ALBERT

Description: Prognosis of patients with CLL has been traditionally assessed by using clinical parameters. Although useful, such parameters are a mere reflection of the biological diversity of CLL. In this regard, the mutational status of VH genes or ZAP-70 expression separates CLL into two clinical forms with different presenting features and outcome. Formins are multidomain proteins characterized by the presence of two conserved prolin-rich regions, namely formin homology 1 and 2. These proteins are implicated in a wide range of processes, including regulation of the cytoskeleton and in the regulation of the signal for cell survival. Formin is normally expressed in spleen, lymph node, and bone marrow cells, and it has been recently found to be overexpressed in T-cell lymphomas. The aim of this study was to analyze the expression of FMNL-1 in normal B-cell subsets and in a series of 73 patients (median age, 59 years; male/female 40/33; Binet A: 90.2%) with CLL. FMNL-1 expression was analyzed by Western Blot in separate subpopulations and by quantitative RT-PCR using expression in Jurkat as baseline. Among normal lymphocytes, FMNL-1 was only expressed in memory (CD19+CD27+) B-cells and in T-cells. In CLL cases with a low percentage of T-cells, mean of FMNL-1 expression was 2.18 AU (SD, 1.01 AU). Using an arbitrary cut-off of 3.2 AU, cases with increased expression of FMNL-1 were associated with a younger age at diagnosis (〈 50 yrs), elevated lymphocyte count, high serum β2-microglobulin (β2-m) levels, increased ZAP-70 and CD38 expression, shorter time to progression, and shorter survival as compared to cases with low FMNL-1 expression. No relationship was observed with genetic abnormalities (table). In summary, among B-cell lymphoproliferative disorders, FMNL-1, a gene that regulates cell survival, is found only in CLL and its overexpression correlates with adverse clinical and biological parameters, particularly in young patients. Variable FMNL-1 normal FMNL-1 increased p value Age 〈 50 yrs 15% 86% 0.0001 Lymphocyte count 〉 50.000/ μL 14% 57% 0.018 Increasedβ2-microglobulin 17% 66% 0.038 CD38 〉 30% 28% 100% 0.001 ZAP-70≥20% 50% 100% 0.014 Time to progression (median) 5.1 yrs 0.5 yrs 0.003 Survival (median) 16.4 yrs 8.5 yrs 0.009

Description: CLL has a heterogeneous clinical course. Although some genetic abnormalities such as del(17p) have been associated with disease progression, the mechanisms underlying such a phenomenon are not well-known. The aim of the present study was to compare protein expression profiles in CLL cells at diagnosis and upon disease progression in patients with early, low-risk CLL. We studied 6 patients in early stage and without poor risk cytogenetics (i.e., +12, 11q-, 17p-) for which leukemic cells at diagnosis and at disease progression were available. Patients with low-risk disease progressing or receiving therapy within the first 2 years after diagnosis were not eligible for the study. Cell purity of samples at diagnosis and at progression was high(mean CD5+/CD19+ cells 90% and 91%, respectively). Protein expression profile was analyzed by using a Fluorescence 2-D Difference Gel Electrophoresis (DIGE). Image analysis and statistical quantification of relative protein levels were performed using DeCyder V. 5.0 software (GE Healthcare) and the identification of differential spots by MALDI-MS analysis. Different protein expression patterns between diagnosis and disease progression samples were onserved both in the whole group of patients (table 1) and in paired samples. Proteins undergoing significant changes in their expression levels are involved in the ubiquitin-dependent degradation pathway, carbohydrate metabolism, and RNA cytoplasmic transport. In addition several of the proteins identified, such as EF-2, HNR, annexin A1 and nucleophosmine, have a role in cell proliferation and human oncogenesis. In conclusion this study identified changes on the expression of a number of proteins that are part of important oncogenic pathways in CLL progression. Identification of differential spots Identification (p value 〈 0.05/1.2 fold) Ratio (Pr/Dx) Pr: Progression; Dx: Diagnosis Protein Catabolism Ubiquitin thiolesterase −1.59 Ubiquitin-protein ligase E1 −1.42 Elongation factor 2 (EF-2) −1.39 Acyaminoacyl-peptidase −1.25 Protein disulfide-isomerase precursor −1.21 Carbohydrate Catabolism Glucose-6-phosphate 1-dehydrogenase −1.31 Fructose -bisphosphate aldolase A −1.25 Phosphoglycerate kinase 1 −1.21 RNA Processing Heterogeneous nuclear ribonucleoprotein C 1.49 Heterogeneous nuclear ribonucleoprotein A3 1.30 Heterogeneous ribonuclear particle protein A1. Beta 1.27 Pre-mRNA cleavage factor I 25 kDa subunit 1.25 Cytoskeleton ACTB −1.67 Actinin alpha 4 −2.03 CAP1 −1.31 Cytoplasmatic dynein intermediate chain 2 −1.35 L-Plastin −1.42 Tropomyosin alpha 4 chain −1.38 Vinculin −2.48 Others Annexin A1 −1.6 Glycine-tRNA ligase (EC 6.1.1.14) precursor −1.34 HSU12596 −1.53 IQGAP1 protein −1.51 Peroxiredoxin 3 1.28 probable transitional endoplasmic reticulum ATPase −1.52 Nucleophosmin 1.25 Proteinase inhibitor 9 −1.34 purH bifunctional enzyme −1.32 tryptophan-tRNA ligase −1.31 WDR1 protein −1.51 Zeta-crystallin/quinine reductase (NADPH) 1.25

Description: Abstract 1382 The effectiveness of rituximab maintenance in the treatment of CLL has been investigated in a phase II clinical trial that includes two treatment parts. First, patients were given R-FCM up to 6 cycles as induction therapy, achieving an overall response rate of 93% and 46% of CR with negative minimal residual disease (MRD) (Bosch et al. JCO, etc). Second, three months after concluding R-FCM, patients having achieved CR or PR receive rituximab maintenance (375 mg/m2) every three months for two years (up to 8 cycles). We present here the preliminary results of the second part of the study, namely the efficacy of rituximab maintenance. Evaluation of response was performed three months after the last cycle of maintenance and included bone marrow (BM) examination, MRD assessment in peripheral blood and BM by four-color flow cytometry. Patients in whom rituximab maintenance was prematurely interrupted due to toxicity were considered as failures. Fifty-six patients (median age 60 years, 70% female) responding to R-FCM were evaluable for response to rituximab maintenance. Median number of cycles of maintenance given was 8 (range, 3 to 8), 77% of patients completed the entire planned treatment, whereas 91% received 6 or more cycles. Treatment was delayed due to insufficient hematological recovery in 12 cycles (2.7%). Toxicity was mainly hematological, with neutropenia being observed in 31.8% of cycles (Grade 3&4 in 8.9%), thrombocytopenia in 3.4% and anemia in 3.9%. Hypogammaglobulinemia occurred in 38% of patients (low levels of IgA in 50%, IgG in 34%, and IgM in 60%). Eight patients, three of them with hypogammaglobulinemia, experienced grade 3&4 infectious episodes (4 pneumonia, 2 gastrointestinal, 1 myositis, and 1 cerebral abscess). Herpes virus (I/VZ) reactivation was observed in 8 patients. Two patients died due to multifocal leukoencephalopathy and hemophagocytic syndrome, respectively. After rituximab maintenance, 44.6% of patients were in CR MRD negative, 41% in CR, 3.6% in PR, and 10.7% failed to treatment. Failures were due to disease progression (two patients), development of severe neutropenia (two patients), and death (two patients). Among 28 patients that were in CR MRD (-) at the onset of the maintenance part, 19 held the MRD negative status at the end of maintenance, 5 (18%) turned negative into positive MRD (probability of conversion, 40% at 30 months), whereas 4 failed to treatment (2 neutropenia, 1 progression, 1 death). Moreover, 5 of 24 patients (22%) in CR MRD(+) after R-FCM became MRD negative after rituximab maintenance, 17 maintained the CR, one patient achieved a PR, and one patient progressed under maintenance (Table 1). In conclusion, rituximab maintenance after chemoimmunotherapy seems to prolong duration of response and, in some cases, improves the quality of response towards a CR with negative MRD. Maintenance with rituximab had the major benefit in patients in CR with positive MRD. The exact role and the best dosage and treatment schedule of rituximab as maintenance therapy in CLL should be now investigated in randomized clinical trials. Disclosures: Bosch: Hoffman La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Rituximab is currently not approved as maintenance therapy for patients with chronic lymphocytic leukemia. Garcia-Marco:ROCHE: Consultancy, Honoraria, Research Funding.

Description: The prognosis of patients with CLL has been traditionally assessed by using clinical stages. Clinical stages, however, are a mere reflection of the biological diversity of CLL. In this regard, we and others have recently shown that ZAP-70 expression separates CLL into two clinical forms with different outcome. The aim of this study was to analyze the distribution of age, gender, and different prognostic parameters according to ZAP-70 expression in 222 pts with CLL (median age, 62 yrs; female/male: 89/133). ZAP-70 was determined by flow cytometry, a high expression being defined as 〉20% ZAP-70 positive CLL cells. Median follow-up of the series was 7.1 years. Clinical stages at diagnosis were: Binet stage A, 187 pts; B, 21 pts; and C, 14 pts. Rai Stage 0, 123 pts; I, 53 pts; II, 28 pts; III, 7 pts; and IV, 11 pts. Overall median survival was 13 years. Parameters associated with a high ZAP-70 expression were lymphocyte doubling time 〉12 mos., atypical morphology, bone marrow infiltration 〉 60%, increased serum LDH and timidin kinase, CD38 expression 〉20%, del(13q14), unmutated status of IgVH, and development of Richer syndrome. Interestingly, ZAP-70 expression distribution correlated with Rai’s stage (0 vs. 1 to 4). Also, CD38 expression was able to separate two subpopulations with different survival among CLL cases with low ZAP-70 expression (median survival 18 yrs vs. 13 yrs), but not in pts. with ZAP-70〉20%. About 50% of pts in Binet A progressed during the follow-up. Median time to progression for patients with high ZAP-70 expression was 3.3 years whereas it was not reached for patients with low ZAP-70 expression. Median survival of pts with low ZAP-70 expression was 16.3 years, whereas it was of 8.5 years in those with high ZAP-70 expression. In conclusion, ZAP-70 expression identifies a subgroup of patients with CLL with unfavorable prognostic factors related to the proliferation and progression of the disease. Prognostic Parameters according to ZAP-70 expression Variable ZAP-70 〉20% ZAP-70 〈 20% p= Median age 60 yrs 63 yrs Gender (female) 39% 41% LDT 〈 12 mos 42% 23% 0.009 Atypical morphology 54% 12% 0.000 BM infiltration 〉60% 50% 33% 0.03 Increased LDH 13% 4% 0.028 Increased TK 66% 28% 0.000 CD38 〉 20% 67% 32% 0.000 Del(13q14) 38% 55% 0.027 Unmutated IgVH 88% 11% 0.000 Richter Syndrome 8% 2% 0.039 Rai Stage 〉 0 53% 37% 0.039 TTP (Binet A) 3.3 yrs NR 0.000 Median Survival 16.3 yrs 8.5 yrs 0.000

Description: Imaging studies are not routinely performed to evaluate response to therapy in patients with CLL. To ascertain whether CT scans should be part of the maneuvers to assess response in patients with CLL we have investigated response duration according to CT results in 34 previously untreated patients (median age, 56 years; range, 38 to 65 years; males: 79%) uniformly treated with FCM (fludarabine 25 mg/m2 i.v. on days 1 to 3, cyclophosphamide 200 mg/ m2 on days 1 to 3, and mitoxantrone 6 mg/m2 i.v. on day 1, given at a 4-week intervals up to six courses) as part of a phase II study. Out of 69 patients included in the study, 64% achieved CR as defined by the NCI-Working Group criteria. Of those, 30% had abdominal lymphadenopathy as assessed by CT scans. The median follow-up of the series was 30 months. As shown in the figure, response duration was significantly shorter (54% at 20 months) in CR patients with abnormal CT (CT+ CR) than in those with no detectable lymphadenopathy (CT- CR) (95% at 20 months). Interestingly, response duration in patients with CT+ CR was not different from that of patients in PR (54% vs. 42% at 20 months, respectively; p=NS). These results demonstrate that residual abdominal lymphadenopathy negatively influences response duration in patients with CLL in whom by all other criteria a CR has been obtained. Therefore, CT scans should be performed in patients having achieved CR by conventional, NCI-Working Group criteria, and patients with residual disease by CT should be considered in PR rather than in CR. Figure Figure

Description: Follicular lymphoma (FL) is typically a nodal disease. Primary extranodal FLs, that represent less than 10% of the cases, might have differentiated clinicobiological features. The aim of the present study was to analyze the main clinicobiological characteristics, response to therapy and outcome of a series of patients with FL primarily extranodal in origin, and compare them with nodal FLs. Twenty two patients (12M/10F; median age, 59 years) with FL with primary origin in extranodal location diagnosed in a single institution during a 24-year period, with primary origin in extranodal location were the subject of the study. The control group was constituted by 212 patients with nodal FL diagnosed during the same period of time. Main clinicobiological features were recorded and analyzed. The sites of the primary disease were: skin, 5 cases; Waldeyer’s ring, 4; GI tract, 3; bone marrow, CNS and parotid (two cases each); and pancreas, thyroid, kidney and orbit (one case each). Main histological and clinical features are listed in the table. Treatment was given without considering the nodal or extranodal origin of the disease and consisted of: monotherapy with alkylating agents (38 cases), polychemotherapy (149), and fludarabine alone or with other drugs (14) and others, including surgery and observation (33). CR rate was higher in extranodal than in nodal FL (82% vs. 53%, respectively; p=0.02), but no differences were found in overall survival. FLIPI score was the most significant variable predicting overall survival in the global series as well as in either in nodal or extranodal FL. In conclusion, extranodal FL had some peculiar clinicobiological features with respect to nodal cases. Regarding the outcome, although patients with extranodal FL showed a higher CR rate, the overall survival was similar in both groups. Extranodal FL (N=22) Nodal FL (N=212) p Age (median, range) 59 (28–82) years 55 (24–93) years NS Sex (M/F) 12/10 100/112 NS Histological grade 3 (%) 12 10 NS CD10+(%) 85 90 NS Bcl2+ (%) 67 91 NS Bcl2/JH (%) 37 65 0.03 Stage IV (%) 50 64 NS Bone marrow + (%) 36 62 0.02 LDH 〉 450 IU/L (%) 15 24 NS B2-microglobulin 〉 2.3 mg/L (%) 7 41 0.058 High-risk FLIPI (%) 19 35 NS CR rate (%) 82 53 0.02 5-year OS (%) 75 74 NS 5-year FFS (%) 67 27

Description: Abstract 1236 Poster Board I-258 Glucocorticoids (GC) apoptotic effect in chronic lymphocytic leukemia (CLL) cells is known for many years. However, in CLL their use is often confined to their immunosuppressive activity in order to control autoimmune phenomena or as palliation. The fact that GC, particularly dexamethasone (DEX), can overcome p53 mediated resistance to therapy has renewed the interest in the use of GC as therapeutic agents in CLL. GC apoptotic induced cell death mechanism seems to depend on cell type and few studies were performed in CLL. GC increasing importance as apoptotic agent in CLL prompted us to analyze DEX apoptotic activity in CLL cells in order to clarify GC apoptotic mechanisms. For this, peripheral blood samples from 45 patients with CLL were selected for in vitro studies. Patients were analyzed for IGHV mutational status and ZAP-70 expression. Tumour cells were cultured over 24 hours with DEX at 13.25uM and viability was then determined by surface annexin V binding and propidium iodide (PI) staining flow cytometry analysis. To determine early apoptotic signal onset, BIM mRNA GC induced expression was quantified at different time points by quantitative RT-PCR. Genome-wide expression profile of CLL cells was done to discriminate genes involved in DEX apoptotic action. After 24 hours of exposure to therapeutic concentrations of DEX, cell viability was higher in mutated cases (M-CLL) than in unmutated IGHV cases (UM-CLL) (85.6% vs 69.5% in mean, respectively; p=0.000). mRNA BIM expression after 24 hours of treatment with DEX correlated with induced apoptotic cell death (R=0.496; p=0.000). As a consequence, UM-CLL had higher levels of induced mRNA levels of BIM than M-CLL cases (p=0.036). Time course experiments have shown that at 6h after DEX treatment BIM mRNA levels were induced 3 times without influence on cell viability. Genome-wide expression analysis of 12 CLL cases (7 UM-CLL, 5 M-CLL) was done after 6 hours of DEX treatment and was compared to the baseline gene expression. In both groups many genes were up and down regulated by DEX (UM-CLL 3359 genes and M-CLL 1008 genes, p adjusted 〈 0.01). Analysis of genes involved in the GC pathway revealed that basal mRNA levels of FKBP5, a protein essential to maintain the GC receptor (GR) complex suitable for GC binding, was more expressed in UM-CLL than in M-CLL cases (1.85 times, p= 0.027). Analysis by quantitative RT-PCR performed in 45 CLL patients to validate micro-array data confirmed that at baseline, FKPB5 expression was higher in UM-CLL than M-CLL (0.97 vs. 0.74 arbitrary units, respectively; p=0.042). The same was observed at protein level, WB analysis of FKBP5 basal levels showed that UM-CLL cases expressed more this protein than M-CLL (Fig. 1). In addition to that, genome-wide analysis revealed that GILZ, a glucocorticoid-induced leucine zipper, was differently induced by DEX in the studied groups. GILZ mRNA was less induced in M-CLL cases than in UM-CLL cases (difference fold change=0.52, p=0.0005). These results were also confirmed in 45 CLL cases by quantitative RT-PCR: in M-CLL, GILZ was induced 3.67 times whilst it was induced 5.62 times in UM-CLL cases (p=0.0001). In conclusion, treatment with GC induces more apoptotic cell death in UM-CLL than in M-CLL. As a downstream effect, BIM expression after GC exposure correlates with GC-induced apoptosis. Moreover, GC apoptotic effect in CLL is the result of several cell pathways imbalance as revealed by gene expression analysis. GILZ induction was proved to be necessary for DEX induced apoptosis in other cell types like multiple myeloma cell lines. In CLL, GILZ differential induction was observed at different degrees in GC-responders and non-responders. Finally, FKBP5 expression, upstream effecter of the GC pathway, correlated with cellular effect of GC and can be used to predict GC apoptotic activity in CLL cases. Figure 1 WB analysis of FKBP5 expression in CLL cells. Figure 1. WB analysis of FKBP5 expression in CLL cells. Disclosures No relevant conflicts of interest to declare.

Description: The addition of monoclonal antibodies to chemotherapy has significantly improved treatment of patients with CLL. Based upon the excellent results obtained with our chemotherapy-only regimen fludarabine, cyclophosphamide and mitoxantrone (FCM) (Bosch et al. Clin Cancer Res, 2008) we have build up a new chemoimunotherapy combination, R-FCM (rituximab plus FCM). In November 2005 we initiated a multicentric phase II clinical trial that includes R-FCM as initial treatment followed by a maintenance therapy phase consisting of rituximab (375 mg/m2 every there months for 2 years). We report here the final results of the initial phase of this study, namely R-FCM treatment. From November 2005 to November 2007, 72 patients under the age of 70 with active CLL according the NCI and IWCLL criteria (Cheson et al. Blood, 1996; Hallek et al. Blood, 2008) were treated. Patients received rituximab 500 mg/m2 on day 1 (375 mg/ m2 in the first cycle), fludarabine 25 mg/ m2 i.v. on days 1 to 3, cyclophosphamide 200 mg/ m2 on days 1 to 3, and mitoxantrone 6 mg/ m2 i.v. on day 1, given at 4-week intervals up to six cycles. Treatment outcome was correlated with clinical and biological parameters. Minimal residual disease (MRD) was evaluated by four-color flow cytometry (Rawstron et al. Leukemia, 2007). Median cycles of R-FCM administered were 5 (range, 3–6), with 91% of patients completing all planed treatment. Response was evaluated three months after finishing therapy. Altogether, the overall response, MRD-negative CR, MRD-positive CR, and PR rates were 93%, 46%, 36%, and 10%, respectively. Variables correlated with a lower CR rate were del(17p) (25% CR) and increased β2-M serum levels (72% CR). No differences in response were observed according to the age of the patients. Severe neutropenia developed in 13% of patients. Major and minor infections were reported in 8% and 5% of cycles, respectively. Treatment-related mortality was 1%. With a median follow up of 24 months no cases of secondary MDS/AML have been observed.. Although based in two different phase II studies that preclude a completely valid statistical comparison, the CR rate obtained with R-FCM (82%, of which 46% MRD-negative CRs) favorably compares with that achieved with FCM (CR 64%, MRD-negative CRs 38%). In summary the 82% CR rate obtained with R-FCM is among the highest ever reported for any form of therapy for CLL. Both high β2-M serum levels and del(17p) predicted lower CR rate. Treatment toxicity was acceptable and manageable. Based on these results, R-FCM warrants further investigation, particularly in randomized clinical trials.

Description: The effectiveness of antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia (ET) is not proven. In this study, the incidence rates of arterial and venous thrombosis were retrospectively analyzed in 300 low-risk patients with ET treated with antiplatelet drugs as monotherapy (n = 198) or followed with careful observation (n = 102). Follow-up was 802 and 848 person-years for antiplatelet therapy and observation, respectively. Rates of thrombotic events were 21.2 and 17.7 per 1000 person-years for antiplatelet therapy and observation, respectively (P = .6). JAK2 V617F–positive patients not receiving antiplatelet medication showed an increased risk of venous thrombosis (incidence rate ratio [IRR]: 4.0; 95% CI: 1.2-12.9; P = .02). Patients with cardiovascular risk factors had increased rates of arterial thrombosis while on observation (IRR: 2.5; 95% CI: 1.02-6.1; P = .047). An increased risk of major bleeding was observed in patients with platelet count greater than 1000 × 109/L under antiplatelet therapy (IRR: 5.4; 95% CI: 1.7-17.2; P = .004). In conclusion, antiplatelet therapy reduces the incidence of venous thrombosis in patients with JAK2-positive ET and the rate of arterial thrombosis in patients with associated cardiovascular risk factors. In the remaining low-risk patients, this therapy is not effective as primary prophylaxis of thrombosis, and observation may be an adequate option.

Description: Abstract 3691 Background. There is currently no established treatment for the management of MALT lymphoma requiring systemic treatment. For patients failing to antibiotics or those with local advanced, refractory or disseminated disease several chemotherapy treatments have been studied. Considering the activity of Bendamustine in relapsed/refractory indolent lymphomas, with or without anti-CD20 antibodies, immunochemotherapy with Bendamustine plus Rituximab (BR) seems very attractive as first-line treatment for MALT lymphoma. Patients and methods. A nation-wide prospective phase II trial (EUDRACT 2008–007725–39) has been carried out in Spain by the GELTAMO group in untreated patients with CD20-positive MALT lymphoma. Patients with lymphoma arisen at any extranodal site and of any stage (Ann Arbor I-IV) could be enrolled. In addition, localized gastric MALT lymphoma previously refractory to H. pylori eradication or those with skin lymphoma not suitable for local therapy or previously treated with selective radiotherapy/surgery were also eligible. Treatment consisted of Bendamustine (90 mg/m2 d1–2) and Rituximab (375 mg/m2 d1), every 28 d. Pts were evaluated after completing 3 cycles: if complete remission (CR), pts received a further cycle (total of 4) and if partial response (PR), pts received 3 more cycles (total of 6). The aims were: feasibility and security of the combination and rate and quality of the responses, and event free survival. From May 2009 to May 2010, 60 patients were enrolled. Clinical characteristics: median age 62 years (range, 26–84); 34 (57%) female; Ann Arbor stage: I in 49%, II in 17% and III-IV in 34%; B-symptoms 5%. 20 patients (33%) had the lymphoma in the stomach, 35 (58%) in extra-gastric sites and the remaining 5 cases (8%) lymphoma was multifocal. The most common extra-gastric sites were lung and ocular adnexa in 11 and 7 patients, respectively. Results. A total of 264 cycles of BR were delivered in the whole population. Only 2 patients received less than 4 cycles. Rituximab dose was no modified at any cycle and only 5 patients required dose reduction of Bendamustine (median dose intensity: 0.98). Only 2 patients have not completed treatment due to toxicity: 1 case after 2 cycles due to severe rituximab-associated toxicity and another one after grade 4 febrile neutropenia in the 5th cycle. Grade 3–4 neutropenia was seen in 18% of patients. A total of 25 grade 3–4 non-haematologic toxicities were documented in 12 patients. Of note, 11 of these episodes were infectious (2 febrile neutropenia, 2 cytomegalovirus enteritis and 7 other).Response after 3 cycles of R was evaluable in 58 patients: 44 achieved CR or uCR and 14 patients PR, for an overall response rate (ORR) of 100% with a CR rate of 76%. CR rate after 3 cycles was higher in patients with gastric origin in comparison with non-gastric (90% vs 64%) (multifocal cases 100%). At the end of treatment, ORR was 100% with CR/uCR of 98%. A remarkable finding was that only 14 pts (23%) required more than 4 cycles of BR. With a median follow-up of 16 months (range, 3–40), one death has been recorded due to a neurologic syndrome and none patient has relapsed. Conclusions. The combination of Bendamustine and Rituximab in first line treatment of MALT lymphoma achieved an ORR of 100% after only 3 cycles. CR rate after completing treatment plan was 98%. Interestingly, a large majority of patients (85%) required only 4 cycles of treatment. This regimen was safe and well accepted by patients, making this response-adapted schedule a foremost therapeutic strategy for this type of lymphoma. Disclosures: Off Label Use: Bendamustine and rituximab are not currently approved for MALT lymphoma in first line, although both are commonly used in the relapse setting.