treated in four prospective trials by the Italian Lymphoma Foundation (FIL) with the aim to assess the risk of CNS relapses and late toxicities in this series of patients with a prolonged follow-up Methods. From 1986 to 2006, 278 patients with DLBCL with aa-IPI 2–3 at diagnosis, were enrolled in four consecutive trials previously reported. Thirty-two into a phase II study, treated with 12 weekly infusion of MACOP-B; 39 into a phase II trial with eight weekly MACOP-B infusions followed by high-dose cytarabine, mitoxantrone and dexamethasone (MAD) plus standard BEAM and autologous stem cell transplantation (ASCT); 95 in a phase III trial that randomized high-dose sequential (HDS) chemotherapy plus ASCT (45 patients) vs six courses of dose-dense intensified CHOP (iCHOP) (50 patients); 112 into a phase II trial with four courses of iCHOP in combination with Rituximab followed by Rituximab-MAD + BEAM and ASCT. CNS prophylaxis was not mandatory in the four protocols. Updated data regarding of survival, CNS relapses and late toxicities were recorded on June 2011. Results. Clinical characteristics were: aa-IPI 2 in 55%, aa-IPI 3 in 45%, PS > 2 in 66%, LDH upper normal value in 89%, number of extranodal sites > 2 in 35%, bone marrow involvement in 27% of patients, with no statistical differences between the four trials. With a median follow-up of five years, 5-year Overall Survival (OS) was 63% (95% CI: 57–69%) in the whole series; 5-year OS by treatment was 41% (95%CI: 24–74%) in MACOPB, 54% (95%CI: 37–68%) in MACOPB+MAD+BEAM and ASCT; 53% (95%CI: 38–67%) in HDS+ASCT; 58% (95%CI: 43–70%) in iCHOP; 79% (95%CI: 70–86%) in R-iCHOP+R-MAD+BEAM and ASCT. In a multivariate analysis, the risk of death was significantly reduced in R-iCHOP+R-MAD+BEAM and ASCT (p<.001) and was adversely influenced by age with a progressive increase of five years at diagnosis (p.008) or aa-IPI3 (p.001). Four patients experienced CNS relapses, three of them in R-iCHOP+R-MAD+BEAM and ASCT and one in MACOPB. Only one of the four patients received CNS prophylaxis with intrathecal Methotrexate, even if all of them were at risk for CNS relapse according to Italian Society of Hematology guidelines (Barosi, Hematol 2006). Cumulative incidence of CNS recurrence at 10 years for R-iCHOP+R-MAD+BEAM and ASCT regimen was 3.6% (0 to 7.8). Most frequent late toxicities were dyslipidemia and secondary amenorrhea. Regarding to secondary malignancies, myelodisplasia or acute myeloid leukemia were recorded in three patients, two of them treated with R-iCHOP+R-MAD+BEAM and ASCT, at a median time of seven years off therapy. The actuarial risk of secondary malignancies at 10 years for R-iCHOP+R-MAD+BEAM and ASCT was 4.2% (0 to 10). Conclusions. The addition of Rituximab to dose-dense iCHOP plus high-dose chemotherapy plus BEAM and ASCT improved the outcome in young untreated DLBCL patients at poor prognosis, with an acceptable risk of secondary malignancies and late toxicities. A careful identification of patients at risk could avoid the risk of CNS relapse. Disclosures: Vitolo: Roche Italy: Speakers Bureau; Celgene: Speakers Bureau; Jannsen-Cilag: Speakers Bureau.

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