ALBERT

Description: In vitro evidences suggest that bisphosponates (BP) may exert some anti-myeloma activities. Indeed, the use of BP has been associated with better survival in selected subgroups of myeloma patients. We have previously reported that pamidronate, a second generation BP, is not useful to prevent or to delay the need of chemo-radiotherapy in patients with early stage or smouldering myeloma, who do not require specific treatments at diagnosis, although such a therapy may reduce skeletal events at the time of disease progression (Musto et al, Leuk Lymphoma2003; 44: 1545). Based on this limited evidence, the recently updated ASCO guidelines still not recommend the use of BP in this specific setting of patients (Kyle et al, J Clin Oncol2007; 25: 2464). On June, 2001, we started a randomised clinical trial comparing zoledronate (ZOL), a third generation, more potent BP, vs simple observation in patients with monoclonal gammopathy fulfilling the diagnostic criteria of stage IA, IIA or smouldering myeloma, not requiring further treatments. These criteria substantially correspond to the current definition of “asymptomatic myeloma”, recently suggested by the International Myeloma Working Group (IMWG, Br J Haematol2003; 121: 749). Accrual was completed on June, 2004. One-hundred-sixty patients were enrolled and randomised (1:1) to receive (n. 80) or not (n. 80) ZOL (Zometa, Novartis Pharmaceuticals. Origgio, Italy) for one year, on an out-patient basis, at the dose of 4 mg as 15′ i.v. single monthly infusion. The two groups were comparable at baseline for time from diagnosis, levels and type of M-component and percentage of bone marrow plasma cells. The most frequent adverse effects observed in ZOL-treated patients were moderate, not clinically relevant hypocalcemia (15 patients: all received oral substitutive therapy and continued the treatment) and fever (7 patients, one of whom stopped drug administration after two cycles). One patient developed reversible osteonecrosis of the jaw, none evidenced renal failure under ZOL therapy. Eight patients (two in the ZOL-treated group and six within controls) died due to unrelated reasons or were lost at follow-up after 6–26 months. No significant reduction of M-component (〉 25%) was observed throughout the study in both groups. After a median follow-up of 55 months (range 36–72), there were 35 (46%) progressions to “symptomatic” myeloma in the ZOL group and 37 (50%) within the controls (p n.s.). Median time-to-progression was 42.2 and 40.7 months, respectively (p n.s.). Bone lesions and/or hypercalcemia at the time of progression were significantly lower (17/35, 48.5%) in ZOL-treated patients than in controls (30/37, 81%) (p 〈 0.02). These mature data suggest that the monthly use of ZOL for one year in patients with early-stage, asymptomatic myeloma is safe, reduces the development of skeletal events at progression, but does not decrease the number of evolutions and does not prolong the time to transformation into “overt” myeloma.

Description: Plasma cell leukemia (PCL) is an aggressive, rare variant of multiple myeloma (MM), with peculiar clinical and biological characteristics, which represents about 2–4% of all MM. PCL exists in two forms: primary PCL (about 60% of cases) presents “de novo”, without previous evidence of MM; secondary PCL, which accounts for the remaining 40%, consists of a leukemic transformation occurring in about 1% of patients with a previously diagnosed MM. We have recently shown that bortezomib is an effective agent for the treatment of both primary and secondary PCL, mainly in the setting of pre-treated disease (Musto et al, Cancer 2007). In the present study we conducted a multicenter retrospective survey focused on unselected patients with a diagnosis of primary PCL who had received bortezomib exclusively as first line therapy for the treatment of their disease, outside of clinical trials. To-date, 15 patients, diagnosed according to International Myeloma Working Group criteria, have been collected, 12 of whom (seven male and five female, 49 to 77 year-old) have been so far evaluated for response. Circulating plasma cells ranged from 3 to 95 × 10e9/L. Seven patients had an IgG M-component, two had IgA, two light chains, while one patient was not secretory. Five patients had concomitant extramedullary disease. Unfavourable cytogenetic abnormalities were observed in 4 out of 7 patients with available karyotype. Bortezomib was generally given using the standard schedule of 1.3 mg/sqm days 1, 4, 8, 11, with an interval of 10 days between cycles. Minor modifications were performed, according to tolerance. Three patients received dexamethasone (VD), two dexamethasone and thalidomide (VTD), six doxorubicin and dexamethasone (PAD), and one oral melphalan and prednisone (MPV) in combination with bortezomib, for 2–6 cycles. Three patients underwent autologous, two allogeneic and one a sequence of autologous followed by non-myeloablative allogeneic stem cell transplantation after induction therapy. One out of five eligible patients failed to collect peripheral blood stem cells. Grade 3–4 hematological, neurological, infectious and renal toxicities occurred in 6, 2, 1 and 1 patient, respectively. Other toxicities (diarrhoea, nausea, skin rash) never reached grade 3. According to the International Uniform Response Criteria, 4 partial remissions (reduction of M-component 〉 50%), 5 very good partial remissions (reduction of M-component 〉 90%, with positive immunofixation), and 3 complete remissions (negative immunofixation) were achieved (100% overall response). In all patients circulating plasma cells disappeared. One patient with pre-existing renal damage died of progressive disease after 3 months, developing more severe renal failure. Another patient died in CR 6 months after diagnosis, while performing allogeneic stem cell transplantation. Three patients relapsed after 5–8 months and 2 of them died with progressive disease within 4 months from relapse. The remaining 8 patients are alive, and 6 of them maintain their remission phase after 9 to 19 months. One-year progression-free survival and overall survival were 50% and 66.6%, respectively. Primary PCL is usually characterized by poor prognosis. Global response rate to standard chemotherapy is less than 50% and median survival is only 7 months. Stem cell transplantation may be more effective in some, but not all cases. Our findings suggest that, in these patients, the front-line use of bortezomib induces a very high rate of good quality responses, whose duration, however, may be short. This suggests that, in primary PCL, bortezomib should be integrated within more intensive therapeutic programs, including other active drugs and, when possible, stem cell transplantation.

Description: Abstract 1748 Introduction: Polycythemia vera (PV) is a chronic myeloproliferative neoplasms characterized by erythrocytosis, vasomotor disturbances, pruritus, risk of disease progression into acute myeloid leukemia or myelofibrosis and cardiovascular events, the last representing the main cause of morbidity and mortality. Since 2005 the V617F point mutation in Janus Kinase 2 (JAK2) gene gained a dominant role in determining the molecular basis and the diagnosis of PV. We compared the clinical epidemiology of the 1638 patients included in the ECLAP trial in the years 1997 to 2001, with that of a “modern” cohort of 365 PV, JAK2-positive patients included in the Italian CYTO-PV randomized clinical trial and followed from the year 2008 to 2012. Methods: Patients were eligible in CYTO-PV trial and in ECLAP study if they met WHO-2008 diagnostic criteria and the criteria established by the PVSG or Pearson/Messinezy respectively. Clinical characteristics have been compared. The incidence of major cardiovascular events (CV death plus major thrombosis [stroke, acute coronary syndrome, transient ischemic cerebral attack, peripheral arterial thrombosis, pulmonary embolism, abdominal thrombosis, deep vein thrombosis) and total CV events incidence has been evaluated. The median follow up was 31.0 months (range 0– 48.13 months) and 33.1 months (range 0–63.6) for patients included CYTO-PV and in ECLAP respectively. Results: In CYTO-PV 49.3% patients with recent PV diagnosis were included (within 2 years prior inclusion) while in ECLAP the proportion was 35.5%. Mean age at recruitment was similar for patients in CYTO-PV (64.5 yrs) and ECLAP (65.4 yrs). History of thrombosis was reported in 28.9 % vs 38.6% patients in the CYTO-PV and in ECLAP, respectively (p

Description: Abstract 4 Introduction Current treatment recommendations in polycythemia vera (PV) have emphasized to maintain the hematocrit (HCT) values

Description: Abstract 2925 Primary plasma cell leukemia (PPCL) is an aggressive variant of multiple myeloma, accounting for 0.5–4% of all newly diagnosed myeloma cases and characterized by a short survival (generally less than 1 year), which is only moderately improved by transplant procedures. Novel agents seem to be able to ameliorate the poor clinical outcome of both primary and secondary leukemic phases of myeloma; however, no data are currently available on the use of lenalidomide as first line therapy in PPCL. On March, 2009, we started a multicenter, phase II trial aiming to evaluate safety and antitumor activity of lenalidomide in combination with dexamethasone (LD) in previously untreated PPCL. Here we report the final results of this study. Newly diagnosed PPCL patients received lenalidomide at a dose of 25 mg/d for 21 days and oral dexamethasone at a dose of 40 mg on days 1, 8, 15, and 22 for each 28-day cycle. After 4 cycles, responding patients not eligible for stem cell transplantation (SCT) continued until 8 cycles of full-dose LD, if tolerated, followed by a maintenance dose of single agent lenalidomide equal to 10 mg/d on days 1–21 of each 28-day cycle. Patients responding after 4 cycles and eligible for SCT proceeded according to single Centre transplant policy. Patients not responding after 4 cycles or progressing during this treatment were considered off-study. The primary endpoint was early response rate according to International Uniform Criteria. The secondary endpoints were PFS, OS, safety and percentage of eligible patients able to undergo autologous or allogeneic SCT. Appropriate dose reductions, contraception methods and anti-thrombotic prophylaxis were applied. Twenty-three patients, as requested by the Simon Optimal Two-Stage Adaptive Design adopted, were enrolled. The trial was therefore closed on May, 31, 2011. M/F ratio was 0.7, mean age was 62 years (range 44–80). Circulating plasma cells ranged from 2.1 to 115 × 10e9/l. Moderate renal failure, increased LDH and extramedullary disease occurred in 39.1%, 43.5% and 13 % of patients, respectively. Hb was 〈 10 g/dl in 19 patients (82.6%), while platelet count was 〈 50 × 10e9/l in 5 patients (21.7%). Karyotype abnormalities were detected by FISH in 21 out of 22 tested patients; in particular, 1p loss was found in 9 patients, 1q gain in 10 patients, del(13q) in 16 patients, del(17p13) in 7 patients, t(11;14) in 7 patients, t(4;14) in 3 patients and MAF translocations, including t(14;20) and t(14;16), in 8 patients. Seventeen patients had a combination of two (n. 5) or more (n. 12) cytogenetic lesions. On intention-to-treat analysis, 14 patients completed the initial four planned cycles and all of them responded. In particular, 6 PR (26.1%), 4 VGPR (17.4%), 1 near-CR (4.3%) and 3 CR (13%) were achieved (ORR 60.8%, VGPR or better 34.7%). Causes of early treatment discontinuation were: a) progressive disease (4 patients, after an initial, brief response in 2 cases); b) severe adverse events (4 patients: one acute renal failure, one Stevens-Johnson's syndrome, one pneumonia suspected for Pneumocystis carinii etiology, one multi-organ failure); c) death in PR due to causes unrelated to treatment or disease (one patient). Other relevant non-hematological toxicities included four episodes of pneumonia and one case of DVT. Grade 3–4 hematological toxicities occurred in about half of cases, requiring Lenalidomide dose adjustments. So far, among subjects achieving a response after 4 LD cycles, 8 eligible patients have successfully collected peripheral blood stem cells: 5 of them have completed single or double autologous SCT, one patient received tandem autologous-allogeneic non myeloablative SCT from a MUD donor. All patients transplanted after LD are currently alive and in remission phase. The maintenance phase has been reached in 3 responding patients not eligible for SCT, 2 of whom have relapsed after 2 and 8 months, respectively. With a mean follow-up of 15 months, OS and PFS are 65.2% and 52.1%, respectively. LD is a possible initial therapeutic option for PPCL, particularly in patients who receive SCT after a short course of induction treatment. Caution is required to prevent and to manage renal and hematological toxicities, as well as infectious complications. Considering some previous results obtained with other novel agents, the combination of lenalidomide and bortezomib might be an appealing approach to investigate prospectively in PPCL patients. Disclosures: Musto: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Petrucci:Celgene: Honoraria. Cascavilla:Celgene: Honoraria. Di Raimondo:Celgene: Honoraria. Caravita:Celgene: Honoraria. Morabito:Celgene: Honoraria. Offidani:Celgene: Honoraria. Bringhen:Celgene: Honoraria. Boccadoro:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palumbo:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Abstract 729 Introduction: The prognosis of primary plasma cell leukemia (PPCL) remains poor. The “novel agents” have recently shown promising results in PPCL patients in case reports or small retrospective series. Here we describe the first prospective, multicenter, phase II clinical trial of PPCL, where lenalidomide in combination with low dose dexamethasone (Ld) was tested as initial therapy in newly diagnosed patients fulfilling the IMWG diagnostic criteria of PPCL. Patients and methods: Ld regimen consisted of lenalidomide 25 mg/d for 21 days and oral dexamethasone 40 mg on days 1, 8, 15, and 22 for each 28-day cycle. After 4 cycles, responding patients not eligible for stem cell transplantation (SCT) continued until 8 cycles of full-dose Ld, followed by a maintenance dose of single agent lenalidomide equal to 10 mg/d on days 1–21 of each 28-day cycle. Patients responding after 4 cycles and eligible for SCT proceeded according to the treatment centre's transplant policy. Patients not responding after 4 cycles or progressing during this treatment were considered off-study. Appropriate dose reductions (in particular for patients with reduced renal function at baseline), double contraception methods and anti-thrombotic/anti-infective prophylaxis were recommended. The primary end-point was early response rate according to IMWG uniform response criteria. Secondary end-points were PFS, OS, feasibility and efficacy of SCT, safety. Results: According to the Simon optimal two-stage adaptive design, twenty-three patients were enrolled in between March 2009 and May 2011. The male/female ratio was 1.1, and median age was 60 years (range 44–80). The median absolute number and percentage of circulating plasma cells were 4.280/μl (range 1.500–114.660) and 34% (range 21–90) respectively. Fifteen patients (65.2%) had abnormal renal function at presentation. Twenty-one patients (91.3%) were tested by FISH analysis and cytogenetic abnormalities were detected in all of them, del13q being the most frequently found (16 patients). Seventeen patients showed multiple chromosomal lesions. Involvement of chromosome 14 was observed in 18 patients, three of whom showed t(4;14). Chromosome 1q gain and del17p were detected in 10 and 7 patients, respectively. In the intention-to-treat (ITT) population, overall response rate (ORR) after at least one Ld cycle was 73.9% (17/23), with 8 patients (34.7%) achieving partial remission (PR), 5 (21.7%) very good PR (VGPR), 3 (13%) complete response (CR), and 1(4.3%) near CR (nCR) (VGPR or better: 39%). In the efficacy-evaluable (EE) population, 14 out of 15 patients who received the initially planned 4 Ld cycles (65.2% of the ITT population) responded (ORR 93.3%), achieving 5 PR (33.3%), 5 VGPR (33.3%), 1 near-CR (6.6%) and 3 CR (20%) (VGPR or better: 59.9%). The maintenance phase was reached and safely performed in 4 responding patients not eligible for SCT, 3 of whom relapsed after 2, 8 and 22 months, respectively. After Ld induction therapy, 8 patients received single (n. 4) or double (n. 4) autologous SCT (ASCT); another patient underwent a sequence of ASCT followed by non-myeloablative allogeneic SCT (AlloSCT). Six eligible patients did not receive ASCT frontline, due to initial Ld failure or adverse events; three of them underwent single ASCT (n. 2) or tandem ASCT/non-myeloablative AlloSCT (n. 1) after a bortezomib-based salvage therapy, achieving 2 CR and 1 PR. After a median follow-up of 23 months, median OS and PFS in ITT population were not reached and 22 months, respectively. All transplanted patients remained alive, although three of them relapsed and started salvage treatments; OS was 12 months in the 11 patients who did not receive ASCT (p 〈 0.001). The correspondent figures for PFS were 29 and 16 months, respectively (p 〈 0.01). Considering ITT population, multivariate analyses showed that SCT was positively correlated to both OS and PFS. There were 17 episodes of grade 3/4 non hematological toxicity, which occurred in 13 patients (5 infections, 3 renal, 3 metabolic, 2 gastro-intestinal, 2 skin, 1 fatigue, 1 thromboembolic), causing early interruption of Ld treatment in 4 patients. Grade 3/4 hematological toxicity (mainly neutropenia) occurred in 11 patients (47.8%). Conclusions: Ld may be a feasible and effective initial therapeutic option for PPCL, particularly in patients who receive ASCT after a short course of induction treatment. Disclosures: Musto: Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide as first line therapy of plasma cell leukemia. Petrucci:Celgene: Honoraria. Cascavilla:Celgene: Honoraria. Di Raimondo:Celgene: Honoraria. Caravita:Celgene: Honoraria. Morabito:Celgene: Honoraria. Offidani:Celgene: Honoraria. Bringhen:Celgene: Honoraria. Boccadoro:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Palumbo:Celgene: Consultancy, Honoraria.

Description: Abstract 2971 Introduction: Bendamustine is a bifunctional alkylating agent approved for the treatment of several lymphoproliferative disorders. Studies have evidenced its efficacy in multiple myeloma (MM), but data so far available in this setting are scarce. We performed a retrospective analysis of Italian patients with relapsed/refractory MM, who had received bendamustine as salvage therapy within a national compassionate use program. Patients and methods: Seventy-eight patients (42 males, 36 females) were collected in 19 hematological centers. Mean age was 64.2 years (range 38–84). ISS was equally distributed, with about one third of patents being represented in single stages. Twenty-three of 43 analyzed patients had cytogenetic abnormalities, the most frequent being del13q (14 patients); t(4;14) and t(11;14) were observed in 4 and 2 patients, respectively, while t(6;14), del17p or complex karyotype occurred in single patients. The median number of prior lines of therapy was 4 (range 1–10). Ninety-seven percent of patients had previously received bortezomib, 94% IMIDs, 85% melphalan, 74% cyclophosphamide, 45% anthracyclines, 26% other drugs, 33% radiotherapy. Sixty percent of patients had undergone autologous and 4% allogeneic stem cell transplantation. The last treatment before bendamustine was a bortezomib-based regimen in 31%, an IMIDs-based regimen in 42%, a combined bortezomib/IMIDs-based regimen in 9%, while 18% of patients had received other therapies. Seventy-three percent of patients were resistant to last therapy received, while 27% had relapsed. Median duration of response to last treatment received before bendamustine was 9 months (range 2–46). Median Hb value was 10.1 g/dl (range 7.6–14.9), WBC count 2.700/μl (range 550–15.200), PLT count 130.000/μl (range 6.000–410.000). Serum creatinine, calcium, beta2-microglobulin and LDH levels were increased in 12 (15%), 4 (5%), and 44 (56%) patients, respectively, while albumin levels were decreased in 27 patients (35%). The median percentage of marrow plasma cells (as evaluated in 57 cases) was 60% (range 1–100). Seventy-six percent of patients had osteolytic bone involvement and 78% extramedullary localizations, with 13% showing secondary plasma cell leukemia and 7% documented amyloidosis or proteinuria. Finally, 45% of patients presented with at least one severe comorbidity, mainly cardio-vascular, liver or pulmonary dysfunction, and diabetes. Results: A total of 236 cycles was administered (median 3, range 1–9). In 47% of patients bendamustine was variously associated to bortezomib (23%), or IMIDs (21%), or to a combination of both (3%). In 80% of patients receiving bendamustine +/− steroids, a median dose of 90 mg/sqm for two consecutive days every 28 days was employed; the median dose was 80 mg/sqm when bendamustine was combined with bortezomib, 60 mg/sqm with IMIDs (total range: 40–140 mg/sqm). The remaining patients received single, monthly doses ranging from 60 to 150 mg/sqm. According to IMWG uniform response criteria, 21 out of 73 evaluable patients achieved a response after a median time of 3 months. In particular, there were 16 PR, 1 VGPR, 1 sCR, and 3 CR; overall response rate (ORR) was, therefore, 29%. Response rate was 10% (4/39) in bendamustine single agent +/− steroids, 38% (5/13) in bendamustine + bortezomib and 62% (10/16) in bendamustine + IMIDs subgroups, respectively. Responders had received a lower number of previous treatments than non responders (median 3 vs 4). Response rate was higher in relapsed (12/21, 57%) than in resistant patients (10/57, 17%). The time to best response ranged from 1 to 8 months. After a median follow-up of 8 months, median PFS duration was 6 months, with 13 out of 21 responding patients not yet progressed. Median OS of the entire cohort was 6.2 months (7 months in responders and 4 months in non responders, range 0–27). Grade 3–4 hematological and non-hematological toxicities occurred in 56% and 15% of patients, respectively, causing three interruptions of the treatment. Conclusions: Though with the clear limits due to the high heterogeneity of treatments applied and of population analyzed, our data indicate that bendamustine may be a therapeutic option in heavily pretreated MM, suggesting a possible non cross-resistance with other agents. Its earlier use with appropriate doses and combinations might further improve the results obtained in this study. Disclosures: Musto: Mundipharma: Honoraria. Off Label Use: Bendamustine in relapsed/refractory myeloma. Fragasso:Mundipharma: Honoraria. Baldini:Mundipharma: Honoraria. Storti:Mundipharma: Honoraria.

Description: Darbepoetin (DPO), a long acting erythropoiesis stimulating protein, is effective in inducing erythroid responses in 40–71% of anemic patients with myelodysplastic syndromes (MDS) when given at fixed doses of 150–300 mcg once-a-week. Of interest, some of these responses have been reported in MDS patients previously treated with (and occasionally unresponsive to) recombinant erythropoietin (r-EPO). We aimed to explore, on a compassionate basis, the effects of a higher DPO dose, administered with longer intervals, specifically in this last setting of patients. A single s.c. injection of DPO at the dose of 500 mcg s.c. was given every 3 weeks (Q3W) in fifteen anemic MDS patients, who had a history of an unsuccessful prior treatment with alpha or beta r-EPO (total weekly doses of r-EPO received: 30.000–80.000 U, for at least 8 weeks), both primary resistant or with loss of efficacy after an initial response. Informed consent was obtained in all cases. Nine patients were male, six female; mean age was 71 years (range 62–82). According to WHO classification, there were 5 RA, 3 RARS, 6 RCMD and 1 RCMD-RS. IPSS score was low in 6 patients and intermediate-1 in the remaining 9 subjects. Baseline Hb levels ranged from 6.2 to 9.1 g/dl, twelve patients being transfusion-dependent. All patients were treated with at least 3 DPO doses (nine weeks of therapy) and were evaluable for short term response and safety. No relevant adverse effect attributable to DPO was recorded. According to recently revised IWG criteria, three patients (20%) achieved an erythroid response. Transfusion-independence was obtained in one of two transfusion-dependent responders. All responses occurred after 2 doses of DPO in patients with baseline endogenous EPO below 200 miu/ml, two of whom previously treated with r-EPO 10.000 U s.c. t.i.w, while one had received 40.000 U s.c. b.i.w. Erythroid responses were maintained prolonging intervals between two DPO administrations up to 6 weeks. Based on the previously described possible synergism between r-EPO and myeloid growth-factors in MDS and to the concomitant presence of symptomatic neutropenia, five patients non-responding to DPO alone received Peg-filgrastim, a novel, pegylated form of granulocyte-colony stimulating factor (G-CSF) with prolonged terminal half-life, at the dose of 6 mg s.c. every 3 weeks, in combination with DPO, for an additional period of 9 weeks. The treatment was well tolerated, but no improvement in Hb levels or reduction in transfusional support was observed. A significant increase in peripheral blood WBC count occurred in all patients treated with Peg-filgrastim. In this preliminary experience, DPO given at the fixed dose of 500 mcg Q3W was effective in some anemic MDS patients considered unresponsive to r-EPO. However, it should be taken into account the fact that at least two of responders had probably previously received r-EPO at sub-optimal doses (less than 40.000 U per week). The adjunct of Peg-filgrastim in this setting of patients resulted in an improvement of neutropenia, without effects on Hb levels.

Description: Mantle-cell lymphoma (MCL) is recognized as a distinct clinico-pathologic entity, accounting for 3–10% of all non-Hodgkin’s lymphomas, with median overall survival not exceeding 3–4 years. Patients with MCL are typically older adults with a male predominance and usually present with stage IV disease. The neoplastic cells are characterized as CD20+ CD5+ CD23−, with a t(11;14)(q13;q32) and cyclin D1 overexpression on immunohistochemistry. The current, most diffused regimens for the treatment of MCL include either R-CHOP or R-HyperCVAD, followed by autologous stem cell transplantation or observation, depending on the patient’s eligibility. However, considering that MCL is frequently diagnosed in elderly subjects with relevant co-morbidities, high dose chemotherapy or the use of drugs with potential cardiotoxicity, such as anthracyclines, may result not feasible in a significant proportion of patients. In this setting, recent data suggest that the proteasome inhibitor bortezomib is well tolerated and has significant single-agent activity in patients with MCL. Thus, we evaluated safety and efficacy of the RBC regimen, a 21-day cycle, anthracycline-free combination of rituximab (375 mg/m(2) on day 1), bortezomib (1.3 mg/m(2) on days 1, 4, 8, and 11) and hyper-fractionated cyclophosphamide (600 mg/m(2)/d given as a double, three-hour infusion on days 1–3) in “true” (≥ 75 year-old) elderly patients with advanced MCL. Diagnosis was made according to standard histological, phenotypic and molecular criteria. The results of an early analysis on feasibility in the first six patients enrolled (3 male, 3 female) are reported here. Mean age was 79.8 years (range 75–84). All patients had stage IV disease, evidencing extranodal localizations (n. 2) or marrow/leukemic involvement (n. 4). IPI score was 2 in three patients, 3 in two patients and 4 in one patient. Three patients received RBC as first line therapy, the others were treated at relapse after (R)-CHOP- like regimens. Hematological toxicities consisted in grade 1 (n. 2) and grade 2 (n. 1) thrombocytopenia, while one patient experienced grade 3 neutropenia, requiring G-CSF support. No extra-hematological toxicities higher than grade 1 were observed. Full doses of RBC were constantly administered. One patient, who presented with a WBC count 〉 200.000/μl, died during the first cycle due to progressive disease; another patient showed an initial response in extranodal sites and then progressed before the fourth planned cycle. The remaining four patients received six cycles: one patient achieved a partial response and three obtained a complete response, one of whom showing a molecular remission using PCR for t(11;14) bcl-1/IgH determination. All responders (66.6%) maintain their remission phase 7–10 months after the start of RBC treatment. Although very preliminary, these results indicate that RBC regimen is feasible, well tolerated and may be effective (including the possibility to obtain molecular response) in very elderly patients with advanced MCL. Larger and more mature data will be presented at the Meeting.