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Incidence of Medication-Related Osteonecrosis of the Jaw (MRONJ) related to cancer and myeloma treatments is yet to be assessed, with scarce epidemiologic data available from surveys of limited investigated populations. A 16-year (Jan 1 st , 2003 - Dec 31 st , 2018) regional-wide, multicenter retrospective survey was carried out through the regional database of the cancer network in North-Western Italy (Rete Oncologica di Piemonte e Valle d’Aosta), aiming to assess overall frequency, raw incidence and main characteristics of MRONJ cases among myeloma/cancer patients, over a population of 4.4 million inhabitants. Main characteristics: 691 patients (261 M, 430 F); mean age: 68 (38-90) years. Underlying diseases: metastatic breast cancer (43.8%), myeloma (24.1%), metastatic prostate cancer (19.1%), other cancer (13%). Main treatment: zoledronate (71.9%), denosumab (5.3%), other drugs/sequences (22.8%). Sites of MRONJ: mandible (63.3%), maxilla (27.7%), maxilla and mandible (9%). Median number of MRONJ cases: 44 (range: 3-66) cases/year. MRONJ occurrence was registered mostly after 12-36 months of treatment (range: 1-227 months). As a result of cases observed in the regional cancer network centers, we estimated a raw unadjusted incidence ranging between 4.8 and 13 cases/million/year, with a mean of 9.5 cases/million/year and a median of 10.1 cases/million/year. The present, decades-long multicenter retrospective study represents un almost unprecedented collaboration between Oncology, Hematology, Oral Medicine / Surgery and Oral Maxillo-Facial Surgery units, to investigate the issue of MRONJ, in Italy. According to these data, MRONJ does not seem to be a rare event in metastatic cancer and myeloma populations, and should require the pursuit of such a multidisciplinary effort both in prevention and treatment.

Survival of cancer and myeloma patients after diagnosis of bone lesions is largely variable. Appropriate medical therapy together with antiresorptive treatment (bisphosphonates or denosumab) can obtain prolonged survival with adequate quality of life. Osteonecrosis of Jaws (ONJ) is not rare in patients with bone metastatic cancer and myeloma patients, occurring mostly after prolonged antiresorptive treatment. Expected survival can influence the choice of antiresorptive treatment, the perception of ONJ risk, and even the ONJ management. We reviewed survival data after start of antiresorptive treatment of 509 ONJ patients registered in a cancer network database (Rete Oncologica Piemonte-Valle d’Aosta, North-Western Italy). Main characteristics: 196 males, 313 females; median age: 68 (39-89) years. Underlying disease: breast cancer: 42.9%; myeloma: 25.3%; prostate cancer: 17.2%; lung cancer: 6.7%; renal cancer: 2.5%; other cancer types: 4.3%. Main antiresorptive treatment: zoledronic acid: 79.4%; denosumab: 5.3%; other drugs/sequences: 15.3%. Actuarial median survival (range) after the start of antiresorptive treatment was 66.0 (95% CI 57-77) months for breast cancer patients, 77.3 (95% CI 61.9-86.8) months for myeloma patients, 47.3. (95% CI 37.8-51.9) months for prostate cancer patients, 29.4 (95% CI 20.4-40.1) months for lung cancer patients, 39.4 (95% CI 20-107.3) months for renal cancer patients, 82.4 (95% CI 51.9-150.9) months for other cancer patients. Two-, three- and four-year actuarial survival rates were respectively 91.7%%, 80.2%, 67.4% for breast cancer patients, 91.4%, 83.7%, 68.9% for myeloma patients, 78.4%, 61.2%, 41.9% for prostate cancer patients; 55.8%, 32.3%, 23.5% for lung cancer patients; 61.5%, 53.8%, 46.1% for renal cancer patients; 81.8%, 77.3%, 68.1% for others cancer types. Our data support careful evaluation of short and long-term actuarial ONJ risk (versus short-term absolute risk) in the choice of antiresorptive treatment duration for bone metastatic cancer and myeloma patients. Furthermore, exclusion of jawbone surgery due to expected short survival in most of ONJ patients seems not warranted.

Treatment for follicular lymphoma (FL) in the elderly is not well standardized. A phase II, multicentre, single arm trial was conducted in this setting with a brief chemoimmunotherapy regimen. Treatment consisted in four monthly courses of rituximab, bendamustine and mitoxantrone (R-BM) followed by 4 weekly rituximab as consolidation; rituximab maintenance was not applied because the drug was not licensed at the time of enrolment. The primary endpoint was the complete remission rate (CR). Seventy-six treatment-naive FL patients (aged 65-80 and a "FIT" score, according to the Comprehensive Geriatric Assessment) were enrolled. CR was documented in 59/76 patients (78%), partial remission in 12 (16%) and stable/progressive disease in five (6%) with an overall response rate in 71/76 (94%). Median follow-up was 44 months with 3-year progression-free-survival (PFS) and overall-survival of 67% and 92% respectively. Nine deaths occurred, three of progressive disease. The regimen was well tolerated and the most frequent severe toxicity was neutropenia (18% of the cycles). Bcl-2/IGH rearrangement was found in 40/75 (53%) of evaluated patients. R-BM was highly effective in clearing polymerase chain reaction-detectable disease: 29/31 (96%) evaluated patients converted to bcl-2/IGH negativity at the end of treatment. A brief R-BM regimen plus rituximab consolidation is effective and safe in "FIT" elderly, treatment-naive, FL patients, inducing high CR and molecular remission rates with prolonged PFS.

Key Points The prognosis of patients with advanced HL who achieved CMR after both 2 and 6 ABVD cycles is excellent without consolidation RT.An additional benefit of consolidation RT of sites >5 cm is likely to be small and could not be proved for this small sample size., Visual Abstract, The role of consolidation radiotherapy (RT) for bulky lesions is controversial in patients with advanced-stage Hodgkin lymphoma who achieve complete metabolic response (CMR) after doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD)–based chemotherapy. We present the final results of the Fondazione Italiana Linfomi HD0801 trial, which investigated the potential benefit of RT in that setting. In this phase 3 randomized study, patients with a bulky lesion at baseline (a mass with largest diameter ≥5 cm) who have CMR after 2 and 6 ABVD cycles were randomly assigned 1:1 to RT vs observation (OBS) with a primary endpoint of event-free survival (EFS) at 2 years. The sample size was calculated estimating an EFS improvement for RT of 20% (from 60% to 80%). The secondary end point was progression-free survival (PFS). One hundred sixteen patients met the inclusion criteria and were randomly assigned to RT or OBS. Intention-to-treat (ITT) analysis showed a 2-year EFS of 87.8% vs 85.8% for RT vs OBS (hazard ratio [HR], 1.5; 95% confidence interval [CI], 0.6-3.5; P = .34). At 2 years, ITT-PFS was 91.3% vs 85.8% (HR, 1.2; 95% CI, 0.5-3; P = .7). Patients in CMR randomly assigned to OBS had a good outcome, and the primary end point of a 20% benefit in EFS for RT was not met. However, the sample size was underpowered to detect a benefit of 10% or less, keeping open the question of a potential, more limited role of RT in this setting. This trial was registered at www.clinicaltrials.gov as #NCT00784537.

BACKGROUND Azacitidine (AZA) is the standard treatment for myelodysplastic syndromes (MDS); however, many patients prematurely stop therapy and have a dismal outcome. METHODS The authors analyzed outcomes after AZA treatment for 402 MDS patients consecutively enrolled in the Italian MDS Registry of the Fondazione Italiana Sindromi Mielodisplastiche, and they evaluated the North American MDS Consortium scoring system in a clinical practice setting. RESULTS At treatment discontinuation, 20.3% of the patients were still responding to AZA, 35.4% of the cases had primary resistance, and 44.3% developed adaptive resistance. Overall survival (OS) was better for patients who discontinued treatment while in response because of planned allogeneic hematopoietic stem cell transplantation (HSCT; median OS, not reached) in comparison with patients with primary resistance (median OS, 4 months) or adaptive resistance (median OS, 5 months) or patients responsive but noncompliant/intolerant to AZA (median OS, 4 months; P = .004). After AZA discontinuation, 309 patients (77%) received best supportive care (BSC), 60 (15%) received active treatments, and 33 (8%) received HSCT. HSCT was associated with a significant survival advantage, regardless of the response to AZA. The North American MDS Consortium scoring system was evaluable in 278 of the 402 cases: patients at high risk had worse OS than patients at low risk (3 and 7 months, respectively; P < .001). The score was predictive of survival both in patients receiving BSC (median OS, 2 months for high-risk patients vs 5 months for low-risk patients) and in patients being actively treated (median OS, 8 months for high-risk patients vs 16 months for low-risk patients; P < .001), including transplant patients. CONCLUSIONS Real-life data confirm that this prognostic scoring system for MDS patients failing a hypomethylating agent seems to be a useful tool for optimal prognostic stratification and for choosing a second-line treatment after AZA discontinuation.

This phase-II study assessed activity and toxicity of substituting conventional doxorubicin with nonpegylated liposomal doxorubicin in the conventional ABVD regimen for the treatment of elderly or cardiopathic patients with HL. Stage I-IIA and IIB-IV patients were treated with three courses of MBVD plus radiotherapy, or six courses of MBVD, respectively, plus radiotherapy limited to bulky or residual disease areas. The primary endpoints were CR rate and the rate of cardiac events. Forty-seven patients were enrolled. Median age was 75 years, 13 had stage I-II disease. Overall, CR was achieved by 36 patients (77%, 95% CI: 62-88), 100% and 68% in stage I-II and III-IV, respectively. With a median follow-up of 40 months (IQR: 36-45). Three-year overall survival (OS) and progression-free survival (PFS) were 70% and 43%, respectively. Cardiac events grades 3-5 were reported in two patients. In conclusion, MBVD's activity and safety profile was comparable to historical ABVD data.

Purpose The clinical impact of positron emission tomography (PET) evaluation performed early during first-line therapy in patients with advanced-stage Hodgkin lymphoma, in terms of providing a rationale to shift patients who respond poorly onto a more intensive regimen (PET response-adapted therapy), remains to be confirmed. Patients and Methods The phase II part of the multicenter HD0801 study involved 519 patients with advanced-stage de novo Hodgkin lymphoma who received an initial treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and who underwent an early ifosfamide-containing salvage treatment followed by stem-cell transplantation if they showed a positive PET evaluation after two cycles of chemotherapy (PET2). The primary end point was 2-year progression-free survival calculated for both PET2-negative patients (who completed a full six cycles of ABVD treatment) and PET2-positive patients. Overall survival was a secondary end point. Results In all, 103 of the 512 evaluable patients were PET2 positive. Among them, 81 received the scheduled salvage regimen with transplantation, 15 remained on ABVD (physician’s decision, mostly because of minimally positive PET2), five received an alternative treatment, and two were excluded because of diagnostic error. On intention-to-treat analysis, the 2-year progression-free survival was 76% for PET2-positive patients (regardless of the salvage treatment they received) and 81% for PET2-negative patients. Conclusion Patients with advanced-stage Hodgkin lymphoma for whom treatment was at high risk of failing appear to benefit from early treatment intensification with autologous transplantation, as indicated by the possibility of successful salvage treatment in more than 70% of PET2-positive patients through obtaining the same 2-year progression-free survival as the PET2-negative subgroup.

Summary Background: >A cooperative study was undertaken to evaluate the efficacy and toxicity of a very brief course of chemotherapy followed by locoregional radiotherapy in patients with localized-stage intermediate- to high-grade non-Hodgkin's lymphoma (NHL). Patients and method: From January 1988 to November 1994, 84 patients with localized stages IA and IIA intermediate- to high-grade NHL underwent a combined modality treatment. AU patients underwent a six-week chemotherapy regimen, ACOP-B (doxorubicin 50 mg/sqm and cyclophosphamide 350 mg/sqm on weeks 1, 3, 5; vincristine 1.4 mg/sqm and bleomycin 10 mg/sqm on weeks 2, 4, 6; prednisone 50 mg p.o. daily throughout the first two weeks and thereafter every other day), followed by locoregional radiotherapy (36 Gy). Results: The median age was 58 years, with 35% older apthan 65 years; 52 patients had stage I and 32 stage II; 39 patients had extranodal ± nodal involvement, and 4 had testicular involvement. Treatment was well tolerated, with only 38% suffering from mild mucositis and no toxic deaths. Seventy-nine patients achieved CR after ACOP-B and 83 at the end of the program. With a median follow-up of four years, relapse-free survial was 79% with 15 relapses (93% disseminated). Two patients with testis lymphoma had CNS relapses. Overall survival was 90% at four years. Conclusion: This combined program is effective and probably curative in localized stage intermediate- to highgrade NHL, with low toxicity, also in elderly people. Patients with NHL of the testis, as primary site, require CNS prophylaxis due to the high likehood of CNS relapse.

Bendamustine is an alkylating agent with a nitrogen mustard group and a purine-like benzimidazole group. The aim of this study was to collect all the Italian experiences with this drug in order to evaluate the results in term of response to therapy and toxicities. We analyzed lymphoma patients treated in 24 Italian haematological centres with bendamustine alone or in combination with anti-CD20 antibody. One hundred seventy-five relapsed or refractory lymphoma patients were enrolled. The median age was 69 years (range 26-87). Seventy-nine patients were relapsed, 35 were refractory and 61 presented a progressive disease after partial response. The diagnoses were 60 indolent non-follicular lymphomas, 34 diffuse large B-cell lymphomas, 48 follicular lymphomas, 30 mantle cell lymphomas and three peripheral T-cell lymphomas. All patients were evaluable for response: 52 (29%) with complete remission, 72 (43%) with partial response with an overall response rate of 71%, and 51 non-responders. With a median observation period of 10 months (1-43), 70% of patients are alive. In summary, this retrospective study shows that treatment with bendamustine alone or in combination with rituximab is a safe and effective regimen in a subset of multi-resistant patients.

Background. Bortezomib, an inhibitor of the proteasome, is effective in relapsed mantle cell lymphoma (MCL) and indolent lymphomas and it is synergistic with Rituximab to enhance apoptosis and NFkB depletion. On these basis, the FIL conducted a phase II multicenter study aimed to evaluate safety and efficacy of Bortezomib in association with Rituximab in relapsed/refractory non-follicular Lymphoma (Linfocytic, LL and Marginal Zone Lymphoma, MZL) and MCL, not eligible to high dose chemotherapy with stem cell transplantation. Patients and methods. The study was a prospective single arm phase II trial, designed on Simon two-stage Optimal Design. Primary end-point was to obtain an Overall Response Rate (ORR) > 40%. The aim of this analysis is to evaluate long term follow-up of Bortezomib and Rituximab combination. A central histological revision was planned in all the patients at the enrollment. Inclusion criteria were: 18-75 years, relapsed/refractory LL, MZL, MCL after 1-4 lines. Treatment schedule was: one course of 1.6 mg/sqm Bortezomib weekly in combination with standard 375 mg/sqm Rituximab on days 1, 8, 15, 22 followed by two courses of four weekly intravenous bolus of Bortezomib alone; patients with complete (CR), partial remission and stable disease at the intermediate evaluation were planned to be given three further courses with the same schedule. Results. From September 2006 to March 2008, 55 patients were enrolled and six were excluded at central histological revision. Clinical characteristics were: median age 68 (50-74); 16 (33%) LL, 8 (16%) MZL, 25 (51%) MCL; 42 (86%) stage III/IV; 33 (67%) bone marrow involvement. Median number of previous treatments was 2 (range 1-7); 34 (69%) were Rituximab pretreated; 21 (43%) had refractory disease. Thirty (61%) patients completed the treatment and 233 courses were delivered (median: 4.7 courses/patient); 19 (39%) patients did not because of no response in 13, adverse events in five, with only one toxic death due to interstitial pneumonia. ORR was 53% (CR 26.5%); no response was seen in 43% and 4% were not evaluable for response. ORRs by clinical subgroup were: LL 37%, MZL 50%, MCL 64%; Rituximab pretreated 62%, Rituximab naïve 33%; relapsed 64% and refractory 38%. With a median follow-up of 85 months, median Overall Survival (OS) was 61.5 months (95%CI: 35.0-81.5), with 5-years OS 51% (95% CI: 36-65) and median Progression Free Survival (PFS) was 8.9 months (95%CI: 5.3-18.3), with 5-years PFS 16% (95% CI: 7-28%). Five-years PFS by histology was: 12% (95% CI: 2-31) for LL, 17% (95% CI: 5-34) for MCL and 19% (95% CI: 11-53) for MZL. PFS rates were not different between Rituximab pretreated versus naïve nor international prognostic index 1-2 versus 3-4-5 nor refractory versus relapsed. By number of previous therapies, 5-years PFS for 1 previous therapy versus 2 versus 3 or more was: 24%, 14% and 13%, respectively, p=0.36. Conclusions. Weekly infusion of Bortezomib in combination with Rituximab is effective in relapsed/refractory indolent and MCL and represents a treatment option in this setting of patients. Disclosures No relevant conflicts of interest to declare.

Recently, management of limited stage diffuse large cell lymphoma (DLCL) is trending toward a low intensity chemotherapy approach. Since 1993 we have used a brief weekly (6 weeks) chemotherapy scheme (Doxorubicin, Cyclophosphamide, Bleomycin, Vincristine, and Prednisone = ACOP-B) followed by involved field radiotherapy in 207 consecutive patients with well defined localized DLCL without age limit (median 57 years, range 18-85). Treatment was completed as designed in 183 of 207 patients (88%). One hundred and ninety-nine patients (96%) achieved complete remission. At a median follow-up of 66 months 170 patients are alive (82%), 168 of them free of disease. Twenty-nine patients experienced relapse after achieving a complete remission. Kaplan-Meier, risk of relapse was 24% after 13 years. Thirty (14.5%) patients have died, 14 (6.8%) due to lymphoma progression, one due to regimen toxicity and 15 (7.2%) from other causes while remaining in complete remission. The probability of overall survival and event free survival at 13 years was 78% (95% CI 70-87%) and 63% (95% CI 50-75), respectively. Crude rate of secondary malignancy was 5.26 /1000 person-years. The ACOP-B regimen plus involved field radiotherapy is well tolerated both short and long term and is an effective chemotherapy scheme for very well defined limited stage aggressive non-Hodgkin lymphomas in all age categories.

Abstract 3758 Poster Board III-694 Introduction The combination of Bortezomib (B) and Rituximab (R) has been shown in vitro synergistic apoptosis and enhanced NFkB depletion in Mantle Cell Lymphoma (MCL) and Marginal Zone Lymphoma (MZL) cells. Rituximab in combination with Bortezomib is well tolerated without overlapping toxicities. Our study was aimed to evaluate safety and efficacy of the association of Rituximab and Bortezomib in relapsed/refractory indolent non follicular and mantle cell lymphoma patients not eligible to high dose chemotherapy and ASCT. The study was designed according to Simon's two stage Optimal Design and the primary endpoint was the achievement of an Overall Response Rate (ORR) > 40%. Patients and methods From September 2006 to March 2008, 54 patients were enrolled into the study. Histology was centrally reviewed in all cases: 49 diagnosis fulfilled the inclusion criteria and were evaluable for the analysis. Clinical characteristics were as follows: 28 males and 21 females; median age 68 years (range 50-74); 16 lymphocytic/lymphoplasmacytic (LL), 8 MZL and 25 MCL; seven stage I-II disease, nine III and 33 IV; 33 were BM positive; according to IPI 36 patients were at low-intermediate risk and 18 at intermediate-high/high risk; 11 patients had 1 and 38 > 2 prior lines of chemotherapy; 15 were R-naïve patients and 34 R-pretreated, 21 patients had refractory disease ( 1 yr). The treatment plan was: one course of 4 weekly doses of Rituximab (375 mg/sqm) and Bortezomib (1.6 mg/sqm IV bolus) followed by 2 courses of 4 weekly IV bolus of B (1.6 mg/sqm) as single agent. Responding (CR+ PR) and stable disease patients were planned to be given three further courses with the same schedule. Results ORR was 26/49 (53%). Responses were as follows: 13 CR (26.5%) and 13 PR (26.5%). ORR by histology was: 6/16 (37.5%) in LL, 4/8 (50%) in MZL and 16/25 (64%) in MCL respectively. Pretreatment with Rituximab did not adversely affect the ORR: 21/34 (62%) in R-pretreated patients and 5/15 (33%) in R-naïve patients (p .06). ORR was higher in relapsed patients compared with refractory ones: 18/28 (64%) and 8/21 (38%) (p .06). With a median follow-up of one year, Overall Survival (OS) was 93% (95%CI: 79.7-97.9) and 1-year Progression free survival (PFS) was 45% (95%CI: 30-59) (Figure 1). A total of 233 courses were delivered with a median of 4.7 courses per patient. Twenty-eight patients completed the treatment plan and 21 were withdrawn from the study because of: 17 PD during treatment and 4 AE (1 concomitant gastric neoplasia, 1 neurotoxicity grade II, 1 pleural effusion and 1 toxic death due to interstitial pneumonia). Grade 3-4 CTC haematological toxicity was rare with neutropenia in 5% of the courses and thrombocytopenia in III in 5. Conclusions This study suggests that the combination of Rituximab and Bortezomib is feasible and effective in relapsed/refractory indolent non follicular lymphoma and MCL. This treatment combination is a good therapeutic option without chemotherapy mainly in MCL and MZL also in Rituximab pretreated patients. Our data suggest a promising PFS in this subset of heavily pretreated patients. The combination of Rituximab plus Bortezomib should be explored in further and larger studies. Disclosures: Vitolo: Roche: lecture fees. Off Label Use: Bortezomib was provided free by Jansen-Cilag who gave a research grant to support the study.

PURPOSE In our previous study with MACOPB, we identified a high-risk group of patients with a poor 3-year survival rate of 29%. These patients were defined as having at diagnosis advanced-stage disease with high tumor burden (TB) and elevated lactate dehydrogenase (LDH) level or bone marrow (BM) involvement. A novel therapeutic scheme was investigated to improve the outcome of these patients. PATIENTS AND METHODS Fifty patients with high-risk diffuse large-cell lymphoma (DLCL) were enrolled. The therapeutic scheme includes three phases: induction with 8 weeks of MACOPB; intensification with a 3-day course of mitoxantrone 8 mg/m2 plus high-dose cytarabine (HDARA-C) 2 g/m2 every 12 hours plus dexamethasone 4 mg/m2 every 12 hours (MAD protocol) and granulocyte colony-stimulating factor (G-CSF) 5 microg/kg on days 4 to 17 to harvest peripheral-blood progenitor cells (PBPC); consolidation with carmustine (BCNU), etoposide, ARA-C, and melphalan (BEAM) regimen; plus autologous stem-cell transplantation (ASCT) with PBPC, marrow, or both. RESULTS Thirty-six patients (72%) achieved a complete response (CR), 11 (22%) showed no response (NR), and three (6%) died of toxicity. Among the 22 PRs or NRs after the induction phase, 56% of patients achieved a CR with subsequent intensified therapy. With a median follow-up duration of 32 months, the overall survival and failure-free survival rates were 56% and 50%, respectively. The disease-free survival rate is 69% at 32 months. Leukapheresis after MAD and G-CSF yielded a median of 32 x 10(6)/kg CD34+ cells and 80 x 10(4)/kg granulocyte-macrophage colony-forming units (CFU-GM). Thirty-nine patients were autografted and 11 did not undergo ASCT: six because of disease progression, four due to toxicity, and one because of patient refusal. The median times to achieve engrafment were 11 days (range, 7 to 19) to a neutrophil count greater than 0.5 x 10(9)/L and 12 days (range, 8 to 60) to a platelet count greater than 50 x 10(9)/L. CONCLUSION This sequential scheme with intensified and high-dose chemotherapy with ASCT is feasible with moderate toxicity and may improve the outcome in high-risk DLCL.

Introduction Erythropoiesis stimulating agents (ESAs) have been demonstrated to reduce the transfusion requirements in International Prognostic Scoring System (IPSS) low/Int-1 risk MDS patients and response to ESAs is associated with an improved quality of life. Response to ESAs varies from 20 to 60% according to the different studies and an association between ESAs response and a better overall survival (OS), without any disease evolution to AML has been reported. Aim of our study is to analyze the real life use of ESAs in Italy and to assess which group of lower risk MDS patients can benefit more by this treatment. Methods From 1999 to 30 Jun 2013, 2487 patients affected by MDS were included in the Network of the Italian MDS Registries. Morphological MDS diagnosis was confirmed. Among them, 1411 IPSS low/int-1 patients with follow-up data available were selected. Furthermore we excluded the following cases: 87 patients who were treated at any time by azacytidine (n=61) or lenalidomide (n=26), 95 patients with WHO 2002 diagnosis of CMML and aCML, 96 patients with incomplete data, 84 patients unhomogeneously treated with ESAs other than EPO alpha. We obtained a final data base of 1049 cases. OS and leukemic evolution (LE) according to EPO treatment were analyzed using the Kaplan-Meier product-limit survival curve estimates and log-rank tests. Results Median age was 74 years, 59% of the patients were male and 41 % female. WHO 2002 classification was as follows: 296 (28 %) Refractory Anemia, 347 (33 %) refractory cytopenia with multilineage dysplasia, 94 (9%) refractory anemia with ringed sideroblasts, 46 (4 %) Del 5q, 188 (18 %) refractory anemia with excess of blasts and 78 (7 %) MDS unclassifiable. Median hemoglobin level at baseline was 10.0 g/dL. One hundred and twenty patients (11%) were previously transfused with a Hb baseline level less than 8.0 g/dL; 448 not yet transfused patients (43%) presented a mild anaemia with Hb ranging from 8 to 10 g/dL and 481 patients (46%) had a Hb level higher than 10 g/dL. Patients classification according to IPSS was as follows: low 55% (n=575); int-1 45% (n=474). 335 (32%) out of 1049 patients received EPO alpha treatment while the remaining 714 patients (68%) were supported without any ESAs treatment. The rate of erythroid response to EPO therapy was 61%. Median duration of response was 82 weeks. The response rate to EPO was significantly higher in non transfused than in transfused patients: 69% versus 14% respectively (p value < 0.001). Only 52 out of 1049 patients showed a LE and a higher incidence of LE in EPO treated patients was not observed. Considering the whole group of patients, the OS of EPO treated patients was not statistically different from untreated ones. However EPO responders patients showed a better OS in comparison to both the non responders and non-EPO treated patients (p value < 0.05). When we stratified patients according to the basal hemoglobin level (lower than 8 g/dL, from 8 to 10 g/dL and higher than 10 g/dL) in patients with Hb ranging from 8 to 10 g/dL we observed a significant improvement in OS following successful EPO treatment (median survival: EPO vs. non-EPO 64 vs. 43 months respectively; p 10 g/dL. Even if adverse events were not prospectively recorded in the Registry, no frequent thromboembolic events was reported in EPO group in comparison to non treated patients. Conclusions Our survey can suffer from selection bias due to the limits typical of a voluntary-based registry, but it can be considered a good real life picture of EPO alpha therapy in lower risk Italian MDS patients. Our data confirm that EPOa treatment is globally safe and that patients who can benefit more are the mild anemic untransfused subjects, with baseline Hb level ranging from 8 to 10 g/dL. Disclosures: Santini: Celgene: Honoraria; Novartis: Honoraria; GSK: Honoraria; Janssen: Honoraria.

Introduction The role of interim-PET (i-PET), after two cycles of chemotherapy, in advanced stage Hodgkin's lymphoma is well defined; the same role in diffuse large B cell lymphoma (DLBCL) is still controversial. The Fondazione Italiana Linfomi planned a prospective randomized phase III trial, addressed to young poor prognosis DLBCL patients at the diagnosis, with a 2x2 factorial design aimed at investigating the possible benefit of intensification with R-HDC+ASCT after R-dose-dense chemotherapy delivered at two different level of dose (R-CHOP14/R-MegaCHOP14). During this study an ancillary study was designed to define the prognostic impact of i-PET on progression free survival (PFS) after two cycles of immunochemotherapy in all treatments arms. Patients and methods As described by Vitolo et al (oral communication, abs 688 ASH 2012), patients were stratified according to aa-IPI and randomized at diagnosis to receive: R-CHOP14 x 8 cycles; R-MegaCHOP14 (1200 mg/sqm Cyclophosphamide, 70 mg/sqm Doxorubicin, standard dose Vincristine and Prednisone) x 6; R-CHOP14 x 4 + R-HDC (Rituximab + High Dose Cytarabine + Mitoxantrone + Dexamethasone) followed by BEAM and ASCT; R-MegaCHOP14 x 4 + R-HDC + BEAM and ASCT. G-CSF support was mandatory. Seventeen centers agreed to participate in the study and enrolled patients. All evaluable patients had performed basal PET and i-PET. A visual dichotomous criteria, according to Deauville Criteria (First Consensus Conference, 2009), was used to define the i-PET result. The final response was identified according to 2007 Cheson response criteria. Results From June 2005 to September 2010, 399 patients were randomized in the overall DLCL04 study and 130 were enrolled for the ancillary PET study , 69 in the R-HDC+ASCT and 61 in R dose dense therapy respectively. The clinical characteristics, as in the overall DLCL04 study, were well balanced among the four arms of therapy excluding a selection bias in the group of patients studied with i-PET. The i-PET result was positive in 74 patients and negative in 56 patients, no differences were observed between negative and positive i-PET results according to clinical characteristics and group of treatment. In particular, in R-dose dense arm 27 were negative and 34 positive, in R-HDC+ASCT 29 were negative and 40 positive, according to immunochemotherapy scheme in R-CHOP14 29 were negative and 40 were positive, in MegaCHOP14 27 were negative and 34 were positive. With a median follow-up of 36 months, 3-year PFS and 3-year Overall Survival (OS) rates for the whole series were: 64% (95% CI:59-69) and 79% (95% CI:74-83) respectively. No differences in PFS was reported according to i-PET result. In particular 3-year PFS were 87%(95% CI:75-94) in i-PET negative patients and 76% (95% CI: 65-85) in i-PET positive patients respectively (p: 0.09 The 3-year PFS according to I- PET results in the different treatment arm were: in the R-HDT+ASCT group i-PET negative or i-PET positive patients had a 3-year PFS of 83% (95% CI:63-92) and 79% (95% CI:63-89) respectively; in the R-dose dense i-PET negative or i-PET positive patients had a 3-year PFS of 92% (95% CI:73-98) and 72% (95% CI:54-85) with a p value near the significance (0.07). According to OS, i-PET negative and i-PET positive patients had a 3-year OS of 89%(95% CI:76-95) and 83%(95% CI:72-90) respectively, p=0.219. Conclusions In our multicenter prospective study, addressed to young poor prognosis DLBCL patients at the diagnosis, i-PET, performed after two immunochemotherapy cycles and analyzed with a visual method, is not able to identify two different risk population. To confirm our data, we are planning in the near future a centralized revision of all evaluable PET. In conclusion, our feeling is that the i-PET after two cycles in poor prognosis DLBCL patients is too early to predict a chemorefractory disease and more parameters must be considered to define clinical response in these patients. Disclosures: No relevant conflicts of interest to declare.

Background: Erythroid stimulating agents (ESAs) are a common treatment for lower risk anaemic MDS patients (pts). The response rate varies from 20 to 60% according to the different published studies and ESAs are recommended in International Guidelines. Many clinical and biological parameters have been proposed as predictors of response. Little is known about ESAs therapy in real life. Purpose:We performed an analysis based on the network of regional Italian MDS Registries in order to assess which group of patients could benefit more of ESAs treatment. Materials and Methods: From 2487 pts enrolled in the Registry from 1999 to November 2012, we selected a group of 1411 low or intermediate-1 cases with follow-up data available. No differences in leukemic evolution rate have been observed by ESAs treatment (p=0,279). Subsequently, in order to study the effect of ESAs on survival, we excluded the 92 pts who experienced a leukemic evolution and the cases whose evolution was influenced by lenalidomide and/or azacytidine treatments. Cases treated with ESAs other than erythropoietin alpha (EPOa) were excluded because of the low number of observations and/or incomplete information and/or inhomogeneous dosages. Finally, we obtained a data base of 1110 pts treated by EPOa or observation only. We evaluated Overall Survival (OS) according to EPOa treatment considering the degree of anaemia at baseline. Results: The 1110 pts were subdivided according to Hb level as follows: 123 (11%) with Hb 10 g/dL. Three hundred and fifty six pts were treated by EPOa. The difference in OS by EPOa treatment in the whole cohort was not statistically significant. However, when considering patients not yet transfusion dependent with Hb levels ranging from 8 g/dL to 10 g/dL, there was a clear statistically significant difference in OS: median time 216 months in EPOa treated group vs 99 months in non treated pts (p=0,002). The influence of EPOa on OS in pts with Hb 10 g/dL did not reached a significant level. Additionally, no statistically significant difference was observed in deaths for thrombotic events. Conclusions: Our real life experience confirms that EPOa treatment is safe inMDS patients and it is particularly useful in prolonging OS of the selected group of lower risk pts with mild anaemia not yet transfusion dependent.

Abstract 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 Disclosures: Vitolo: Roche Italy: Speakers Bureau; Celgene: Speakers Bureau; Jannsen-Cilag: Speakers Bureau.

Abstract 611 Background: Improvements in hematologic parameters have been associated with iron chelation therapy (ICT) in transfusion-dependent patients with chronic anemia associated with hematologic malignancies. Data from a significant cohort of myelodysplastic syndromes (MDS) patients enrolled in the EPIC study and treated with deferasirox reported a percentage of 22.6% of erythroid responses. Several sporadic reports showed hematologic improvement in patients treated with deferoxamine or deferasirox in patients affected by myelofibrosis (PMF) and Aplastic Anemia (AA). The aim of this study was to retrospectively evaluate the hematologic response in the entire cohort of chronic anemias with iron overload receiving ICT with both deferasirox (DFX) or deferoxamine (DFO) in 6 hematological Italian centers from 1993 to 2011. Methods: 105 patients received ICT for at least 3 months. Sixteen were PMF, 8 AA, 75 MDS, 4 Chronic Myelomonocytic Leukemia (CMML), 2 Acute Myeloid Leukemia (AML). 30 patients received deferoxamine (6 PMF, 3 AA, 1 CMML, 2 AML, 18 MDS), and 68 deferasirox (9 PMF,5 AA, 3 CMML, 51 MDS), and 7 received deferasirox after a prior treatment with deferoxamine (1 PMF, 6 MDS). The median serum ferritin levels at the time of ICT was 1983 ng/ml and it was not significantly different between the two cohorts (p=0,8). Patients, at the time of ICT, had transfused a median of 30 Units of RBC (40 in the DFO cohort and 24.5 in DFX cohort, p=0.001). 25 out of 105 were receiving EPO therapy at the time of chelation, started at least 6 months before ICT, without a significant clinical improvement and three were receiving a JAK2 inhibitor started at least 1 year before ICT. Patients receiving any kind of therapy able to modify the erythroid response including azacitidine were excluded as well as patients receiving EPO started less than 6 months before ICT or JAK2 inhibitors or immunosuppressive therapy less than 12 months before. Hematological response (HR) was evaluated as follow: Achieving a RBC transfusion independency (complete HR) or Hematological improvement (HI-e) for patients showing a Hb increase of 1.5 g/dL or a reduction of 4 RBC transfusions/8 weeks (IWG 2006). Results: We retrospectively analyzed an unselected cohort of patients with transfusion dependent iron overload affected by different hematologic malignancies who received ICT outside clinical trials thus allowing the inclusion of high risk MDS/AML. 13 patients were not evaluable because they were receiving ICT for less than 3 months. 41 patients out of 92 (42.7%) evaluable patients achieved a hematologic response. In details: 18 (19,5%) became completely RBC transfusion independent. Six (1 AA, 3 RARS, 1 RCMD, 1 AML) were under DFO treatment and 12 (3 AA, 2 RA, 3 RARS, 1 RAEBII, 1 CMML, 2 PMF) under DFX. In addition, all 4 AA patients who achieved transfusion independency significantly increased the number of platelets ( median 17.000/mm3 before ICT and 35.000 and 55.000 after 6 and 12 months of ICT). Median time to response was 15 months for DFO and 3 months for DFX. 16 patients (17.3%) (6 RA, 4 RARS,1 RCMD, 1 RAEB, 4 PMF) obtained HI-e defined as a reduction of 4 U/8 weeks (5 in DFO and 11 in DFX cohorts) after a median of 6 months for both DFO and DFX. HI-e defined as an increased of 1.5 g/dL was observed in 7 patients (7.6%) ( 4 RA, 1 RARS, 1 RCMD, 1 PMF) after a median of 6 months for DFO and 3 for DFX. The hematologic improvement is not strictly related to an effective reduction of serum ferritin (p=0,4). Conclusions: Our data show a high rate of complete responses, mainly in AA and RARS but also in high risk MDS/AML representing 11% of those achieving complete transfusion independency. Notably 50% of AA achieved RBC and platelet transfusion independency. Despite the limitation due to the retrospective collection of data we suggest the ICT could result in hematologic improvement in a wide population including patients who are, at present, outside the published ICT guidelines. This study warrants further investigation on the mechanism of action of ICT in inducing erythroid response. Disclosures: Saglio: Novartis, Brystol Myers: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract 3965 Introduction. Gene-profiling studies demonstrated a constitutive activation of the NFκB signalling pathway in Mantle Cell Lymphoma (MCL) and Marginal Zone Lymphoma (MZL). Bortezomib, a potent inhibitor of the 26S proteasome, is a good candidate to block this pathway and was tested in relapsed or refractory MCL with encouraging results (objective response up to 45%, with a median PFS of 5–7 months). In vitro, the combination of Bortezomib and Rituximab has been shown synergistic apoptosis and enhanced NFkB depletion in MCL and MZL cells. Aim. On these bases, the IIL conducted a phase II multicenter study to evaluate safety and efficacy of Rituximab and Bortezomib combination in relapsed/refractory indolent non-follicular lymphoma (Linfocytic Lymphoma, LL, or MZL) and MCL not eligible for high-dose chemotherapy. Patients and methods. Inclusion criteria were: age 18–75 years, histological proven relapsed or refractory LL, MZL and MCL after 1–4 lines of therapies. Treatment plan was: one course of four weekly intravenous bolus of 1.6 mg/sqm Bortezomib in combination with four infusion of 375 mg/sqm Rituximab followed by two courses of four weekly bolus of 1.6 mg/sqm Bortezomib. Patients with complete (CR), partial remission (PR) and stable disease at the intermediate evaluation were planned to be given three further courses with the same schedule. Results. From September 2006 to March 2008, 55 patients entered into the study. Central histology revision was performed. Forty-nine patients fulfilled inclusion criteria and were evaluable. Clinical characteristics were: median age 68 (50-74) years; 16 LL, eight MZL, 25 MCL; 42 stage III/IV; 33 bone marrow involvement; 20 at intermediate-high/high International Prognostic Index (IPI) risk. Thirty-eigh patients performed more than two prior lines of chemotherapy; 34 were Rituximab-pretreated; 21 refractory and 28 relapsed disease. Overall Response Rate (ORR) was 53% (CR 26.5%, PR 26.5%); no response 43% and 4% off therapy for other causes. ORR by histology was: 37% in LL, 50% in MZL and 64% in MCL. ORR was not adversely affected by Rituximab pretreatment: Rituximab-pretreated 62% and Rituximab-naïve 33%. ORR was higher in relapsed patients compared with refractory ones: 64% and 38% (p .06). (Table 1). With a median follow-up of 25 months, 2-year Overall Survival (OS) was 80% (95%CI: 66–89) and 2-year PFS was 25% (95%CI: 14–38) (Figure 1A, 1B). Two-year PFS by histology was shown in Figure 1C. A total of 233 courses were delivered with a median of 4.7 courses/patient. Thirty patients completed the treatment plan; 19 did not due to progression disease in 13, adverse events in five (concomitant gastric neoplasia, neurotoxicity grade II, sepsis, pleural effusion and toxic death due to interstitial pneumonia). Grade 3–4 CTC haematological toxicity was rare: neutropenia in 5% of the courses and thrombocytopenia in Table 1. ORR (%) MCL/MZL/LL 64/50/37 Rituximab-pretreated/Rituximab-naive 62/33 N of prior therapies Disclosures: Off Label Use: The use of Bortezomib is off-label in Relapsed/Refractory Indolent Non-Follicular and Mantle Cell Lymphoma. Vitolo:Roche-Italy: Advisory committee; Celgene-Italy: Advisory committee; Janssen-Cilag: Lecture Fee.

Abstract 2316 Poster Board II-293 Introduction: DLBCL at diagnosis with an intermediate/high or high-risk score according to age-adjusted International Prognostic Index (aa-IPI) had a dismal prognosis. High-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) was showed an effective salvage treatment for chemo-sensitive relapsed patients, but conflicting results were observed as first line treatment in randomized trials. The addition of Rituximab to standard chemotherapy significantly improved the outcome, but so far less data are available in young DLBCL patients with a poor prognosis. Aim of the analysis was to test the role of four important steps in first line treatment in DLBCL at poor prognosis: HDC and ASCT, Rituximab, new regimens as dose-dense chemotherapy MegaCEOP versus third generation MACOP-B chemotherapy, involved-field radiotherapy (IF-RT), in 309 untreated patients & 61 years enrolled from 1986 to 2006 into four GIMURELL and IIL consecutive trials. Patients and methods: 42 patients were enrolled into a phase II study and treatead with: 12 weekly infusion of MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin) chemotherapy (Vitolo U, J Clin Oncol 1992); 40 patients into a phase II trial with 8 weekly MACOP-B as induction therapy, followed by HDC with 2 courses of MAD (mitoxantrone, high-dose cytarabine, dexametasone) and BEAM and ASCT (Vitolo U, J Clin Oncol 1997); 107 patients into a phase III randomized trial, 48 treated with high dose sequential (HDS) chemotherapy with ASCT and 59 with 6 beweekly infusions of MegaCEOP (epirubicin, cyclophosphamide, vincristine, prednisone), respectively (Vitolo U, Haematol 2005); 120 patients into a phase II trial with an induction phase with dose-dense chemoimmunotherapy Rituximab-MegaCEOP for 4 cycles followed by HDC with 2 courses of Rituximab-MAD and BEAM plus ASCT (Vitolo U, Haematol 2009). IF-RT was performed at the end of treatment as consolidation of bulky disease or residual disease. A Cox proportional hazard model was performed for Overall Survival (OS) and Progression-Free Survival (PFS) to estimate the HRs of the 4 treatment variables (with/without Rituximab, HDC + ASCT, new regimens vs third generation regimen MACOP-B, radiotherapy yes/not), adjusted by aa-IPI, age and sex. Results: All 309 patients were evaluable for clinical characteristics and for response evaluation: median age 44 years (15-60); 178 males and 131 females; 10% were at Low-Intermediate, 51% at Intermediate-High and 39% at High risk according to aa-IPI score; PS >2 59%, 96 31% had BM involvement, 53% bulky disease, 84% LDH >normal, 34% >2 extranodal sites and 12/19/69% stage II/III/IV respectively. Rituximab was performed in 120 patients; IF-RT in 108 patients. New generation regimens were performed in 227 patients, MACOP-B in 82. As intention to treat, ASCT was scheduled for 208 patients. ASCT was performed in 171 patients (82%), 39 did not because of: progression disease in 22, toxicity in 9 and poor mobilization in 6. Complete response at the end of treatment was achieved in 212 pts (69%), PR in 23 (7%), 57 (18%) did not respond and 17 (6%) died of toxicity. Secondary haematological malignancies or solid tumour were observed in only 3 patients. With a median follow-up of 10 years, 10-yr OS and 10-yr PFS rates were: 59% (95%CI: 53-65) and 48% (95%CI: 41-55). The Cox's multivariable model showed that long term survival was significantly improved in patients treated with Rituximab compared to those treated without immunotherapy (HR=0.36, 95% CI=0.21-0.63, p .0003) and in patients that underwent IF-RT (HR=0.42, 95% CI: 0.27-0.66, p .0002), while no clear benefit could be detected for new regimens vs MACOP-B (HR=0.86, 95%CI: 0.57-1.31, p .482) and for ASCT (HR=0.94, 95%CI: 0.62-1.41, p .751). No important differences were observed after stratification by IPI. Similar results were obtained for PFS. Discussion: the introduction of immunotherapy and the irradiation of involved fields have played a major role in the improvement of long term survival of young patients with untreated DLBCL at poor prognosis, while little, if any, benefit has derived from newer dose-dense regimens and from ASCT. Randomized trials are ongoing to evaluate the impact of HDC and ASCT supplemented with Rituximab in poor-prognosis DLBCL compared to standard or dose-dense chemoimmunotherapy in the Rituximab era. Disclosures: Vitolo: Roche:.

Abstract 1662 Poster Board I-688 Introduction Bendamustine is an alkylating agent with a nitrogen mustard group and a purine like benzimidazol group. Recently this drug was introduced in Italy. We analized all pts treated in sixteen haematological Italian centers with Bendamustine alone or in combination with anti-CD20 antibody. Patients and methods On an intention to treat basis pts who have received at least one complete cycle were evaluable for response and toxicity. The treatments consisted of: Bendamustine 60-90 mg/m2 days 1,2 alone or in combination with Rituximab 375 mg/m2 day 0, every 21 or 28 days. 173 pts were analized, median age was 67 (range 31-87), 114 were male, 63 chronic lymphatic leukaemia 41 indolent non-follicular lymphoma, 26 diffuse large B cell lymphoma, 26 follicular lymphoma, 15 mantle cell lymphoma, 2 Peripheral T cell lymphoma. Pts were heavily pretreated, the median number of previous treatments was 3,5 (range 1-8), 121 pts have experienced more than three chemotherapy schemes. One hundred and twenty-seven pts were previously treated with Rituximab and 24 performed an autologous peripheral blood stem cell transplantation. The Bendamustine pre-treatment condition was: 70 relapsed pts, 40 with refractory disease and 63 with a progressive disease after partial response. The median number of Bendamustine cycles was 4.3 (range 1-11). Results All patients were evaluable for response: 48 pts (28%) obtained a complete remission, 78 (45%) a partial response or stable disease with an overall response rate of 73% and 47 were non responders. According to histotype we observed that 10/15 pts (67%) with mantle cell lymphoma obtained a response (6 CR;4 PR), 37/41 (9 CR; 28 PR) indolent non follicular lymphoma and 25/26 (96%) follicular lymphoma obtained a response (12 CR;13 PR), 46/63 CLL obtained a response and 8/26 (31%) DLBCL obtained a response to therapy (4 CR;4 PR), none of the two T lymphoma pts responded to therapy. With a median period of observation of 12 months (1-46) 121 (70%) pts are alive and 83 pts are in complete remission or with stable disease without any other treatment. The overall survival was 82%, 72%, 68% and 27% respectively for indolent, CLL, mantle cell and diffuse large B cell lymphoma. The progression free survival was 31%, 27%, 15% and 10% respectively for indolent, CLL, mantle cell and diffuse large B cell lymphoma. Fifthy-two pts died, 47 for progressive disease, 11 due to infection and sepsis (6%) and 2 due to other causes not related with therapy or disease. In this group of heavily pretreated pts 760 cycles were performed. The extrahematological toxicity was mild the most important problem were infections (Herpes Zooster, pneumonia, enteritis) reported in 16 pts, hepatic in 4 and cardiologic in 2 pts. The hematological toxicity was trombocytopenia grade 3-4 in 20 pts (12%), neutropenia grade 3-4 in 40 pts (23%) and anemia grade 3-4 in 19 pts (11%). Discussion In conclusion this retrospective study shows that treatment with Bendamustine alone or in combination with Rituximab is a safe and efficacy regimen in a subset of pluriresistent patients. This data shows also that the best results could be obtained in indolent lymphoma and CLL incouraging data in mantle cell lymphoma are reported. Disclosures No relevant conflicts of interest to declare.

Introduction: The addition of antibody monoclonal anti CD20 Rituximab to CHOP chemotherapy resulted in improved CR, progression free survival and overall survival rates for patients with diffuse large B cell lymphoma (DLBCL). RIT with Zevalin, as single agent, has been shown to be effective in the treatment of relapsed refractory elderly DLBCL, namely in Rituximab naïve patients. However, in patients pretreated with Rituximab the reported response rate was lower. The aim of this study was to evaluate the efficacy and safety of Zevalin in a group of patients with relapsed or refractory aggressive lymphoma, all heavily pretreated with Rituximab containing regimens. Patients and methods: Inclusion criteria were as follows: age over 18 yrs; relapsed or refractory CD20+ aggressive lymphoma (follicular grade IIIb, PML or DLBCL); WHO performance status of 0 to 2; stage II bulky, III or IV; bone marrow involvement 150 × 109/l received Zevalin at 0.4 mCi/kg whereas those with platelets < 150 109/l received 0.3 mCi/kg. Results: 24 patients were treated with RIT. Five patients had stage II, and 19 stage III/IV; bone marrow involvement was present in 11/24. Nine patients had grade IIIb follicular, 14 DLBCL and one mantle cell lymphoma. Eighteen patients received 0.4 mCi/kg and six patients 0.3 mCi/kg. Eleven patients were treated with RIT alone, six received RIT after standard salvage chemoimmunotherapy and seven were treated with RIT in combination with BEAM and subsequent autologous stem cell transplantation (ASCT). Status of disease before Zevalin treatment was: progressive disease (PD) in 14; complete response (CR) and partial response (PR) after salvage chemoimmunotherapy in 4 and 6 patients respectively. All patients in CR before RIT (4/24) maintained a continous CR after treatment. Overall response rate (ORR) after RIT for patients not in CR (20/24) was: 4 patients (20%) achieved a CR, 7 patients (35%) a PR and 9 patients experienced no response/progression (ORR 11/20 patients 55%). Six of seven patients treated with RIT + BEAM + ASCT achieved a response (CR 4 patients and PR 2 patients), one patient progressed immediately after the end of program. ORR in 11 patients treated with RIT alone and in six patients treated with chemotherapy + RIT were 46% and 50% respectively. With a median follow up of 32 months, OS and PFS rates were 67% and 52%. Eight patients died, all because of lymphoma. The most common grade 3–4 adverse events were neutropenia and thrombocytopenia. Discussion: the results of this study suggest that RIT with 90Y-Ibritumomab Tiuxetan is a safe and effective treatment for patients with relapsed/refractory aggressive lymphoma even if they were pretreated with Rituximab containing chemotherapy.

Introduction: The addition of antibody monoclonal anti CD20 Rituximab to CHOP chemotherapy has resulted in improved CR, progression free survival and overall survival rates for patients affected by diffuse large B cell lymphoma. Recently, RIT with Zevalin has been shown effective in the treatment of relapsed refractory elderly DLBCL. We report the results of a study to evaluate the efficacy and safety of Zevalin in relapsed or chemoresistant aggressive lymphoma previously treated with Rituximab. Patients and methods: Elegibility criteria were as follows: age over 18 years, refractory or chemoresistant CD20+ aggressive lymphoma (grade III follicular, PML or DLBCL de novo) WHO performance status of 0 to 2, stage II bulky, III or IV, bone marrow involvement < 25%, written informed consent in accordance with institutional guidelines. All patients were previously treated with Rituximab and almost two lines of chemotherapy. Patients with pre-treatment platelet counts of > 150.000/mm3 received Zevalin at 0.4 mCi/kg whereas those with platelets < 150.000/mm3 received 0.3 mCi/kg. Results: Fourteen patients were treated with RIT: 5 patients were stage II, 3 stage III, 6 stage IV (5 with bone marrow involvement). Six patients had grade III follicular, 4 primary mediastinal and 4 DLBCL de novo. Ten patients received 0.4 mCi/kg and 4 patients 0.3 mCi/kg. Five chemoresistant patients after 2 or more lines chemoimmunotherapy received RIT in combination with BEAM and subsequent autologous stem cell transplantation (ASCT) and 9 patients were treated with Zevalin alone. Two months after RIT we reported CR 4 patients, PR 5 patients and no response/progression 5 patients (ORR 9/14 patients 64%). All 5 patients treated with RIT + BEAM + ASCT achieved a response (CR 2 patients and PR 3 patients ORR 100%). ORR in 9 patients treated with RIT alone was 46% (CR 2 patients and PR 2 patients). No toxic deaths were observed, two patients died of lymphoma (one patients 1 year after Zevalin infusion and the second progressed and died 5 months after RIT). The most common grade 3–4 AE were neutropenia and thrombocytopenia. Discussion: RIT with 90Y-Ibritumomab Tiuxetan is a safe and effective approach for patients affected by aggressive lymphoma and heavily pretreated with Rituximab + chemotherapy. The effective role of RIT alone or in combination with high dose chemotherapy + ASCT as salvage therapy has to be studied in this subset of patients.

Introduction: the efficacy of Rituximab (R) with standard chemotherapy in DLBCL is well known. We investigated efficacy and safety of Rituximab as adjuvant to dose-dense and HDC as part of first line treatment in untreated pts with aa-IPI at Intermediate-High (IH) or High (H) risk with DLBCL. Patients and methods: 77 previously untreated pts Results: median age was 45 yrs (19–60); 47% were at H risk; 31% had bone marrow involvement, 78% had LDH level >normal and 35% extranodal sites>1. Complete Response at the end of the treatment was achieved in 60 pts (78%), PR in 2 (3%) and 11 pts (14%) did not response. Four pts (5%) died of toxicity during treatment. Few severe early toxicities (WHO grade 3–4) were reported and late toxicity was minor, with no MDS or ANLL or solid tumour. With a median follow-up of 39 months, 3-yr FFS and 3-yr OS rates were: 71% and 78%. These results were compared to those ones achieved into 41 pts, with the same clinical characteristics, enrolled in a previous phase II clinical trial with up-front HDC and ASCT but without R. Treatment in HDC control group consisted in an induction treatment lasting two months with MACOPB chemotherapy × 8 weekly infusions followed by the same intensified and HDC regimens (MAD× 2 courses + BEAM and ASCT). Three-yr FFS and OS in control group were: 46% and 54%. To properly evaluate the efficacy of R-HDC therapy, a Cox’s model was performed to adjust the effect of treatment for competing risk factors (age, IPI, BM involvement, number of extranodal sites). In this multivariate analysis the risk of failure and death was confirmed as significantly reduced in R-HDC group: adjusted hazard ratio (R-HDC vs HDC) was 0.56 (95% CI=0.30–1.01, p=.05) for FFS and 0.42 (95% CI=0.21–0.88, p=.02) for OS. PBSC harvest and time to engraftment were similar into two groups, with no statistically significant differences: all pts in both groups collected more than 2×106 CD34+/kg; median time to neutrophils engraftment (neutrophils >500/mm3) was 9 days in R-HDC group and 10 days in HDC group and median time to platelets engraftment (platelets >50000) was 15 vs 16 respectively. Conclusions: these results suggest that Rituximab as adjuvant to dose-dense and HDC may improve the outcome of DLBCL at poor prognosis. This promising new treatment strategy need to be compared to Rituximab dose-dense chemotherapy without HDC as R-CHOP14. Such a randomized trial is currently undergoing conducted by Intergruppo Italiano Linfomi.

Patients with Ann Arbor stages I and II diffuse large cell lymphoma (DLCL) represent a significant proportion of patients with aggressive lymphoma. Recent clinical research are developing low intensity chemotherapy approach in order to minimize short and long term side effects while maintaining high success rate. Moreover very limited studies are available on elderly patients. Since 1993 we used a brief weekly (six weeks) chemotherapy scheme (Doxorubicin, Cyclophosphamide, Bleomycin, Vincristine and Prednisone = ACOP-B) followed by involved field radiotherapy in patients with localized stage aggressive lymphoma and examined long term results and side effects in a general haematology population without age limit. Two hundred and six consecutive patients (89 females) affected by localized aggressive lymphoma aged from 18 to 85 years old (median 57) treated between January 1st, 1993 and December 31st, 2004 were enrolled in this analysis. Minimum follow up was 18 months. Inclusion criteria was well documented nodal or extranodal stage IA (including bulky) or IIA disease. Bulky disease was defined as a 10 cm or more mass in maximal diameter. Treatment was completed as designed in 183 over 206 patients (88%). Three patients did not complete the six scheduled cycles of chemotherapy: one died during chemotherapy and two because of disease progression. Twenty additional patients did not receive radiotherapy: 12 patients had an initial site of disease totally resected (9 with gastric lymphoma and 3 with small or large bowel lymphoma). One hundred and ninety-seven patients (96%) achieved a complete remission, two patients obtained a partial response; three patients had no response (four patients were not valuable). At a median follow-up 66 months one hundred and seventy patients are alive (82 %) 168 of them free of disease. Twenty-nine patients (15%) experienced relapse after achieving a complete remission. The median time to relapse was 46 months with a very wide range (1–143 months). Among these twenty-nine patients eighteen (62%) are alive and free of lymphoma after second line therapy. Twenty-six (13%) patients have died, 13 (5%) by lymphoma progression, one for toxicity and 12 (6%) from other causes while in complete remission. After 13 years the Kaplan-Meier (K-M) probability of overall survival and disease free survival were 80% (95%CI 72–88%) and 55% (95% CI 33–76%), respectively. We specifically analyzed patients over 60 years: they were 93 (median age 70 years). In this group of elderly patients the treatment was completed as designed in 90% and the 12 years K-M probability of overall survival was 60%. Seven patients presented secondary malignancies which were diagnosed at a median of three years (range 2–8) after chemo-radio therapy. Four patients died by solid neoplasm. Overall incidence of secondary malignancy was 0.68/100/anno. The ACOP-B regimen plus involved field radiotherapy is a short and long term well tolerated and effective chemotherapy scheme for very well defined limited stage aggressive non-Hodgkin lymphomas in all age categories.

Introduction: We investigated efficacy and safety of adding Rituximab (R) to induction and intensified HDC as part of first line treatment in pts with aa-IPI at Intermediate-High (IH) or High (H) risk with B-DLCL at diagnosis. We compared two groups of similar pts enrolled in two consecutive non-randomized phase II clinical trials with up-front HDC and ASCT with or without R with identical inclusion criteria conducted by GIMURELL. Patients and methods: 118 previously untreated pts Results: Pts characteristics in both trials were comparable with no statistically significant differences: median age was 45 years (19–60); 51% were at H risk; 36% had bone marrow (BM) involvement, 80% had LDH level >normal and 42% extranodal sites>1. Complete Response at the end of the treatment was: 60 pts (78%) in R-HDC group and 28 (68%) in HDC group (p=.25). Failures (17% vs 24%) and toxic deaths (5% vs 7%) were comparable between the two groups (R-HDC vs HDC). Short-term toxicity appeared similar. Median follow-up was 27 months in study group and 69 months in control group. Two-year failure-free survival (FFS) and 2-yr overall survival (OS) rates in R-HDC group compared to HDC group were: FFS 70% vs 49% (p=.036); OS 78% vs 56% (p=.009). A better outcome for pts treated with R-HDC was confirmed in both IPI groups (IH and H risk). A Cox’s model was performed to adjust the effect of treatment for competing risk factors (age, IPI, BM involvement, number of extranodal sites). In this multivariate analysis the risk of failure and death was confirmed as significantly reduced in R-HDC group: adjusted hazard ratio (R-HDC vs HDC) was 0.54 (95% CI=0.30–0.98, p=.02) for FFS and 0.42 (95% CI=0.21–0.84, p=.03) for OS. Germinal center and non germinal center subtype analysis is ongoing in both treatment groups. Conclusions: these results suggest that the addition of Rituximab to induction and intensified chemotherapy before BEAM and ASCT is effective and safe in B-DLCL at poor prognosis improving the outcome of these pts.

6696 Background: The most common approach for limited-stage low-grade non-Hodgkin’s lymphoma (NHL) is localized radiotherapy (L-RT). However, some studies have reported prolonged disease-free survi...

Abstract 2720 Introduction: Bendamustine is a promising agent that has been showed high efficacy in combination with Rituximab in indolent lymphomas; however experiences on its use in combination with other cytotoxic agents are scant, particularly in FL. A previous FIL trial showed that a brief R-FND induction chemoimmunotherapy with only 4 courses of R-chemotherapy followed by 4 rituximab doses as consolidation can achieve high CR and PFS rates in FL patients, supporting the feasibility of this regimen in the elderly (Vitolo et al, ASH 2011). These promising results prompted FIL to investigate safety and efficacy of a similar combined brief regimen substituting Bendamustine for Fludarabine aimed at reducing toxicity and maintaining efficacy. Patients and methods: From September 2009 to November 2011, 76 elderly patients (age 65–80) with advanced stage FL at diagnosis were enrolled. Inclusion criteria were: untreated grade I, II and IIIa FL; advanced disease requiring treatment (stage III/IV) or stage II including at least one of the following conditions: bulky disease (>7 cm), active disease with rapid lymph node progression, lactate dehydrogenase or β2 microglobulin above normal, systemic symptoms and extranodal involvement. A comprehensive geriatric assessment (ADL, I-ADL, CIRS) was also performed at diagnosis and only “FIT” patients were enrolled into the study. Treatment plan was: 4 monthly courses of R-BM (375 mg/m2 Rituximab day 1, 90 mg/m2 Bendamustine days 1–2, 8 mg/m2 Mitoxantrone day 1), followed by consolidation with 4 weekly Rituximab infusions. Polymerase chain reaction (PCR) for BCL2/IgH rearrangement was performed on bone marrow samples at diagnosis, after R-BM and after consolidation. Results: At the time of analysis, 69/76 patients are evaluable for clinical characteristics, response to treatment and toxicity. Median age was 71 years (range 65–80); 26 males, 43 females; WHO grading was as follow: I 16%, II 55% and IIIa 29%; 19% had advanced stage II disease, 27% stage III and 54% stage IV; 49% had BM involvement, 19% B symptoms and 7% leukemic dissemination; 58% patients had no comorbidity, 20% one and 22% two or more comorbidities. According to FLIPI patients were: 12% at low, 30% at intermediate and 58% at high risk. PCR analysis was carried out in 64 patients at diagnosis: 58% were Bcl-2 positive. Sixty three patients completed the planned treatment and the whole program was completed according to the planned time in 60/63 patients. Six patients did not complete the treatment: 1 for progressive disease, 4 for adverse events (2 haematological toxicity with prolonged neutropenia; 1 CMV colitis and 1 for infection and concomitant worsening of pre-existing oral pemfigo) and 1 patient for worsening of performance status. Overall response after R-BM + Rituximab was observed in 64 (96%) patients with 52 (75%) patients in complete remission and 12 (18%) in partial remission (PR). Response to 4 cycles of R-BM was as follow: 27 (39%) in CR, 37 (54%) in PR and 5 (7%) patients in stable (SD) or progressive disease. Of the 40 patients in PR or SD after 4 R-BM, 26 (65%) converted to CR following further Rituximab consolidation. At the time of this analysis, of the 37 patients Bcl-2 rearranged at diagnosis, 19 (51%) were evaluable for molecular response during and after treatment. PCR negativity was achieved in 16/19 (84%) patients after R-BM and in 18/19 (95%) patients at the end of treatment. A total of 521 courses of R-BM and Rituximab were given. The most frequent severe toxicity (CTC grade 3–4) was neutropenia reported in 18% of the courses; nevertheless only four serious infections were recorded (all due to bacterial agents). Pulmonary and cardiac toxicities were < 1%. Two deaths were recorded: one due to lymphoma after second line treatment and one due to hepatic carcinoma occurred 3 months after completion of therapy. Conclusions: A brief course of chemo-immunotherapy R-BM followed by Rituximab consolidation is safe and effective with a high CR rate in elderly patients with untreated advanced stage FL. Planned future analysis of the entire study will give further information on late toxicity and outcome. Disclosures: Off Label Use: In Europe use of Bendamustine in first-line treatment of follicular lymphoma is off-label. Drug was provided free by Mundipharma. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees.

Introduction: The PET is mostly used in staging of NHL patients at diagnosis and as response assessment at the end of treatment. The evaluation by PET after few cycles of chemotherapy may be useful to predict chemosensitivity and then response, progression-free survival and overall survival in this subset of patients. In our study we introduced the PET in the mid-treatment evaluation (PET-2) of aggressive NHL disease. Patients and methods: From June 2004 to December 2006, 25 consecutive aggressive NHL patients were evaluated for this study: 17 males and 8 females respectively with median age of 49 years (range 21–67). We included: 18 Diffuse Large B Cell, 1 anaplastic, 2 mantle cell, and 4 follicular grade III NHL. Patients characteristics were: 11/25 bulky disease; 20/25 intermediate or high IPI risk; 3/25 stage II, 3/25 stage III and 19/25 stage IV. All patients were staged according to standard imaging procedures completed by PET at the diagnosis and at the end of treatment. After 2 or 4 cycles of Rituximab-CHOP-like chemotherapy PET-2 was repeated in all of them. Results: PET-2 demonstrated: 16/25 patients negative and 9/25 patients positive. The conventional and PET restaging performed at the end of treatment were 21/25 negative and 4/25 positive. Among the 16 patients PET-2 negative, 14/16 remained negative at the final PET evaluation and achieved CR, 2/16 became positive with demonstration of progression disease. Among the 9 patients PET-2 positive, 7/9 became negative with achievement of CR. The other 2/9 patients remained positive at the end of therapy: one of them was false positive because of parotid gland carcinoma without NHL involvement. Among 21/25 patients PET negative at the final evaluation, 20/25 patients remained in CR with a median follow-up of 18 months and only one patient negative at the PET-2 and at the final PET demonstrated disease progression. Finally, with a median follow-up of 18 months, FFS was 84% in all pts, 81% in PET-2 negative patients and 89% in PET-2 positive patients respectively. Conclusions: The PET is an important imaging technique for staging and end-treatment evaluation in lymphoma disease, because it can better define CR patients. In Hodgkin disease several studies demonstrated that the early evaluation by PET is a crucial prognostic factor to test chemosensitivity and then to predict favourable outcome. In our study the mid-evaluation of response by this procedure had not so clear predictive value of response assessment, because patients, even if positive at PET-2, can achieve CR at the end of treatment. More large studies are needed to determine the real impact of on-course PET as response assessment in aggressive NHL patients.

Introduction: The addition of R to dose-dense chemotherapy CHOP and to high-dose chemotherapy seems to improve the outcome of advanced stage DLBCL. Patients and methods: From August 2000 to September 2006, 120 previously untreated patients (pts) Results: All 120 pts were evaluable: median age 47 years (19–60); 65 males and 55 females; 6% were at Low-Intermediate, 52% at Intermediate-High and 42% at High risk according to aa-IPI score; PS ≥2 65%, 27% BM involvement, 48% bulky disease, 80% LDH >normal and stage II/III/IV 8/19/73% respectively. Complete response at the end of treatment was achieved in 98 pts (82%), PR in 5 (4%), 12 (10%) did not respond and 5 (4%) died of toxicity. IF-RT was performed as consolidation of bulky disease or residual disease on 36% of pts. With a median follow-up of 42 months, 4-yr FFS and 4-yr OS rates were: 77% and 80%. In 101 pts (84%), PBSC yeald was good, with a median of 9.7 × 106 cells CD34/kg (range 2.5–56.3). Nineteen pts (16%) were not autografted: 5 because of inadequate PBSC yield, 9 of progression disease and 5 of toxicity. All 101 pts who underwent ASCT achieved a complete hematological engraftment with a median of 9 days (3–27) to neutrophil counts >0.5 × 109/L and a median of 14 days (1–72) to a self-sustaining platelet count >50 × 109/L. Transfusional support was: platelets and red-cell package respectively in 8% and 24% of pts during 4 R-MegaCEOP, 92% and 70% during 2 R-MAD and 96% and 74% during BEAM consolidation. Few severe toxicities (WHO grade 3–4) were reported; most frequent (12%) were infection and mucositis during R-MAD and BEAM phase. Five patients died of toxicity due to: E.coli sepsis in 2 pts respectively after R-MegaCEOP and R-MAD, one of sepsis ndd after R-MAD, one of Staphilococcus pneumonia after R-MAD and one of P.aeruginosa pneumonia after BEAM regimen. There are no secondary MDS or ANLL or solid tumour. Conclusions: This study suggests that Rituximab as adjuvant to dose-dense and high dose chemotherapy with ASCT support is effective and safe in high risk DLBCL.

Summary Background Chemotherapy regimens devised for elderly patients with intermediate-high grade NHL are a matter of discussion. The aim is to reduce general toxicity without loosing an antilymphoma effect. The most important limiting factor of chemotherapy is myelotoxicity; for this reason the use of growth factor may be useful in these patients. Patients and methods From November ′91 to November ′92, 67 pts older than 65 years with intermediate-arid high-grade advanced-stage NHL were treated with the P-VEBEC regimen, an original scheme with epirubicin 50 mg/m2, cyclophosphamide 350 mg/m2 and etoposide 100 mg/m2 on weeks 1, 3, 5, 7; vinblastine 5 mg/m2 and bleomycin 5 mg/m2 on weeks 2, 4, 6, 8, prednisone 50 mg/m2/day p. os in the first 2 weeks and thereafter every other day. Twenty-eight pts received r-GSF 5 (μg/kg/day throughout the treatment starting on day 2 of every week for 4 consecutive days. Their median age was 71 years (65–80), 31 pts were male and 36 female, histology according W.F. was D 6; E 17; F 16; G 19; H 9. Twenty-five percent of pts had B symptoms, 35% had bulky disease, 41% LDH level > normal, 44% stage IV and 26% had B.M. involvement. Results CR. was achieved by 66% of pts. Adverse prognostic factors for CR were E histology, stage IV, bone marrow infiltration and LDH above normal. Severe toxicity was never recorded, no toxic death was observed. With a median follow-up of 24 months OS, DFS and EFS were 55%, 52%, and 33%, respectively. EFS was influenced by stage, BM involvement and level of LDH. The relative dose intensity (RDI) was calculated by the method of Hryniuk and Bush. Patients who received rG-CSF had a significantly higher median RDI (94% vs 79%) and lower myelotoxicity (neutrophil nadir 80% (89% vs 56%). EFS was also better in pts who received a RDI higher than 80% (50% vs 18% p = 0.05). Conclusion P-VEBEC is a feasible cycle in elderly patients; the use of rG-CSF improves RDI. In patients with adverse prognostic factors (BM involvement, poor performance status) a RDI >0.80 could play a role in improving the outcome.

The results of a prospective trial of an 8 week treatment for elderly patients with advanced intermediate-high grade NHL are reported. Our aim was to reduce general toxicity without losing an antilymphoma effect. For this reason the use of growth factor was studied. We also analysed the behavior of different histological groups (E + F vs G + H). From November 1991 to November 1993 100 patients older than 65 years with combination intermediate-high grade advanced stage NHL were treated with the P-VEBEC regimen, an original including epirubicin 50 mg/sqm, cyclophosphamide 300 mg/sqm and etoposide 100 mg/sqm on weeks 1, 3, 5, 7; vinblastine 5 mg/sqm and bleomycin 5 mg/sqm on weeks 2, 4, 6, 8; prednisone 50 mg/sqm/day per os in the first two weeks and thereafter every other day .46 pts received rG-CSF 5 micrograms/Kg/day throughout the treatment starting on day 2 of every week for 4 consecutive days. Twenty eight pts had B symptoms, 41 had bulky disease, 37 LDH levels above normal, 50 stage IV patients and 30 had bone marrow involvement. Sixty two percent achieved a complete remission (CR). Adverse prognostic factors for CR were E and F histology, stage IV disease, bone marrow infiltration, serum LDH levels above normal, international Prognostic Index (I.I.) intermediate-high and high risk categories and relative dose intensity (RDI) less than 0.80. Severe toxicity was rarely recorded and only one toxic death was observed. With a median follow-up of 33 months OS, DFS and EFS were 44%, 60% and 30% respectively. EFS was influenced by stage, BM involvement, level of LDH and I.I. intermediate-high and high risks. The 52 patients with DLCL (diffuse large cell lymphomas--G + H according to WF) did better with a higher CR, OS, DFS and EFS rates, than the other WF subtypes. In conclusion P-VEBEC is a feasible combination to use in elderly patients, mainly in DLCL. The use of rG-CSF improves the RDI. A RDI > 0.80 could play a role in improving the outcome, especially in patients with adverse prognostic factors. For other subgroups another schedule is probably justified.