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Purpose: Hodgkin's lymphoma (HL) is a highly curable disease even in advanced-stage, with >90% of long-term survivors. Currently, the standard of care is ABVD (doxorubicin, etoposide, vinblastine and dacarbazine), as it is less toxic and as effective as other more intensive chemotherapy regimens. Alternatively, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) has been proposed as front-line intensified regimen with a better initial disease control and prolonged time to relapse when compared to ABVD. However, this advantage is associated with higher rates of severe hematologic toxicity, treatment-related deaths, secondary neoplasms and infertility. To date, the debate regarding which regimen should be preferred as first line for advanced-stage HL is still ongoing. To shed some light on this open question we compared efficacy and safety of both regimens in clinical practice. Patients and Methods: From October 2009 to October 2018, patients with HL stage III-IV treated with either ABVD or BEACOPP escalated (BEACOPPesc) were retrospectively assessed in 7 European cancer centers. Results: A total of 372 consecutive patients were included in the study. One-hundred and ten patients were treated with BEACOPPesc and 262 with ABVD. The baseline characteristics of the two groups did not differ significantly, except for a higher rate of high-risk patients in the BEACOPPesc group in contrast to the ABVD one (47% vs 18%; p= 0.003). Complete response rate (CR) assessed by PET imaging at the end of the second cycle was 67% and 78% for the ABVD and BEACOPPesc group (p= 0.003), respectively. Thirteen patients of the ABVD group achieved stable disease (SD) and 6 had a progression disease (PD). On the other hand, 4 of the patients in the BEACOPPesc group progressed, another 2 interrupted therapy because life-threatening toxicity. At the end of the therapy, CR was 76% in the ABVD group and 85% in the BEACOPPesc group (p= 0.01). A total of 20% patients in the ABVD group and 14% patients in the BEACOPPesc group received consolidation radiotherapy on the mediastinal mass at the dose of 30Gy. After radiotherapy, the number of patients with CR increased to 79% and 87% in the two groups (p= 0.041), respectively. Thirty-nine patients (35%) in the BEACOPPesc group required dose reduction of chemotherapy due to toxicity compared to 12 patients (5%; p= Conclusion: We confirm that the ABVD regimen is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control especially in high-risk patients, the long-term outcome remains similar between the two regimens. Disclosures Ferrero: EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau. Martinelli:BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Novartis: Consultancy. Willenbacher:European Commission: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujimoto: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: Despite the important progress in the research of myeloproliferative neoplasms (MPN) in the last years, treatment options are still limited. Currently, a cytoreductive approach is the backbone treatment, with hydroxyurea (HU) being the most important agent. However, this drug is not always well tolerated and seems to be associated with a potential leukemogenic effect. A valid alternative treatment is interferon alfa (IFN-α), but is reserved for selected patients due to the unfavorable toxicity profile. Furthermore, studies directly comparing IFN-α to HU are lacking, which is why we performed the so far largest Philadelphia negative (Ph-) MPN real-life analysis. Methods: From 2000 to January 2016 we prospectively assessed 63 Ph- MPN patients who received either HU at induction dosage of 25 mg/kg daily until achievement of hematologic remission, followed by maintenance therapy at 10 to 15 mg/kg daily, or IFN-α 3 MU subcutaneously three times a week. The treatment was selected based on physician's choice. All patients were screened for molecular genetic and cytogenetic analysis at diagnosis and during treatment. Results: Between January 2000 and January 2016, 63 consecutive patients were diagnosed with Ph- MPN: 28 were affected by polycythemia vera (PV) and 35 by essential thrombocytosis (ET). Fifteen patients with PV (54%) and 20 with ET (57%) were treated with IFN-α, while 13 with PV (46%) and 15 with ET (43%) received HU, respectively. Clinical characteristics were similar between both treatment groups and no significant differences were observed. During a median follow-up period of 81 months (range, 48-168 months) 97% of the patients treated with IFN-α achieved a hematologic response [60% complete (CHR), 37% partial (PHR)] compared to 78% in HU group (56% CHR, 20% PHR; p< 0.01). Molecular responses were limited to patients treated with IFN-α. Among these, the overall molecular response rate was 60% in both PV and ET. Complete molecular response (CMR) was achieved in 20% patients with PV and in 10% with ET, whereas partial molecular response (PMR) in 33% and 20% of patients with PV and ET, respectively. (Fig.1) Importantly, no patient who achieved CMR was observed to experience hematologic or molecular relapse after a median follow up of 92 months (range 53-132 months), suggesting that this drug is able to modify the natural course of Ph- MPN. In contrast, HU did not influence molecular response. In addition to molecular genetic analysis, we performed conventional cytogenetics on all patients at diagnosis and during treatment. Six patients were found to have abnormalities on metaphase cytogenetics pretreatment with IFN-α. Of these 6 patients, 1 had a resolution of cytogenetic abnormalities during the study. We did not observe the acquisition of new cytogenetic abnormalities in these 6 patients or in the others with normal baseline cytogenetics during therapy. Four patients were found having cytogenetic abnormalities before HU and two more developed new abnormalities over the course of the treatment, suggesting that this drug is not able to prevent leukemogenesis. IFN-α was well tolerated with no secondary malignancy, while HU was associated with more toxic events and seemed to increase risk of leukemia. Conclusion: We provide evidence that IFN-α might be a more valid therapeutic option due to its more profound hematologic responses, the ability to induce molecular responses and the potential ability to reduce the risk of leukemic transformation. Disclosures No relevant conflicts of interest to declare.

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

Background. Mantle Cell Lymphoma (MCL)represents an aggressive lymphoma for which an effective treatment has still to be determined. The FIL-MCL0208 phase III trial (EudraCTNumber: 2009-012807-25) is exploring R-CHOP followed byi) high-dose cytarabine, autologous stem cell transplantation, and ii) randomization between lenalidomide maintenance vs observation (Cortelazzo et al, EHA 2015). We performed genome-wide DNA profiling to identify unbalanced copy number variations (CNVs) with a clinical significance in patients enrolled in the FIL-MCL0208 phase III trial. Patients and Methods. The study included untreated, advanced stage MCL patients ( Results. 161 patients were currently evaluable for CNVs and clinical outcome. Patients had an intermediate/high-risk MIPI and a Ki67 ³ 30% in 43% and 42% of the cases, respectively. Twenty-five recurrent unbalanced CNVs were defined (Table 1). By multiple test corrected univariate analysis, seven CNVs had a negative impact on PFS: +3, 7p gain, 9p loss (CDKN2A), 17p loss (TP53), 8p loss, and 2 losses at 22q (Table 1). MIPI (intermediate/high vs low risk), Ki67+ and the TP53/KMT2D model (Rossi et al, ASH 2015) were also statistically significant. Combining CNVs and mutations, TP53 was inactivated in 27/147 cases (18%): mutated/deleted in 7/147 (5%), deleted but not mutated in 14/147 (10%), and mutated but not deleted in 6/147 (4%). The negative prognostic impact was equal for all the 3 inactivation modalities, which were then considered as a single group for further analyses. ATM was inactive in 69/147 (47%): mutated/deleted in 24/147 (16.3%), deleted in 12/147 (8%), and mutated in 33/147 (22.4%). KMT2D (MLL2) was inactive in 18/147 (12%): mutated/deleted in 1/147 ( The lesions with a significant impact at univariate were included in a multivariate analysis alongside MIPI, KMT2D inactivation and Ki67+ as continuous variable. Only TP53 inactivation by deletion and/or mutation, 7p22.2-p12.1 gain and KMT2D inactivation maintained their independent prognostic significance. Conclusions. Genome wide DNA profiling in the FIL-MCL0208 phase III trial identified lesions, namely TP53 and KMT2D inactivation and gains at 7p, which maintain a poor outcome significance in young MCL patients even following high-dose cytarabine and autologous stem cell transplantation. Disclosures Rossi: Gilead: Honoraria, Research Funding; Abbvie: Honoraria; Janseen: Honoraria. Stelitano:Azienda Ospedaliera: Employment. Gaidano:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria.

INTRODUCTION: Secondary central nervous system (CNS) dissemination is a lethal event in patients (pts) with aggressive lymphomas. A few studies focused on the treatment of this condition are available, confirming the dismal prognosis and the high rate of severe neurotoxicity in pts managed with radiotherapy-based induction. Thus, the most effective treatment for secondary CNS lymphoma remains an important, unmet clinical need. Herein, we report the final results of a multicenter phase II trial addressing a new treatment in pts with aggressive B-cell lymphoma and CNS involvement (NCT00801216). Experimental treatment is based on the encouraging experiences with high doses of antimetabolites in pts with primary CNS lymphoma (Ferreri et al. Lancet 2009), and with high-dose sequential chemotherapy combined with rituximab (R-HDS) and supported by autologous stem cell transplant (ASCT) in pts with relapsed aggressive B-cell lymphoma (Tarella et al. JCO 2008). METHODS: Selection criteria were: 1) histological diagnosis of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma blastoid variant (MCLb) or grade-3 follicular lymphoma (FL); 2) secondary CNS involvement at diagnosis or relapse; 3) age 18-70 years; 4) ECOG PS ≤3; 5) absence of HIV infection; 6) adequate organ functions. Pts with primary CNS lymphoma (exclusive CNS disease at diagnosis) were excluded. Experimental treatment consisted of an induction phase with 2 courses of methotrexate 3.5 g/m2 d1 + cytarabine 2 g/m2 x2/d d2-3, followed by an intensification phase with R-HDS (cyclophosphamide 7 g/m2 d1; cytarabine 2 g/m2 x2/d d22-25; pts with residual extra-CNS disease received also etoposide 2 g/m2 d43) and a consolidation phase with BCNU-thiotepa conditioning + ASCT (figure). Treatment included 8 doses of rituximab and 4 of intrathecal liposomal cytarabine. The primary endpoint was 2-year PFS; the planned accrual was 38 pts. RESULTS: 39 pts were registered (age 32-70 ys, median 59; M/F ratio 1.5): 33 had DLBCL, 3 MCLb, 3 FL. CNS disease (brain 21, meninges 5, spinal cord 2, multiple 11) was detected at diagnosis in 16 pts (all with extra-CNS disease) and at relapse in 23 (8 with extra-CNS disease). The median TTP from the previous treatment line was 3 months (range 0-77 months). Thirty-four pts completed the induction phase; 73 (93%) of 78 planned courses were actually delivered; G4 neutropenia, thrombocytopenia and anemia were recorded in 77%, 63% and 5% of courses, G3-4 febrile neutropenia in 16%, CMV reactivation in 3 pts. Transient G4 transaminases increase (3% of courses) was the only G4 non-hematological toxicity. Drugs dose reduction was indicated in 3 pts. Response after induction phase was complete in 11 pts and partial in 19 (ORR= 77%; 95%CI=64-90%). Thirty pts were referred to intensification phase (figure); 58 (97%) of 60 planned courses were actually delivered; G4 neutropenia, thrombocytopenia and anemia were recorded in 67%, 60% and 7% of courses, G3-4 febrile neutropenia in 22%, G4 sepsis in 8%. CMV reactivation was diagnosed in 4 pts, pulmonary aspergillosis in 1. No cases of G4 extra-hematological toxicity were recorded. Response after intensification phase (before conditioning) was complete in 22 pts and partial in 2 (ORR= 62%; 95%CI=47-77%). ASCs were collected in 21/22 (95%) pts (median 9.5 x 106/kg; range 6-19); 20 pts underwent ASCT. Response at the end of the whole program was complete in 23 pts and partial in 1 (ORR= 62%, 95%CI= 47-77%), 1 pt had SD, 10 experienced PD (all in the CNS), and 4 died of toxicity (sepsis 2, stroke, acute tracheal obstruction). Importantly, no pt was irradiated to the brain to achieve lymphoma remission, and no evidence of neurotoxicity was recorded in pts with a survival longer than 3 years. One pt was referred to sibling-donor transplant due to sMDS, and is alive and NED at 91 months of follow-up. At a median follow-up of 42 months, 16 pts remain relapse-free, with a 2-yr PFS of 42±8%. Sixteen pts are alive, with a 2-yr OS of 42±8%; 2-yr OS of transplanted pts was 72±11%. Extra-CNS and/or meningeal disease did not affect outcome, and survival was similar in both pts treated at presentation or at relapse. CONCLUSION: This radiotherapy-free combination of high doses of antimetabolites, R-HDS and ASCT is feasible and effective in pts ≤70 ys with secondary CNS lymphoma. Toxicity is usually haematological and manageable. Survival benefit is attainable also in pts with meningeal and/or concomitant extra-CNS disease. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: The salivary gland is one of the most common sites of involvement by non-gastric extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT). This multicenter, international trial sought to characterize the clinical course, treatment and outcome of patients with salivary gland MALT lymphoma. Methods: Patients were identified from multiple international sites including the Mayo Clinic Lymphoma Database (n=89), three International Extranodal Lymphoma Study Group (IELSG) cohorts (n=138), and the University of Athens (n=21). All patients had biopsy-confirmed MALT lymphoma of the salivary gland by WHO criteria. Clinical characteristics, treatment, and outcomes were obtained from the respective patient databases. Survival probability was estimated using the Kaplan-Meier method and compared between groups with the Wilcoxon or log-rank. The impact of variables on survival was assessed by the Cox proportional hazards model. Results: Patients and clinical features: From 1983 to 2012, 247 patients with MALT lymphoma were included. Clinical characteristics are shown in Table 1. The median age at diagnosis was 59, and the male-to-female ratio was 1:3. The majority of patients (76%) presented with limited stage disease, and the parotid gland was the most common site of involvement (78%). There was a history of antecedent autoimmune disease in 41% of patients, and Sjögren’s disease was the most common (83%). Treatment: Information on initial treatment was available on 242 patients. 137/242 patients (57%) initially received local therapy with either surgery (n=81), radiation (n=26), or both (n=30). Of these, 25 received adjuvant systemic therapy. 90/242 patients (37%) were treated initially with systemic therapy, of whom 54% had localized and 46% had stage IV disease. Rituximab was used alone (n=16) or in combination with chemotherapy (n=26) in 42 of the 90. 15/242 patients (6%) were initially observed. Survival: The median OS for all patients was 18.3 years. PFS following primary therapy was 9.3 years. There was no difference in the outcomes between patients receiving local or systemic therapy in first line for all patients, or for those with stage I or II disease. On univariate analysis age Relapse/progression: The site of progression was known in 51 of 76 patients who progressed. 15 (29%) patients progressed in the same salivary gland or regional nodes; in 16 (21%) recurrence involved the contralateral salivary gland; 20 (31%) had distant progression. Relapse histology was identified in 30. The most common pathology at relapse was MALT (n=28), with one patient progressing to diffuse large B-cell lymphoma. A second patient developed a mantle cell lymphoma. Conclusions: Salivary gland MALT lymphoma commonly presents at an early stage, and has a favorable prognosis with a median OS of 18 years. Surgical or radiation therapy does not appear to have benefit over systemic therapy. Patients with Sjögren’s disease appear to have a better survival. The role of rituximab and optimal first-line therapy should be evaluated further in prospective trials. Table 1: Characteristics of 247 patients with salivary MALT Characteristic N (%) Age, median; range 59; 18-93 Sex, Male: Female 62: 185 (25: 75) Primary site of involvement Parotid 193 (78) Submandibular 12 (5) Other/not specified 42 (17) Extent (unilateral: bilateral) 89:21 Missing data 137 Autoimmune disorder* 101(41) Sjögren’s 84 (33) Rheumatoid arthritis 9 (4) Raynaud’s phenomenon 8 (3) Scleroderma 5 (2) Other 19 (8) Stage IE 147 (59) IIE 42 (17) IV 56 (23) Missing data 2 (1) IPI Score Low (0-1) 126 (51) Low-Intermediate (2) 20 (8) High-intermediate (3) 21 (8) High (4-5) 5 (2) Missing data 75 (31) Elevated LDH 17 (7) ECOG PS 0-1 246 2 1 Extranodal sites 1 58 (23) 2 187 (76) Missing data 2 (1) B symptoms 9 (4) * Percents may not equal 100 as some patients had more than one disorder. Figure One: Overall survival of patients with and without Sjögren’s disease Figure One:. Overall survival of patients with and without Sjögren’s disease Disclosures Nowakowski: Celgene, Morphosis: Consultancy. Zucca:Roche, Mundipharma, Novartis, Jannsen, Celgene: Consultancy, Honoraria, Research Funding.

Abstract 3906 The clinical course of CLL patients ranges from an indolent and chronic disease to a rapidly progressing leukemia or lymphoma necessitating aggressive treatment. Very recent data have shown that genomic complexity evaluated by conventional karyotyping with DSP30/IL2 stimulation (Rigolin et al, Blood 2012) can be helpful in the prediction of the clinical course of patients with a normal fluorescence in situ hybridization (FISH) panel according to Dšhner et al (NEJM 2000). However, large studies investigating the impact of genomic complexity on the clinical course and possible correlations with other clinical parameters at time of diagnosis are still lacking. Therefore, we analyzed the role of genomic complexity in a large series of 329 CLL patients with available clinical data. Also, since SNP-array might soon represent an alternative to standard FISH in the clinical routine, we performed the so far largest comparison of FISH versus SNP-array in CLL. Methods. Copy-number data, obtained using the Affymetrix Human Mapping GeneChip 6.0 arrays (SNP6), were derived from our previously reported CLL dataset (Rinaldi, Mian, Kwee et al, BJH 2011). The FISH panel interrogated deletions at 13q14.3, 11q22, 17p13 and trisomy 12. CLL diagnosis and management were based on the NCI Working group criteria (Hallek et al., Blood 2008). Real-time PCR on genomic DNA was performed to validate discordant FISH/SNP6 results. Results. Seventy-seven of the 329 CLL patients (23%) presented a normal FISH. Among those, 17 patients (22%) had at least one large (>5 Mb) genomic aberration, different from those described by Dšhner et al (NEJM 2000). There was no correlation with the presence of TP53 mutations, since 13/13 were wtTP53. The DNA gains or losses did not occur at specific genomic loci, and their presence significantly affected the TTT (P= 0.0010; R=2.8; 95% CI, 1.5–5.5) (Figure 1), but not overall survival (OS) (p= 0.098; HR 2.3; 95% CI, 0.83–6.6). In a multivariate analysis including age, Binet stage, IGHV genes mutational status and the large genomic lesions, the latter three factors emerged as independent prognosticators for TTT with a significance of P The concordance between FISH and SNP-array results was 93% for all analyzed genomic regions: 97% for trisomy 12, 96% for del 11q, 95% for del 17p and 84% for del 13q. False positive FISH results were observed for del 13q, while among the 18 cases with 17p loss by FISH half of the 10 cases with less than 40% of nuclei carrying the lesion were classified as normal by SNP6. We applied the FISH-based prognostic model developed by Dšhner et al (NEJM 2000) to our cohort classifying the 329 patients using results obtained by FISH or by SNP6: the Kaplan-Meier curves were comparable between FISH and SNP-array, both for OS as for TTT, and the log-rank test was highly significant for both approaches. Conclusions. Patients with a normal FISH but with large genomic lesions detected by SNP-array have a worse TTT. As a whole, SNP-array has a high sensitivity and specificity and is able to identify the most important known prognostic genomic aberrations of CLL. A validation in prospective trials is needed. Disclosures: No relevant conflicts of interest to declare.

Abstract 3922 Backgrounds The therapeutic activity of Bendamustine ± Rituximab in CLL patients and, in particular, its effect in relationship to clinical and biologic prognostic factors has been analysed only in few studies. Purpose To evaluate in the contest of everyday practice the efficacy and safety of Bendamustine ± Rituximab in CLL patients according to different clinical and biological risk groups. Patients and Methods Nine hematological centers from the North-East of Italy reported retrospectively their experiences regarding the use of Bendamustine in CLL. Outcome and survival analyses were stratified according to the patients' clinical characteristics, previous treatments and cytogenetics. Response status and toxicity were assessed according to IWCLL (Hallek 2008) and to CTCAE V 4.0. Results Clinical data of 142 patients affected by CLL (median age 70 years, range 31–88; 92 males) treated with Bendamustine between January 2005 and June 2012, were analyzed. The investigated series included 39% go-go, 69% slow-go and 2% no-go patients (according to Eichhorst 2009); 11%, 46% and 43% of patients had Binet stage A, B and C, respectively. 19 slow-go patients (13%) were untreated; for the remaining patients, the median number of previous treatments was 2 (range 1–8); 60% of patients previously received a Fludarabine containing regimen; 11% of patients each had stable disease or no response to the last previous treatment. Cytogenetic data was available in 108 patients, being positive for 11q- and 17p- in 27% and 22%, respectively; 70% of patients had an unmutated IGHV status. Bendamustine was administered on day 1 and 2 for a median number of 4 cycles (range 1–6) every 28 days at a dosage of 60–70 mg/m2 in 56% of patients and at 80–100 mg/m2 in 44%; Bendamustine was combined with Rituximab in 84%. 132 patients were valuable for efficacy. Overall 69% responded to Bendamustine; Table 1 summarizes the efficacy results considering different clinical and biological risk groups. Higher response rates were observed among patients with early Binet stage, less number of previous treatments, non 17p- cytogenetic, and in those who received Bendamustine in combination with Rituximab. Median follow up was 9.5 months; overall 1 year estimated PFS and OS were 51%±5% and 76%±2%; significant better 1 year PFS was achieved in patients with previous response to Fludarabine containing regimen, ≤ 2 previous lines of therapy, absence of 17p-, mutated IGHV status, Rituximab combination. Grade 3–4 neutropenia, infectious complications, thrombocytopenia and anemia occurred in 40%, 13%, 11% and 12% of patients, respectively; extra-hematological toxicity was nearly absent. 37 patients died, 23 for causes strictly related to disease progression, 8 because of infections, 1 for colon carcinoma and 5 for other unrelated reasons. Conclusions Although the main clinical and biological prognostic factors which influence the response to Fludarabine containing regimens and, in particular, the presence of 17p- seem not to be overcome by Bendamustine therapy, this drug appeared an active and safe agent for the treatment of patients with CLL (including those with 11q-) in everyday practice, thus suggesting its role as an alternative therapeutic option particularly for “slow-go” patients. The addition of Rituximab to Bendamustine improves response rate and PFS. Disclosures: Zaja: Mundipharma: Honoraria. Fanin:Mundipharma: Honoraria.

Abstract 1784 Introduction. The outcome of MCL is unfavourable, with continuous relapses. The MIPI, a clinical score, defined performance status, age, LDH and leucocyte counts as predictors of MCL outcome. Ki-67 as cell proliferation index was evaluated in biological-MIPI (MIPI-b). Aim of the study was to tested MIPI on a retrospective group of MCL patients treated with Rituximab-chemotherapy with or without High Dose Chemotherapy and autologous stem cell transplantation (R-HDC); secondary endpoints were: to evaluate the feasibility of MIPI-b on a retrospective population and to quantify the predictive discrimination of IPI, MIPI, MIPI-b on the outcome of MCL in the Rituximab era. Methods. Between 1999 and 2009, 206 MCL >18 years at diagnosis consecutively treated in seven Italian institutions were included into the study. Histology was centrally reviewed and, if possible, Ki-67 evaluation was performed. Overall survival (OS) and failure-free survival (FFS) curves were estimated both overall and stratified by MIPI, MIPI-b and IPI score. Differences between curves were tested using the 2-tailed log-rank test. In order to quantify the predictive discrimination of MIPI, MIPI-b and IPI scores, a Cox's model analysis and univariate logistic models (with death and failure event as binary outcomes) were fitted and the area under the receiver operating characteristic (ROC) curves (c-index) was estimated in a subgroup of 120 patients that fulfilled MIPI, MIPI-b and IPI scores. Results. Clinical characteristics were: median age 61 (34-85) years, 78% stage IV, 73% with bone marrow involvement, 16% with blastoid variant; median leucocyte counts at diagnosis was 7.53×103 (2.38-175). First-line treatments were: R-HDC in 51%, Rituximab-Fludarabine based chemotherapy in 12%, Rituximab-CHOP in 32% and other Rituximab containing regimens in 5%. Ki-67 evaluation was performed in 135 patients; median Ki-67 value was 30%. Patients at high-risk (HR) were 29% according to MIPI, 18% according to MIPI-b and 33% to IPI. With a median follow-up of 48 months, 4-year OS was 72% (95% CI:65-78) and 4-year FFS was 49% (95%CI: 41–56). Four-year OS according to MIPI by risk groups was: LR 94% (95%CI: 85–97), IR 66% (95%CI: 47–80), HR 41% (95%CI: 26–55) and according to IPI: LR 87% (95%CI: 73–94), IR 88% (95%CI: 74–95), HR 41% (95%CI: 26–55) (Figure 1). In the subgroup of 120 patients that fulfilled MIPI, MIPI-b and IP scores an univariate logistic model and a Cox's model analysis were fitted. The c-index and Cox-index for death event were 76% and 75% for MIPI, 69% and 69% for MIPIb, 76% and 71% for IPI respectively; the c-index and Cox-index for failure event were 61% and 68% for MIPI, 59% and 64% for MIPIb, 68% and 66% for IPI respectively. A sub-analysis was conducted to validate the role of MIPI in R-HDC group; an univariate logistic model and a Cox's model analysis were fitted and the c-index and Cox-index for death event and for failure event were calculated (Table 1). Conclusions. MIPI score was confirmed as a good predictor of death event in MCL retrospective patients treated with Rituximab-chemotherapy regimens. MIPI score should be a good predictor of death event also in patients treated with R-HDC. The impact of MIPI-b score should be tested in prospective trials, with central histology review. New therapeutic strategies are warranted to improve the outcome of MCL namely in MIPI-HR group. Disclosures: No relevant conflicts of interest to declare.

Abstract 672 BACKGROUND: CLL is the most common adult-onset leukemia in the Western world. The most common known genetic lesion is the 13q14.3 deletion targeting MIR15/MIR16. We applied a very high resolution array to identify new genetic lesions in CLL. METHODS: 266 CLL samples were analyzed with Affymetrix Human Mapping 6.0 arrays, comprising over 1,8 million probes with a median distance of less than 1 Kb. Copy number was inferred using the circulary binary segmentation (CBS) algorithm. Minimal common regions (MCR) were defined using a modified version of the algorithm by Lenz et al. (PNAS 2008), specifically altered to identify very small genomic losses covered by only 2-9 probes and occurring in at least 5% of the cases (mMCRs). mMCRs having 100% overlap with known copy number variations were discarded. RESULTS: mMCRs occurred in 75 known genes. The most commonly affected genes were CDC73 (cell division 73; 63% of the cases, 3 probes), RREB1 (ras responsive element binding protein 1; 60%, 5 probes), JAK2 (47%, 8 probes), CCDC88A (AKT-phosphorylation enhancer,; 47%, 3 probes), AKT3 (43%, 4 probes). Other affected genes at a lower frequency were PIK3CA (26%), EGFR (25%), XRCC4 (18%), JAK1 (18%), PTPRK (15%), RB1 (14%), ERBB2 (10%), PDGFRA (8%), FHIT (7%). A functional analysis performed with DAVID 2008 (http://david.abcc.ncifcrf.gov/) identified the terms “anti-oncogene” and “tyrosine-protein kinase” and five KEGG (http://www.genome.jp/kegg/) pathways (“prostate cancer”, “non-small cell lung cancer”, “pancreatic cancer”, “endometrial” cancer”) as enriched among the 75 genes with a statistically significant p-value CONCLUSIONS: The application of high resolution arrays on a large series of CLL samples has shown frequent small interstitial deletions targeting a discrete number of genes, highly enriched for transcripts coding for kinases. A potential mechanism of action might be the loss of regulatory regions determining gene activation. Once validated, the current data would provide the basis to explore the rationale for the use of kinase inhibitors in the treatment of CLL. Disclosures: No relevant conflicts of interest to declare.

Abstract 444 Post transplant lymphoproliferative disorders (PTLD) are important complications of solid organ transplantation associated with severe morbidity and mortality. DLBCL represents the most common form of monomorphic PTLD. Since knowledge of the pathogenesis of monoclonal PTLD is limited, we studied a series 44 cases of PT-DLBCL with high-density genome wide SNP-based arrays, and compared them with 105 cases immunocompetent DLBCL (IC-DLBCL) and 28 cases of HIV-DLBCL. Methods. DNA was extracted from frozen biopsies. All 177 DNA profiles were obtained using the Affymetrix GeneChip Human Mapping 250K NspI arrays. Recurrent minimal common regions (MCR) were defined using the algorithm by Lenz et al. (PNAS, 2008). Differences in frequencies between subgroups were evaluated using Fisher's exact test followed by multiple test correction. Results. The most common MCR were losses at 2p16.1 (29%) and 17p11.2-p13.3 (22%, TP53), and gains at 11q14.2-q24.2 (22%) and 7q (22%). Amplifications occurred in 7% at 9p23-p24 (PTPRD, JAK2, JMJD2C). MCRs more frequently deleted in PT-DLBCL when compared to IC-DLBCL included a series of small interstitial deletions at 1p32.2, 2p16.1, 3p14.2, 4p14, 14q13.2, 20p12.3, 20q13.32. Some of these aberrations targeted known fragile sites (FRA3B, FRA1B and FRA2E). FRA2E deletion showed the most significant difference with IC-DLBCL (PT-DLBCL 30% vs IC-DLBCL 4%, p Disclosures: No relevant conflicts of interest to declare.

Abstract 2339 Poster Board II-316 BACKGROUND: CLL, the most common adult-onset leukemia in the Western world, has a heterogeneous clinical course. Many advances have led to a better understanding of its pathogenesis and to improvements in treatment strategies, but striking solutions are still missing. We conducted a study to evaluate the impact of genomic aberrations on the clinical course. METHODS: From January 1980 to May 2008, 395 frozen samples of CLL patients, were prospectively collected in four centers. Extracted DNA was analyzed with Affymetrix Human Mapping 6.0 arrays. Normal matched DNA was analyzed for one fourth of the cases. Correlations between minimal common regions (MCR) and clinical parameters were evaluated with the Fisherôs-exact test and their impact on OS with the log-rank test. A p-value after Bonferroni multiple test correction (MTC) (p-adj.) RESULTS: Analysis of the clinical parameters (CPs) and known risk factors (Rai/Binet, age, doubling time, LDH, beta2, IGVH status, p53 mutations, telomere length, CD38, 11q, 17p) was consistent to previous published series. ZAP70 did not affect the clinical course, likely due inter-laboratories variability. After a median follow up of 53 months, 143/239 (60%) of the patients have started therapy and 63/261 (24%) died. 5-yr OS was 82%. Fisher test between the MCRs and CPs revealed an inverse relation between the presence of trisomy 12 by FISH and del13q14.3, an association between del17p and losses of 8p regions and between CD38 and 12q gain. Before MTC, 46 MCRs had a significant impact on OS and 67. After MTC, 3 regions maintained their role: 8p22 loss (38/248, 15%, p-adj.=0.002, median OS: 26 months vs. 48), 17p13.3-11.2 loss (20/248, 8%, p-adj.=0.001; median OS: 10 months vs. 48). In univariate analysis, the log-rank test among pts with 8p-/17p- (8/248, 3%), 8p- (30/248, 12%), 17p- (12/248, 5%), wild type (198/248, 80%) was statistically significant (p CONCLUSIONS: Loss of 8p22 designated a CLL subgroup with a worse outcome among all patients and in the subset with 17p loss. Our data suggested that this aberration might constitute an independent prognostic factor to be evaluated in independent studies. Results, including a Cox regression model, will be presented on all 395 cases. Disclosures: No relevant conflicts of interest to declare.

Primary cutaneous B-cell lymphomas (PCBCL) are a distinct group of primary cutaneous lymphomas with few and controversial reports on their treatment and prognostic factors. The aim of this retrospective study of a large international series of PCBCL patients was to analyze the patient and lymphoma characteristics as well as treatment-related variables associated with clinical outcome. From 1980 to 2006, 507 patients were referred to 19 cancer centers of 6 countries all over the world. The median age was 55 years (range,16–92 years) and the M/F ratio was 1.4. According to the WHO-EORTC classification indolent lymphomas included 341 FCL and 122 MZL, while aggressive NHL were represented by DLBCL, leg type (n=44). Sixty patients (12%) had stage II. The majority of cases was diagnosed in trunk/arms (52%), while in 29% in head/neck and in 13% in the legs; 7% of patients had a generalized disease (>1 site). The maximal lesion diameter was >4 cm in 21% of cases and ≥2 lesions were recorded in 39%. The prevailing type of lesions were nodules (74%), while only a minority of patients (6%) were affected by tumors. Few patients had B symptoms (5%), poor ECOG-PS (9%) or elevated LDH (7%). Two hundred eighty-four out of 446 patients (64%) were treated only with surgery (n=86) or chemotherapy (n=95), mostly consisting of a short course of anthracyclin containing regimens, or radiotherapy (30–50 Gy) (n=103). One hundred sixty two cases (36%) received combined therapy, mostly including surgery or chemotherapy, followed by radiotherapy. A small subgroup of 35 patients were given rituximab alone (n=19) or in combination with other treatments. The remaining 26 patients did not receive any therapy. The response rate of 446 patients was the following: 402 achieved CR (86%), 38 PR and 6 were in SD. Neither histology nor treatment significantly influenced CR rate. Among 402 responders, 128 (32%) eventually relapsed, 86% in the skin, 10% in extracutaneous sites and 4% in both. The relapse rate varied according to histology, ranging from 52% in DLBCL leg-type to 29% in MZL and 28% in FL. Moreover, combined treatments significantly reduced relapse rate (24% vs. 37%; p=0.008). The achievement and maintenance of CR significantly influenced the long-term disease specific survival (at 20 year 99 % vs. 45%; p=0.0001). The CR rate of subgroup of 35 patients treated with rituximab, was 74%, while the relapse rate was 35%. These results were not influenced by the addition of other therapies to rituximab. After a median follow-up of 53 months (range, 2–333 months), 5 and 10-year estimate of OS, disease-specific survival, PFS and DFS were 91%, 92%, 61%, 65% and 82%, 88%, 49% and 56%, respectively. Cox multivariate analysis, stratified for age with a stepwise selection of the significant variables, identified DLBCL, leg-type histology, elevated LDH, type of lesion (nodules and tumors), B symptoms and female gender, as significant predictors of a poor OS. In conclusion this retrospective analysis confirms, on a large series of cases, that patients with PCBCL belong to different risk categories requiring a tailored treatment approach. These data can be usefully taken into account for an adequate management strategy of PCBCL patients.

We updated a cohort study with the aim of evaluating if an up-front Rituximab supplemented high-dose sequential chemotherapy (R-HDS), supported by autologous bone marrow transplantation (ASCT) can induce log-term remissions in Mantle Cell Lymphoma (MCL), with an acceptable toxic profile. From 1997 to 2005, 77 consecutive MCL patients, 1 IPI risk factors, while >1 extranodal sites prevailed in Group 1 and a poor ECOG-PS in Group 2. After 2–3 cycles of either doxorubicin- or cisplatin-containing chemotherapy, Group 1 received R-HDS including: HD-cyclophosphamide (CTX) 7 gr/sqm and HD-Ara-C (2 g/sqm every 12 hours for 6 days), followed by HDS HD-melphalan (180 mg/sqm) and/or HD-mitoxantrone plus melphalan (60 and 180 mg/sqm) and ASCT. Rituximab (375 mg /sqm) was given for a total of 6 doses, twice after HD-CTX and HD-Ara-C, as in vivo purging before CD34+ cells harvest and twice after ASCT. Sixty-nine patients (90%) in Group 1 completed the planned program and a median number of 6.3 x 10^6 cells CD34+/kg were transplanted. In Group 2, 85% of patients received the planned chemotherapy. The CR rate was 86% in Group 1 and 35% in Group 2 and the treatment-related mortality was 1.3% and 0.8%, respectively. Moreover, in Group 1, 4 patient developed sMDS, and 4 died of solid tumors (n=3), or septic shock (n=1). After a median follow-up of 50 months (range 3–111) in Group 1 and 37 months (range 1–141) in Group 2, the rate of 1st CCR was 65% and 14%, respectively. The 5-year projected OS, EFS and DFS were 74%, 61% and 70%, in Group 1 and 31%, 14% and 25%, in Group 2, respectively. Cox multivariate analysis failed to identify within potential prognostic markers factors predictive for OS and EFS. In conclusion, R-HDS induces long-term remissions with a manageable toxicity in patients with newly diagnosed MCL. Studies comparing this program with other intensive regimens are needed for ascertaining the role of R-HDS in the treatment of this otherwise incurable disease.

INTRODUCTION We retrospectively analyzed the impact on post-relapse survival of selected prognostic factors and salvage therapy (finalized to perform an allo-SCT) in 145 patients (pts) with non-APL AML who had been initially treated with standard induction and risk-adapted consolidation. The aim was to identify factors associated with a better outcome at first relapse. METHODS All pts were at first recurrence following consolidation of CR1 with (i) high-dose Ara-C (HiDAC) multicycle therapy supported by blood stem cells (standard risk, as defined by mixed clinico-cytogenetic criteria) or (ii) allo-SCT in case of high-risk prognostic profile. Median pt age was 55 y (range 21–68). CR1 duration was ≤ 6 months in 49 pts (34%), ranging from 0.6 to 6 mo (median 3.7). 25/68 pts (37%) had an unfavourable cytogenetics (CG), and 8.2 % had MDS-related AML. 96 pts (66%) had received HiDAC and 21 (15%) an allo-SCT according to study design. RESULTS 105 pts (72%) received salvage chemotherapy, 10 pts (7%) underwent directly allo-SCT, while the remaining 30 (21%) received palliation and all of them died. Salvage therapy consisted again of HiDAC alone or in combination with fludarabine or anthracyclines. After reinduction, 52/105 pts (49.5%) achieved CR2 and 15 (14%) died of complications. Altogether, 42 pts (29%, group 1) received an allo-SCT following relapse, 27 (64%) in CR2, 5 beyond CR2 and 10 soon after relapse. Of 20 more pts (14%, group 2) in CR2 but without HLA identical donor, 13 could be given further intensive consolidation therapy. Both groups were comparable regarding adverse prognostic features such as age >55 y, WBC count>50,000/μL, unfavourable CG, presence of FLT-3 ITD, prior allo-SCT and 1st CR lasting ≤ 6 mo. At the end of treatment, 37/42 pts (88%) receiving SCT and all 20 pts (100%) given only chemotherapy were in CR2. Logistic regression analysis showed that intensive treatment without HiDAC at induction (p=0.04) as well as CR1 lasting CONCLUSIONS AML patients receiving intensive chemotherapy including HiDAC at 1st relapse reached a high CR2 rate, regardless of type of prior risk-adapted consolidation. Further intensification with allo-SCT may offer substantial salvage rates to younger standard risk patients, thus adding value to the underlying concept of a risk-oriented first-line therapy.

We showed recently that the dismal outcome of MCL might be improved in 28 young patients (pts) (60 years with an age-adapted R-HDS. We report the outcome of 54 young pts (group 1), including the first 28 cases and that of 19 elderly pts (group 2). The majority of both groups had an advanced stage and bone marrow infiltration, while in elderly pts prevail B symptoms and > 1 extranodal site. One third of cases had >2 adverse prognostic features according to IPI. After 2–3 cycles of either doxorubicin- or cisplatin-containing chemotherapy, group 1 received standard R-HDS including: HD-cyclophosphamide (CTX) 7 gr/sqm and HD-Ara-C (2 g/sqm every 12 hours for 6 days). Following HDS chemotherapy a conditioning program with HD-melphalan (180 mg/sqm) and/or HD-mitoxantrone plus melphalan (60 and 180 mg/sqm) with ASCT was planned. Rituximab (375 mg /sqm) was given for a total of 6 doses, twice after HD-CTX and HD-Ara-C, as in vivo purging before CD34+ cells harvest and twice after ASCT. Elderly patients received an age-adapted R-HDS: HD-CTX (3–4 gr/sqm) and HD-Ara-C (1–1.5 g/sqm every 12 hours for 3–5 days), followed by HD-melphalan (120 mg/sqm) and HD-mitoxantrone plus melphalan (40 and 120 mg/sqm). 35 pts (65%) in group 1 and 9 (47%) in group 2 completed the planned program and a median number of 7.6 and 6.8 x 10^6 cells CD34+/kg were transplanted. After ASCT the CR rate was 88% in young and 95% in elderly patients. One young pt (2%) died during treatment, 1 developed sMDS and 5 died of late toxicity including a case of lung carcinoma. Among elderly pts only one died tardily because of cardiac disease. With a median follow-up of 48 months (range 8–101) in group 1 and 25 months (range 9–68) in group 2, the 5-year estimated OS, EFS and DFS were 77%, 60% and 71%, in group 1 and 55%, 53% and not yet achieved in group 2. The Cox multivariate analysis failed to identify within potential prognostic markers factors predictive for OS and EFS. We conclude that R-HDS is an effective regimen for the induction of complete remissions in pts with newly diagnosed MCL. The manageable toxicity of the program in elderly pts proved that an age-adjusted R-HDS regimen can be safely applied to this age subgroup still producing long-term remissions.

High-dose sequential (HDS) chemotherapy followed by ASCT proved to be an effective salvage therapy for patients (pts) with refractory or recurrent non-Hodgkin’s lymphoma (NHL) (Cortelazzo et al Br J Haematol, 2001). The addition of Rituximab to HDS (R-HDS) could enhance the sensitivity to rescue treatment improving the outcome of ASCT. We evaluated retrospectively clinical outcome of two consecutive cohorts of pts with low grade (LG) (n=55) or aggressive (LG-transformed=50, DLBCL=89) NHL treated with HDS chemotherapy with or without Rituximab. Regarding disease status at enrollment 135 pts (70%) were at high risk being primary refractory (n=84), early relapsed (≤12 months; n=21) or relapsed ≥2 (n=30). 86 pts were treated with HDS alone from 10/92 to 5/99 (group1), whereas 108 received R-HDS from 6/99 to 11/05 (group 2). Both groups were comparable regarding age, histology, disease status, B symptoms, bulky disease, bone marrow infiltration, median number of previous chemotherapies and IPI risk factors. After a debulking phase of 2–3 cycles of either doxorubicin- or cisplatin-containing chemotherapy pts received original HDS chemotherapy (n=91): high dose (HD)-cyclophosphamide (CTX) 7 gr/sqm, HD-methotrexate 8 gr/sqm, HD-etoposide 2 gr/sqm or a modified version (n=103) in which HD-methotrexate was replaced by HD-Ara-C (2 g/sqm every 12 hours for 6 days). Rituximab (375 mg/sqm) was given twice after HD-CTX and HD-Ara-C in 108 patients (56%). After HDS chemotherapy a BEAM or HD-mitoxantrone plus melphalan (60 and 180 mg/sqm) conditioning regimen with ASCT was planned. After HDS chemotherapy ORR was 84% in group 1 and 94% in group 2 with 29 and 81 pts achieving complete remission (CR) (34% vs. 75%; p=0.0001). Moreover, 76 pts (88%) in group 1 and 97 (90%) in group 2 underwent ASCT with a median number of 7.2 x 10^6 cells CD34+/kg (range, 3–27) transplanted. At the completion of treatment, 52 pts in group 1 and 94 in group 2 achieved CR (60% vs. 87%; p=0.0001). Regarding toxicity, 2 pts (2%) died in group 1 and one developed a bladder carcinoma, while in group 2 two pts (2%) died, one of secondary MDS and one developed a thyroid carcinoma. With a median follow-up of 36 months (range 3–154) in group 1 and 21 months (range 1–81 months) in group 2, the 5-year estimated OS, EFS and DFS were 47%, 33%, 49% and 75%, 60 %, 70% (p=0.0001). In Cox regression analysis LG histology (p=0.05), R-HDS therapy (p=0.04) and CR prior to ASCT (p=0.0001) emerged as favourable independent prognostic factors, while bulky disease (p=0.01) and ≥2 relapses (p=0.02) were adverse prognostic factors for EFS. This retrospective study shows that addition of Rituximab to HDS improves the CR rate increasing the number of transplant eligible subjects and prolongs survival of these high risk patients.

It is often questionable as to whether or not therapeutic benefit documented in prospective studies reflects that which is observed in routine use. Four prospective studies have explored the efficacy of alemtuzumab in heavily pretreated B-CLL patients, reporting response rates (RR) between 33% to 55%, and median survival between 13–28 months. Here, we report clinical outcomes after therapy with alemtuzumab of 106 consecutive, unselected B-CLL patients treated in 25 centers in Austria. Seventy-two patients were male and 34 female, the median age was 66 years (range, 46–88 years). The majority of patients had advanced stage disease, with 58% having Rai stage IV disease. The patients had received a median of 3 prior therapies (range, 1–11). Alemtuzumab was administered according to guidelines, but in the majority of cases, dosing was individualized, according to tolerability, side effects, and economic considerations. Thus, the median duration of therapy was 7 weeks (range, 2–24 weeks), and median dose was only 390 mg (range, 11–1333 mg). Therapeutic response was determined, strictly adhering to the NCI criteria (duration of complete response [CR]/partial response [PR]/stable disease [SD] ≥ 2 months; adequate radiologic studies of all non-palpable manifestation; marrow for CR). CR, PR, and SD were achieved in 5%, 17%, and 34% of patients (RR 22%). Progressive disease occurred in 34%, and responses were not evaluable in 9%, due to early death. In the 59 patients with overall CR/PR/SD, peripheral blood responses were as follows: 63% CR, 25% PR, and 12% SD. Survival times were encouraging and comparable with other studies. The median survival for all patients was 19 months; 15 months for fludarabine-refractory patients (n = 67) and 31 months for fludarabine-sensitive patients (n = 24; P = 0.04). Survival was dependent on response (P = 0.0001), the number of previous therapy lines (0–3 vs >3; P = 0.0001), and the presence of bulky disease (P = 0.005). Route of administration (IV: 49%; IV to SC 38%; upfront SC 13%) did not influence outcome. Toxicities were within the expected range, with grade 3/4 infections in 37% of patients; grade 4 neutropenia and thrombocytopenia in 25% and 23% of patients, CMV reactivation in 14% (CMV disease in 3%) of patients, and early death (