ALBERT

Description: Key Points Pomalidomide-cyclophosphamide-prednisone is an active combination in multiple myeloma patients who are relapsed/refractory to lenalidomide.

Description: 5-Azacytidine (AZA) is an hypomethylating agent approved in US for the treatment of all FAB subtypes of myelodysplastic syndromes (MDS). Some recent reports have raised the question of a possible efficacy of AZA in selected patients with acute myeloid leukaemia (AML). In September 2007, we started a retrospective study aiming to register and analyse all Italian patients with MDS or AML who had received AZA for the treatment of their disease outside of clinical trials, on the basis of a national patient named program. Among a total of 246 patients treated in 31 different Italian Institutions since 2005, 55 AML diagnosed according to WHO criteria were collected. Median age was 72 years (range 29–87) and 28 patients were male. Poor karyotype was present in 11 patients (20%), while 14 patients (25%) had secondary AML. Median time from diagnosis was 5 months (range 0–72). Eighteen patients (33%) received AZA as front-line treatment, as they were considered not eligible for intensive chemotherapy due to age, co-morbidities or poor performance status. Thirty-seven patients (67%) were pre-treated with growth factors (3 patients) or with one or more lines of chemotherapy (11 and 23 patients, respectively); most of the pre-treated patients (22 out of 34) had received high dose chemotherapy, including autologous or allogeneic stem cell transplantation. Low dose chemotherapy had been employed in the remaining cases. The median number of monthly AZA cycles administered was 4 (range 1–22). Thirty-nine patients (71%) received AZA at the fixed dose of 100 mg/d s.c., 16 patients (29%) received a dose of 75 mg/sqm/d s.c.. A seven-day per month schedule was employed in 43 patients (78%), while 11 patients (20%) received AZA for more than 7 days and one patient for 5 days. Twenty-nine patients (52.8%) received AZA alone, twenty-six (47.2%) in various combinations with growth factors (1), valproic acid +/− ATRA (21) or gentuzumab-ozogamycin (4).The most relevant toxicities observed (grade 3–4) were represented by further myelosuppression (15%), infections (24%: in particular, 1 fungal lung infection, 3 pneumonia and 1 septic shock) and gastrointestinal adverse events (20%). The overall response rate was 35.3% (18/51): 8 patients achieved a complete remission (CR) (15.7%), while a partial response (PR) was observed in 5 patients (9.8%). Five haematological improvements were also seen (9.8%). Response rate was significantly higher in untreated patients compared to pre-treated ones (p=0.02). A statistically significant difference (p=0.04) in response rate in favour of 75 mg/sqm/d versus 100 mg fixed dose was also observed. The actuarial probability of overall survival (OS) at 16 months was 45% for patients responding to AZA and 10% for those non responding (p=0.0027). In conclusion, our data show that: AZA can induce significant responses in about one third of AML patients; the “standard” dose of 75 mg/sqm/d seems to be more effective than 100 mg/d (one single vial) fixed dose; AZA is more effective in de novo as compared to pre-treated (refractory and/or relapsed) disease; AML patients responding to AZA have a significant survival advantage compared to non responders.

Description: Monoclonal gammopathy of undetermined significance (MGUS) occurs in 3% of people older than 50 years and up to 10% in those older than 70; it is associated with a 1%/year risk of progression to Multiple Myeloma (MM). In recent years there have been improvements in risk stratification models (involving molecular markers) of this disorder, which have led to better understanding of the biology and probability of progression of MGUS. In the context of numerous molecular events and heterogeneous risk of progression, developing individualized risk profiles for patients with MGUS represents an ongoing challenge that has to be addressed by prospective clinical monitoring and extensive correlative science. Free Lights Chains (FLC) ratio, plasma cells immunophenotype and DNA aneuplody are now important parameters of progression, in addition to the already known prognostic factors (immunoparesis, type and amount of the monoclonal component (MC). Recent data report immunoparesis and a skewed FLC ratio in 25% and 30%, respectively, of patients (pts) at diagnosis. In this study we evaluated the incidence of these two parameters in a cohort of 114 pts with MGUS, if they are associated and if their incidence is influenced by other parameters (time from diagnosis, type of Immunoglobulin (Ig) and/or light chains). The patients screened were 56 males and 58 females with a median age of 67 years (45-91). Median time from diagnosis to the time of observation was 3 years (0-21). The MC was IgA in 13 pts, IgG in 88, IgM in 13; 74 had a clonal Kappa (K) and 40 a lambda (L) light chain. K/L ratio was abnormal in 57 pts (50%). Immunoparesis was present in 60 pts (52,6%): 22 with a normal K/L ratio (38,5%) and 38 with an abnormal K/L ratio (66,6%) (p-0.004). In 18 pts two classes of Ig were involved. An association between the two parameters occurred in 39 pts (34,2%); it was more frequent in IgA MGUS (61,5%) than in IgG (31,8%) and IgM (23%); we did not observe any differences about immunoparesis between K MGUS (33,7%) and L MGUS (32,5%). The association between a skewed K/L ratio and immunoparesis was present in 25.4% of pts with time from diagnosis of less than 3 years and in 48,8% of pts with a longer time from diagnosis (p-0.04). Our new data confirm that immunoparesis is more frequent in pts with an abnormal K/L ratio. The association seems to be more frequent in case of IgA gammopathy; there are no differences between the two types of light chain. Our data also confirm that the longer is the time elapsed from diagnosis, the higher are the frequency of an abnormal K/L ratio and the incidence of immunoparesis, with a greater probability of association. We need still a larger number of pts with an adequate follow up to evaluate if the association between immunoparesis and abnormal K/L ratio has a prognostic value, although the higher frequency of association in the subset of pts with a longer time from diagnosis seems to contradict this hypothesis. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Diffuse large B-cell lymphoma (DLBCL) relapsed or refractory after chemoimmunotherapy have dismal prognosis; the standard salvage treatment is Rituximab plus high dose chemotherapy with autologous stem cell transplantation (R-HDC). However, no standardized treatment is available for patients not eligible for R-HDC because of age and/or comorbidity. The combination Rituximab plus Bendamustine (R-B) has shown to be non-inferior and with a favorable toxicity profile compared to R-CHOP in indolent B-cell lymphoma. The use of R-B in DLBCL is a matter of debate. Purpose: We designed an Italian multicenter retrospective study aimed to evaluate safety and efficacy of R-B as salvage treatment in patients with DLBCL relapsed or refractory after at least one complete course of Rituximab-chemotherapy, who were not eligible for R-HDC because of age and/or comorbidity or in patients with post-HDC recurrence. Patients and Methods: We retrospectively reported 43 unselected consecutive patients with relapsed or refractory DLCBL treated with R-B in 15 Italian haematological centers between October 2008 and January 2014. Schedule of R-B were: 6 courses of Bendamustine at 90 mg/mq or 70 mg/mq on days 1 and 2 of each 28-day cycle and Rituximab 375 mg/mq on day 1 of each cycle. They were analyzed for baseline characteristics (age, IPI, ECOG, comorbidity), outcome (ORR, PFS, OS) and toxicity (CTCAE). Results: The median age was 76 years (range 56-94). Eighty-three % of patients had advanced-stage disease (III-IV stage) and 67% had IPI score of ≥3. An extranodal involvement was present in 65% of cases (bone marrow, lung, stomach, skin, pleura, pericardium). More than half the patients (51%) presented with poor functional status with ECOG score of ≥2. Comorbidity assessment by CIRS-G revelead 30% of patients with ≥1 severely or very severely (level 3 or 4) affected organs and 27% of patients with moderate or severe (level ≥2) cardiopathy. The mean number of prior therapies was 1,7 (range 1-3). All patients were previously treated with Rituximab-chemotherapy and three patients had already received R-HDC. Twelve patients had a refractory disease and 31 experienced relapse after last treatment. Patients received a median of 5 cycles of planned 6 courses of R-B (range 2-6); 24 patients underwent Bendamustine at 90 mg/mq, 19 at 70 mg/mq. All patients received Rituximab 375 mg/mq. In 38% of patients treatment was stopped because of progression; in 4 patients (9%) progression occurred within the first 2 treatment cycles. The overall response rate was 47%, including 28% complete remission and 19% partial remission. One patient in partial remission after R-B achieved a complete remission after local radiotherapy. The median OS was 16 months (95% CI 10-20). The median PFS was 8 months (95% CI 6-11). The median follow up was 10 months (range 2-60). Nine patients are still alive and in complete remission at last follow up; 7 of these patients had a chemosensitive relapse before R-B (in 5 cases a first relapse) and only 2 had a refractory disease with progression after a previous lenalidomide treatment. Toxicity was moderate, mainly grade 1 and 2. Grade 3-4 adverse events were neutropenia in 14 patients (32%), thrombocytopenia in 5 patients (11%), anemia in one patient, infections in 3 patients (6%), skin rash in one patient, nausea in one patient, diarrhea in one patient. One patient died of septic shock after the third R-B cycle. One patient died of miocardial infarction related to underlying cardiac comorbidity. Conclusions: Bendamustine in combination with Rituximab showed promising efficacy results with a low toxicity profile in a poor prognosis population (advanced stage disease and extranodal involvement, high median age, poor functional status, comorbidities), not eligible for R-HDC. The optimal dosage and schedule of Bendamustine and/or combination with novel drugs should be further investigated, in order to improve the duration of response and reduce the rate of early progression. Disclosures Off Label Use: Bendamustine in diffuse large B-cell lymphoma. Marasca:Mundipharma: Honoraria.

Description: 5-azacytidine (AZA) significantly prolonged overall survival in higher-risk patients with myelodysplastic syndromes (MDS) in a large, international, randomized, phase III trial (AZA-001). However, data about efficacy and safety of AZA in lower risk MDS are less consistent and only few small studies have addressed this topic. Among a total of 246 MDS treated with AZA in 31 different Italian Institutions since 2005 within to a national patient named program, we evaluated 82 patients scored as low/int-1 IPSS risk MDS. Median age was 68 years (range 34–85), male/female ratio 50/32. According to WHO classification, there were 21 RA/RARS, 4 5q-syndromes, 20 RCMD, 24 RAEB-1, 5 RAEB-2, 4 CMMoL, and 4 MDS unclassified. Median time from diagnosis was 27 months (range 1–132). Sixty-eight patients (82.9%) were transfusion-dependent, sixty (74%) had received a prior treatment, mostly with erythropoiesis stimulating agents. AZA was administered as single drug in 61 patients (74.4%), while in the remaining subjects it was variously combined with growth factors, valproic acid or other agents. Forty-eight patients (58.5%) received a “standard” AZA dose of 75 mg/sqm/d s.c., thirty-four (41.5%) a fixed dose of 100 mg/d s.c. Single cycle treatment duration was 7 days in 45 patients (54.9%), 〈 7 days in 32 patients (39%), 〉 7 days in 3 patients (3.7%), unknown in 2 patients (2.4%). The median number of monthly cycles was 6 (range 1–21), and 63 patients (76.8%) completed at least 4 cycles. The most relevant toxicities observed (grade 3–4) were represented by myelosuppression (22%) and infections (6%). According to 2006-updated IWG criteria, overall response rate was 39% (47.5% in patients who had completed at least 4 cycles). In particular, complete response, partial response and hematological improvement occurred in 12.2%, 8.5% and 18.3% of patients (15.8%, 11.1% and 20.6% in those who were treated with at least 4 cycles), respectively. Stable or progressive disease was observed in 29.3%/25.6% and 30.2%/22.2% of patients receiving less than or at least 4 cycles, respectively. Response duration ranged from 1 to +21 months. There were no significant differences in response rate according to dose and schedule employed, although a slight trend in favour of 75 mg/sqm vs 100 mg fixed dose was seen (45.8% vs 29.4%, respectively). There was also no difference in the percentages of response according to age, previous treatment and transfusion dependence. Overall survival at 2 years was 62%. A survival benefit emerged for responding patients, compared to non responders (82% vs 57%) (p=0.015). A favourable trend was also observed for transfusion-independent patients, while age, pre-treatment and AZA dose did not influence survival. These data indicate that AZA may be safe and effective for a subset of patients with low/int-1 IPSS risk MDS, resistant or not suitable for alternative treatments. The efficacy may improve if at least 4 cycles are administered.

Description: CNS involvement in acute lymphoblastic leukaemia is a well-recognized risk and CNS prophylaxis is considered mandatory. In contrast, the overall risk of central nervous system (CNS) relapse in aggressive non-Hodgkin lymphomas (NHL) is approximately 5%. Several large retrospective studies would suggest that prophylaxis of CNS relapse in aggressive NHL should be performed in patients with involvement of specific extranodal sites or in patients presenting with a high-intermediate/high IPI score. Flow cytometry may provide a method to diagnose CNS involvement early it remains unclear as to whether a negative FCM result in a patient with clear clinical risk factors should receive prophylaxis or if a positive FCM result should be treated with CNS directed therapy at all. It seems therefore reasonable to investigate the safety and efficacy of sustained-release liposomal cytarabine (DepoCyte®). Intrathecal (IT) liposomal cytarabine is distributed widely throughout the CSF and has an extended half-life allowing an administration once every 2–4 weeks. Concerns have recently been expressed on an increased risk of severe neurotoxicity in patients with ALL receiving intrathecal liposomal cytarabine with the Hyper-CVAD regimen. The findings of these studies suggest that liposomal cytarabine should not be given prior to or during treatment with high-dose systemic cytarabine. Since February 2007 we have evaluated the safety and efficacy of liposomal cytarabine in CNS prophylaxis in 7 consecutive patients mostly 〉 70 years of age with aggressive NHL and ALL. PZ1: DLBCL in stage IA with IPI 1 and testicular involvement, Karnofsky 75, systemic treatment with R-COMP 21. PZ2: DLBCL in stage IVA with IPI 2 plus paranasal sinus bone and bone marrow involvement; HBV positive; Karnofsky 75, systemic treatment four cycles of R-COMP 21 in a 50% reduced dose because of age + 2 rituximab 375ng/m2 for maintenance. PZ3: DLBCL in stage III E; IPI 2; Karnofsky70; with tonsil and bone marrow involvement, received six cycles R-COM-21 in a 50% reduced dose for age and comorbidity (without steroid because of diabetes). PZ4: DLBCL in stage IVA; IPI 3; Karnofsky 80; received fourth line treatment with two cycles bendamustine day 1,2 and bortezomib day 1,8,15,22 and rituximab day 1 every 28 days. PZ5: MCL stage IIIA; IPI 1; Karnofsky 60; received one cycle COMP 21 day 1 rituximab day 9 and other five cycles R-COMP 21 with a 25% reduced anthracyline dose because of a 60% ejection fraction). PZ6: DLBCL in stage IVA and bone marrow involvement; IPI 1; Karnosky 100,; received six cycles R-COMP 21. PZ 7: ALL; Karnofsky 50; received first-line treatment GMALL 01/81 (Hoelzer 1984–88) in reduced doses for toxicity. All patients received CNS prophylaxis with IT liposomal cytarabine 50 mg followed by systemic injection of steroids for preventing arachnoiditis. flow cytometry and cytospin analysis was performed in all patients on CSF samples obtained at every lumbar puncture. The intrathecal injections were given the day before systemic chemotherapy in NHL cases for a total of 4 administrations. Prophylaxis in ALL was given every 3 weeks during induction for a total of 4 doses. Results: Seven (5 DBLCL, 1 MCL and 1 ALL) patients achieved a complete response (CR) with systemic chemotherapy. At a median follow-up of six months six patients were alive and in continuous CR 6 (5 DLBCL, 1 All). Isolated relapse of leukaemia or lymphoma in the CNS was not seen. One patient died in CR because of a cardiac arrest.. Conclusions: Liposomal cytarabine is safe in the prophylaxis of CNS relapse in patients with DLBCL or ALL. No drug-related neurological or haematological toxicities were recorded. Liposomal cytarabine could be the drug of choice for CNS prophylaxis, particularly in elderly patients, and should be further investigated in clinical trials.

Description: Over the last few years there has been increased interest in laboratory tests for thrombophilia. Testing is predominantly performed to identify asymptomatic individuals at risk for a first thrombosis or patients (pts) at risk of relapse. The results are not always concordant, and the impact on clinical practice is not yet defined, especially for heterozygous forms. We evaluated heterozygous and homozygous Factor V Leiden (FVL) and prothrombin (FII) mutations and the homozygous C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in 98 pts with venous thrombosis distinguishing idiopathic forms from forms that are secondary to malignancy, surgery, forced immobilization or hormone treatments. FII mutation was present in 17% of idiopathic and 5.8% of secondary forms. FVL mutation was present in respectively 17% and 15.8% and MTHFR homozygous state in 31.9% and 21.5%. At least one of FII or FVL mutations was present respectively in 31.9% and 19%, at least one of the three mutations examined was present in 57.4% and 36.2%. In pts with limb venous thrombosis (n-64), the percentages for each mutation are respectively: FII-23.5% and 6.6%, FVL-20.5% and 6.6%, MTHFR 35.2% and 16.6% .At least one mutation between FII and FVL is present respectively in 42.1% and 13.3% (P = 0,028) while at least one of the three mutations is present in 61.7% and 30.5% (P = 0,022) In our pts with pulmonary thromboembolism (n-36) FII mutation was absent while FVL mutation was present in 7.6% of idiopathic and 21.7% of the secondary thrombosis, MTHFR in 30.7% and in 30.4%. At least one of the three examined mutations was present in 38.4% and 47.8%. The mutations we have studied are generally more frequent in idiopathic forms. The difference reaches statistical significance in limb venous thrombosis where they seem to have a significant relevance, although in a heterozygous state, and to promote thrombosis even in absence of other causes. In pulmonary thromboembolism (PTE) pts FII mutation was absent, FVL mutation is less frequent in pts with idiopathic thrombosis and MTHFR homozygous state is equivalent between the two subgroups. Thus, they seem to not influence PTE pathogenesis that would be likely sought in different causes. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Acute myeloid leukemia is a heterogeneous clonal disease often presenting with chromosomal aberrations. However, the t(9;22)(q34;q11) translocation is infrequently found (only 1–2%) in de novo diagnosed AML patients. Whilst CNS involvement with leptomenigeal metastasis (LM) in acute myelogenous leukemia is generally infrequent, the acute myelo-monocytic leukaemia (AMML) subtype is at high risk for development of LM (Chamberlain et al. J Neuro-oncology 2005 75: 71–83). Liposomal cytarabine (DepoCyte®) has shown to be more effective than free cytarabine in patients with LM (Glantz et al. JCO1999; 17:3110; Sancho et al. Haematologica2006; 91). DepoCyte® is a novel sustained-release formulation with a terminal half-life 40 times longer than free cytarabine (Bleyer et al. Clin Cancer Res 99; 5:3349) and is approved for the treatment of adults with lymphomatous meningitis. Intrathecal (IT) liposomal cytarabine is distributed widely throughout the CSF and based on an extended half-life allowing for an administration once every 2–4 weeks only (Chamberlain et al. Arch Neurol1995; 52:912). Case report On March 2004, a 20-year-old male patient was diagnosed with AML (FAB M2). Conventional cytogenetic analysis (CCA) after GTG-banding revealed the translocation t(9;22)(q34;q11) in all metaphases and FISH confirmed the BCR/ABL rearrangement. The patient was initially treated with idarubicin and cytarabine but a complete hematologic remission was not achieved. The patient was also refractory to the second line therapy with MEC. A complete hematologic remission was finally achieved after treatment with Imatinib plus FLAG-IDA. While still in complete clinical and molecular remission he underwent allogenic peripheral blood cells (PBCs) transplantation in December 2004. The patient relapsed with leptomenigeal disease in August 2005 and cranial radiotherapy plus chemotherapy with the Hyper-CVAD regimen was started resulting again in a complete remission. A severe pulmonary infection (Aspergillosis) was successfully treated in January 2006 but one month later the patient presented with a second leptomenigeal relapse. Symptoms like leg weakness indicated spinal involvement and the MRI showed an enhancing mass extending to the cauda equina with infiltration into the gluteus muscles. A lumbar puncture was performed and myeloid blasts were found in the CSF. Therapy with liposomal cytarabine (50 mg every two weeks with concomitant dexametasone (4 mg i.t.) was initiated. We performed five injections every two weeks followed by further two injections every month plus lumbar radiotherapy with a total dose of 30Gy. A CSF sample was obtained before each IT treatment and already 14 days after the first treatment no myeloid blast were found in the CSF. A PET scan showed a very good partial response of the lumbar mass with minimal residual uptake after the end of radiotherapy. BCR/ABL transcripts were still found in the bone marrow and hence the patient was restarted with imatinib treatment leading to a complete haematological and molecular remission. Conclusion We conclude that the administration of liposomal cytarabine, combined in this case with radiotherapy on the lumbar vertebral column appears feasible, well tolerated and produces a better result than traditional i.t. cytarabine treatment in terms of onset and duration of response. At 13 months follow up after end of therapy the CSF persists to be negative for leukemic blasts in this patient with secondary relapsed leptomeningeal metastasis.

Description: Abstract 632 Background: Patients with multiple myeloma (MM) relapsed/refractory after immunomodulatory drugs and bortezomib have limited treatment options. Recently, the combination pomalidomide-dexamethasone has led to at least partial response (PR) of 25–42% in relapsed/refractory MM and 32% in patients refractory to lenalidomide. Aims: In this study we evaluate the safety and efficacy of the combination pomalidomide-cyclophosphamide-prednisone (PCP) in patients with MM who received 1–3 lines of treatment and were relapsed/refractory to lenalidomide therapy. Methods: Between August 2010 and July 2011, 41 patients were enrolled; median age was 69 years (range 49–82); 23 patients relapsed after lenalidomide and 18 patients were refractory to lenalidomide. The first 24 patients entered the phase I of the study to define the maximum tolerated dose (MTD) of PCP: 4 dose levels of pomalidomide (1, 1.5, 2 and 2.5 mg/day, days 1–28) were tested in combination with cyclophosphamide (50 mg every other day, days 1–28) and prednisone (50 mg every other day, days 1–28) for six 28-day cycles. Thromboprophylaxis with aspirin (100 mg/day) was recommended, low-molecular weight heparin was given to high risk patients. Dose Limiting Toxicities (DLTs) were defined as: grade 4 neutropenia for more than 3 days, grade 4 thrombocytopenia, grade 3–4 neutropenic fever, any grade 3–4 non-hematologic toxicity. The MTD was achieved when 25% of patients experienced a DLT, using the Bayesian Continual Reassessment Method. In the phase II of the study, the Simon two-stage design was used and 17 additional patients were enrolled and received the MTD of pomalidomide. Results: DLTs occurred in 1/4 patient who received pomalidomide 1.5 mg (grade 4 thrombocytopenia) and in 3/12 patients who received pomalidomide 2.5 mg (grade 3 neuropathy, grade 3 hepatic toxicity and grade 4 thrombocytopenia). The MTD was defined at 2.5 mg/day, with an estimated DLT probability of 0.258 (95% credibility interval: 0.101–0.468). 32 patients received at least one cycle of therapy and could be evaluated for efficacy and safety. At least PR was reported in 19/32 (59%) patients, including 2 complete response (CR), 5 very good partial response (VGPR), 12 PR. In patients refractory to lenalidomide, at least PR was reported in 11/15 (73%) patients, including 1 CR, 2 VGPR, 8 PR. Grade 4 hematologic toxicities were neutropenia (9%) and thrombocytopenia (9%). Grade 3–4 non-hematologic toxicity included infection (9%), rash (9%), neurologic (6%) and hepatic (3%) toxicities. Thromboembolism occurred in 1 patient. Conclusions: At least PR was achieved in 73% of patients refractory to lenalidomide; grade 4 neutropenia and/or thrombocytopenia were less than 10%. The combination pomalidomide (2.5 mg/day), cyclophosphamide (50 mg every other day), prednisone (50 mg every other day) showed high response rates with limited toxicities in patients relapsed/refractory to lenalidomide. Updated data will be presented at the meeting. Disclosures: Palumbo: Amgen: Honoraria; Merck: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:Janssen-Cilag: Honoraria. Guglielmelli:Janssen-Cilag: Honoraria; Celgene: Honoraria. Giuliani:Celgene: Research Funding; Novartis: Research Funding. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Background: Bendamustine is a bifunctional purine analog alkylating agent with a novel mechanism of action that exhibits strong single-agent activity in multiple haematological malignancies and several solid tumors. While a number of studies with bendamustine single agent or combined with rituximab are reported in indolent NHL, the available published experience in high grade lymphoma is limited. In one study 23 patients mostly aged 〉60 years with resistant or relapsed stage I to IV high grade NHL received a combination of bendamustine (50 mg/m2 on days 1 to 5 or 60 mg/m2 on days 1 to 3 of a 28-day cycle), methotrexate (30 mg/m2 on day 3), mitoxantrone (12 mg/m2 on day 1) and prednisolone (60mg/m2 days 1 to 5). Results were promising with an OR of 48% (CR 13%, PR 35%, NC 4%, PD 48%). In a second study with bendamustine as monotherapy (120 mg/m2/day on days 1 and 2 every 3 weeks) in 17 outpatients with refractory (n = 8) and/or relapsed high grade NHL most of whom had been pretreated with ≥2 other therapeutic regimens an OR of 41% (CR 18%, PR 23%) was reported. Prophylaxis of CNS relapse in high grade lymphoma should be performed in patients with involvement of specific extranodal sites or presenting with a high-intermediate/high IPI score. Liposomal ara-C (DepoCyte®) seems to be an ideal drug for prophylaxis based on its long half life and wide distribution throughout the CSF. The drug appears to be safe and tolerable in aggressive diseases when given sufficiently apart from HD ara-C or with regimens free of HD systemic treatment. Methods: We describe the case of a 69 year old male with diffuse large B cell lymphoma stage IV-A with bone marrow involvement, a splenic lesion and left femoral bone involvement. His initial treatment was six cycles of R-CHOP 14 (completed in Jan.06) which resulted in a partial response. The bone marrow was negative and the nodal lymphoma disappeared after this treatment whilst the femoral bone disease persisted and already in Feb/06 a mediastinal progression was diagnosed. From February to May 06 the patient was treated with four cycles of a dose reduced VIHA schedule because of the age for second line treatment. However, CT and PET scans during treatment showed the persistence of the disease. Therefore, in Jul.06 BEAM high dose chemotherapy with peripheral stem cell infusion followed by radiotherapy in 17 fractions (total dose 30,6 Gy) was conducted and again a partial response was achieved. In September the patient presented pulmonary and medullary tuberculosis and received standard therapy for nine months. In April 08 the patient was admitted to our institution with a suspected relapse of the disease. The total body TC and PET confirmed disease at the thoracic level and progression in the right paraspinal sites. The cytology and flow cytometry analysis of the CSF were negative but the patient had a high’ HCV RNA titer (1.586,811 copies). The patient received a combination of bendamustine, (70mg/m2 day1,2), bortezomib (1,3mg/m2 days 1,8,15,22) and rituximab (700mg/m2 day 1) every 28 days and four intrathecal injections of the DepoCyte® every three weeks for CNS prophylaxis. An early PET after two courses of this chemotherapy showed a complete response which was never achieved with previous treatments. The chemotherapy was well tolerated and the patient continues with the program of six cycles of this combination chemotherapy. Conclusion: Bendamustine in combination with rituximab and bortezomib was shown to be very effective and well tolerated in this heavily pretreated patient with refractory high grade lymphoma. This case report is ongoing and but the impressive initial response would justify further studies to confirm the efficacy of this combination in relapsed or refractory DLBCL Liposomal cytarabine was well tolerated; no neurological side effects or haematological toxicities were recorded. Liposomal cytarabine should be considered the drug of choice for CNS prophylaxis.