Abstract: INTRODUCTION: Bisphosphonates (Bsf) are a recognized and effective class of drugs used intravenously to treat cancer-related conditions, such as multiple myeloma (MM) and others solid tumours for the prevention of pathologic fractures, and in oral form to prevent osteoporosis and osteopenia. Some other activities are described as immunomodulating effects. Evolution of bisphosphonates related osteonecrosis of the jaw (BRONJ) is a rare complication with the risk increasing the longer the patient uses the drug. Pamidronate and Zolendronic acid can induce BRONJ in 0,8% – 12% of patients as described in different casistics. In this study we want describe the evolution and outcome of the BRONJ in a multicentric casistic. MATERIAL AND METHODS: In our group we observed 55 pts with Multiple Myeloma (MM) who developed BRONJ; immunoglobulin isotype was: 25 pts IgG-κ; 6 pts IgG-λ, 12 pts IgA-κ; 3 pt IgA-λ, 5 pts IgM-κ, 3 pts MM light chain κ and 1 pt MM light chain λ. Median age was 72 years (range 56–95), male 16/female 39. All patients were treated with Bsf: Pamidronate 1 pts (1,8 %), Zolendronate 36 pts (65,5 %), Pamidronate/zolendronate 18 pts (32,7 %). The average dose of Pamidronate was 2.022 mg (range 90–6.750 mg) and of zoledronate was 84 mg (range 4–256 mg). Anatomic localisation of the BRONJ was: mandible 29 pts (52,7%); maxilla 22 pts (40%); mandible/maxilla 4 cases (7,3 %). The most common trigger for BRONJ was dentoalveolar surgery, including extractions (43 cases-78, 4%), dental implant placement (3 patients-5, 4%), periodontal disease (5 cases-9 %), and in 3 patients with dental prothesis (5, 4%); 1 patient (1,8%) developed BRONJ spontaneously. All patients stopped bsf therapy after BRONJ diagnosis. RESULTS: All patients were treated with conservative treatment such as antibiotic therapy. In 18 patients (32,7%) antibiotic therapy was the only treatment used. Six patients (10,9%) received antibiotic associated with surgical debridement of necrotic bone. Sixteen patients (29%) were treated with antibiotic therapy in combination with hyperbaric oxygen therapy/ozonotherapy and curettage; twelve patients (21, 8%) required sequestrectomy in association with antibiotic and oxygen/hyperbaric therapy. Three patients (5,4%) refused any therapy. Resolution was observed in 19 cases (34,5%); 24 patients (43,6%) improved as pain and as control of infection of the soft and hard tissue. The osteonecrosis was invariated in 9 patients (16,3%); three patients (5, 4%) did not responde to treatment. CONCLUSIONS: Our retrospective study demonstrate that, in established BRONJ, clinical improvement can be obtained in a high percentage (78%), with a complete resolution of bone necrosis in one third of patients. Surgical treatment, associated with antibiotic therapy, is the most effective treatment to eradicate the necrotic bone. The effectiveness of hyperbaric oxygen therapy is not nowadays well determined, but in our experience it demonstrated its utility. Because the most common trigger for BRONJ was dental extractions, prior to treatment with bsf, all patients should have a thorough oral examination and should be completed all invasive dental procedures, achieving optimal periodontal health. With increased recognition and follow up of the BRONJ, it is likely that our knowledge will improve the risk of developing BRONJ and obtaining in more patients a complete remission.

Abstract: INTRODUCTION MCL is an incurable disease and treatment approach should be adapted to patient's characteristics: age, PS, co-morbidities, social conditions, presence of caregiver, etc. In this study we describe the experience of RELLI in real life about old MCL pts followed in Latium region and diagnosed and registered in our database between January 2013 to December 2017. MATHERIALS and METHODS Data were collected in a regional data base. All new diagnosis of lymphoproliferative disease were considered medical history, clinical characteristics and lymphoma related characteristics were registered starting from an existing data base or medical records of single Institutions. RESULTS In the database were registered 91 pts with MCL (70M/21F) older than 65 years with a median age of 74 yrs (range 66-87). At diagnosis 11/91 (12.1%) were in stage I-II and 80/91 (87.9%) in stage III-IV; only 6 (6.6%) pts presented systemic symptoms. High levels of LDH were present in 45.1% of pts, at least one extranodal localization was reported in 4.4% and Ki67 〉 30% in 48.5%. Prognostic score was evaluated at diagnosis: MIPI (LR 46.5%, IR 19.7%, HR 33.8%) and MIPI-c (LR 36.6%, ILR 22.5%, IHR 22.5%, HR 18.4%). Treatment was evaluated according to the age of pts: 65 -70 and 〉 70 years; in the first group immuno-chemotherapy (ICT) was: Benda containing regimen 43.5% (R-BAC 17.4%, R-B 26.1%) and CHOP-like regimen 36.1% (R-CHOP21 17.4%, R-COMP21 8.7%). In contrast in older pts the choice of ICT was: Benda containing regimen 64% (R-BAC 14.8%, RB49.2%), and CHOP-like regimen 13.1% (R-CHOP21 8.2%, R-COMP 4.9%).The overall response rate (ORR), progression free-survival (PFS) and overall survival (OS) were calculated from the start of treatment and evaluated in the two groups of pts: ORR was 100% in younger (CR 69.6%, PR 30.4%) and 68.8% in older (CR 50.8%, PR 18%). According to the type of ICT, as expected, pts treated with bendamustine containing regimens (+/- Cytarabine) have better response and longer survival. With a median follow-up of 34.5 months, media OS of the entire population isn't reached and PFS is projected at 50% at 60 months. CONCLUSIONS In the era before new biologic drugs the approach to treatment of MCL was sufficiently homogeneous in the Lazio region. In real life Ky67 was principal factor influencing OS. MIPI and MIPI-c score divided the entire population into two groups at high and low risk. Age not change the OS but only the response rate to treatment (Figure 1). Disclosures Abruzzese: BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Di Rocco:Roche: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau; Sandoz: Consultancy. Martelli:F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; Servier: Honoraria.

Abstract: In ‘real‐life’, the Nordic score guides Erythropoietic stimulating agent (ESA) use in lower‐risk myelodysplastic syndrome (MDS) with predicted response rates of 25% or 74%. As new treatments emerge, a more discriminating score is needed. Objectives To validate existing ESA predictive scores and develop a new score that identifies non‐responders. Methods ESA‐treated patients were identified in 3 MDS registries in Italy and Canada (FISM 555, GROM 233, and MDS‐CAN 208). Clinical and disease‐related variables were captured. Nordic, MDS‐CAN, and IPSS‐R‐based ESA scores were calculated and documented ESA responses compared. Results 996 ESA‐treated patients were identified. Overall response rate (ORR) was 59%. The database was randomly divided into balanced derivation (n = 463) and validation (n = 462) cohorts. By multivariate analysis, transfusion independence, erythropoietin (EPO) level 〈 100 IU/L, and IPSS low‐risk were independently predictive of response. Assigning a score of 1 to each resulted in a scoring system of 0‐3 with response rates of 23%, 43%, 67%, and 85%. ORR was concordant in the validation cohort. The ‘ITACA’ score had the highest discriminating power of response. Conclusion ITACA is an internally‐validated predictive SS of ESA response in real‐life ‘good risk’ MDS patients derived from a large international dataset that surpasses others. The incorporation of biologic markers to better identify non‐responders is still needed.

Abstract: Bendamustine, a bi-functional alkylating agent comprising a purine-like benzimidazole ring an a nitrogen mustard group, exerts a peculiar mechanism of action if compared to most conventional alkylators and this may partially explain its effectiveness in alkylator-resistant cells. In patients with MM several studies demonstrated the efficacy and tolerability of bendamustine as monotherapy or in combination with new drugs, particularly bortezomib that was found to enhance the in vitro sensitivity of MM cells to bendamustine. These observations represented the rationale for our protocol design namely to evaluate the combination bendamustine (70 mg/m2 days 1, 8), bortezomib (1.3 mg/ m2 days 1, 4, 8, 11) and dexamethasone (20 mg days 1-2, 4-5, 8-9, 11-12) (BVD). Cycles were administered every 4 weeks up to four cycles. Patients achieving a response less than a PR were taken off-study. Patients obtaining at least a PR received two additional treatment cycles followed by a 12-months consolidation phase with cycles repeated every 2 months. Therefore, patients with a PR after the induction phase could receive up to 18 months of treatment and up to 12 cycles of BVD. Patients with relapsed/refractory MM of any age, with adequate cardiac, liver and hematological function, not refractory to bortezomib and treated with no more than four previous lines of therapy were enrolled in this prospective, single-arm, open-label, phase II study conducted in 21 Italian centres. The primary endpoint was achievement of a response at least PR after four cycles of BVD and response was assessed according to to IMWG criteria. From March 2011 to June 2012, 75 patients were included. Median age was 68 years (range 41-85), 26.5% had ISS stage 3, 19% IgA myeloma and 9% renal failure. In total, 8 of 36 evaluable patients (22%) had adverse cytogenetics. All patients had received prior treatment with new drugs, including targeted agents such as thalidomide (57%), lenalidomide (54.5%) or bortezomib (46.5%). Patients had received a median of one prior line of therapy (range 1-4), including alkylators (69%), anthracyclines (29%) and ASCT (44%). Twenty-four patients (32%) were refractory to IMIDs. The response rate ≥ PR after four cycles of BVD was 71.5%, including 11 patients with CR (16%), 13 VGPRs (18.5%) and 26 PRs (37%). Also, 14 patients (20%) had disease stabilization while 6 (8.5%) had progressive disease. Median time to response was 1.2 months (range 0.9-1.4 months). Only prior treatment with bortezomib significantly reduced the response rate ≥ PR (54.5% vs 86.5%; P = 0.003). At a median follow-up of 12 months (range 6-24), 30 patients had progressed and 18 had died. Median TTP and PFS were 16.5 months and 15.5 months, respectively while median OS had not been reached and 78% of patients were alive at 1 year. The Cox regression analysis identified prior therapy with bortezomib plus lenalidomide as the only factor that significantly reduced TTP (9 vs 17 months; HR = 4.5; 95% CI = 1.7-12.3; P = 0.005) Grade 3-4 adverse events occurred in 55% of patients leading to therapy reduction in 20% and to protocol discontinuation in 10.5% of patients. The most frequent severe adverse events were thrombocytopenia (30.5%), neutropenia (18.5%), infections (12%), peripheral neuropathy (8%), gastrointestinal and cardiovascular events (both 6.5%). Compared with younger, patients aged 〉 70 years had a significantly higher incidence of grade 3-4 thrombocytopenia (22% vs 37%; p=0.042) and severe infections (7 vs 19%; p=0.047) and consequently a higher rate of therapy reduction (9% vs 34.5%; p=0.007) and therapy discontinuation (7% vs 15.5%; p=0.043). Moreover, 4/5 early deaths occurred in patients aged more than 70 years. BVD combination is an effective regimen in relapsed-refractory MM patients since it elicits rapid, high ( 〉 70%) and good quality of response (more than a third of patients achieved CR + VGPR). Moreover, BVD combination is a feasible and well tolerated regimen provided that adapted therapy and adequate antibiotic prophylaxis are employed in patients older than 70 years. Disclosures: Offidani: Mundipharma: Honoraria, Research Funding. Off Label Use: Bendamustine.

Abstract: Abstract 2818 Poster Board II-794 INTRODUCTION: Bisphosphonate (BSFs) are an effective drug which have been mainly used in oncology for the treatment of solid tumour with bone metastasis, as well as for haematologic disease such as multiple myeloma (MM) and Waldenstrom's Macroglobulinemia (WM), but also prescribed in non neoplastic disease such osteoporosis and Paget's disease. As rare complications related to prolonged treatment with BSFs, an osteonecrosis of the jaw (BRONJ) in neoplastic and non neoplastic diseases is reported with an incidence between 2 and 15% as described in different casitics. The aim of this retrospective multicentric study is to describe the clinical aspects and the evolution of the osteo-necrotic lesions in a long term group of MM patients treated with BSFs. MATERIAL AND METHODS: We studied retrospectively 55 patients (pts) with MM or WM who developed BRONJ followed from January 2003 to January 2009 in different haematological departments. Median age was 72 years (range 56-95), male 16/ 39 female. Immunoglobulin isotype was: 25 pts IgG-κ; 6 pts IgG-α, 12 pts IgA-κ; 3 pts IgA-γ, 5 pts IgM-κ (WM), 3 pts MM light chain κ and 1 pt MM light chain γ. All patients have been treated with BSFs for bone lesions and/or factures: Pamidronate was used in 1 pt (1,8 %), Zolendronic acid in 36 pts (65,5 %), Pamidronate followed by zolendronate in 18 pts (32,7 %). The average dose of Pamidronate was 2.022 mg (range 90-6.750 mg) and of zoledronate was 84 mg (range 4-256 mg). Anatomic localisation of the BRONJ was: mandible 29 pts (52,7%); maxilla 22 pts (40%); mandible/maxilla 4 cases (7,3 %). The most common trigger for BRONJ was dentoalveolar surgery, including extractions (43 cases-78,4%), dental implant placement (3 patients-5,4%), periodontal disease (5 cases-9 %), and in 3 patients with dental prothesis (5,4%); only 1 patient (1,8%) developed BRONJ spontaneously. All patients stopped bsf therapy after BRONJ diagnosis. RESULTS: After a median observation of 26 months (range 1-110 months) no death for BRONJ complication was reported. All patients were treated with conservative treatment such as antibiotic therapy. In 18 patients (32,7%) antibiotic therapy was the only treatment used. Six patients (10,9%) received antibiotic associated with surgical debridement of necrotic bone. Sixteen patients (29%) were treated with antibiotic therapy in combination with ozonotherapy and curettage; twelve patients (21, 8%) required sequestrectomy in association with antibiotic and oxygen/hyperbaric therapy. Three patients (5, 4%) refused any therapy. Among the evaluable patients (53) complete response (CR) was observed in 20 cases (37.75%); partial response (PR) in 21 patients (39.6%) with improving as secondary infection and pain; the clinical finding was unchanged (SD) in 9 patients (16,3%) and 3 patients (5,4%) developed a worsening of the osteonecrosis (PD). CONCLUSIONS: In the unvariate analysis association of surgical treatment with antibiotic therapy, is more effective to eradicate the necrotic bone than antibiotic treatment alone (p= 〈 0.053). O2Iperbaric/Ozonotherapy is a very active treatment, because 44.4% of patient obtain complete resolution of ONJ in comparison to 30.8% of patients who didn't performed this procedure (p= 〈 0.0007). A Multivariate analysis was performed to evaluate differences between variables, but no significant association was found. According to our retrospective study, we confirm that the incidence of this complication is between 2% and 15%, and the cumulative dosage of BSFs is important to induce ONJ. Because the most common trigger for BRONJ was dental extractions, it's an universally recognized indication before BSFs' treatment to implement control of periodontal disease, achieving optimal periodontal health. BRONJ is a late complication of the use of BSFs which interfere on quality of life of patients but not on survival because none death was observed. Disclosures: Petrucci: Ortho Biothec, Jannsen Cilag: Honoraria; Celgene: Honoraria.

Abstract: Introduction. Observational studies from patients treated outside controlled clinical trials offer real life information and are relevant to understand whether data derived from prospective trials are reproducible in the clinical practice. A retrospective observational study was carried out by the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) group in order to evaluate the clinical characteristics and outcome of patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib in Italy within a Named Patient Program (NPP). The NPP was intended to offer free and early drug access to CLL patients until ibrutinib became available on the Italian market. Methods. Patients included in the NPP program had refractory or relapsed (R/R) disease with progression within 24 months after prior chemo-immunotherapy, and/or 17p deletion/TP53 mutations. Patients were also required to have an ECOG performance status ≤2; serum creatinine ≤2 times, liver enzymes ≤3 times and total bilirubin ≤1.5 times the upper limit of normal. Key exclusion criteria were: the need of a concomitant treatment with a strong CYP3A inhibitor or warfarin, an allogeneic stem cell transplantation within the past 6 months or an ongoing active infection. All patients included in the program received ibrutinib orally as a single agent at the standard dose of 420 mg daily. Clinical data of 110 patients included in the NPP program between January 2014 and November 2014 have so far been collected and analyzed using the Research Electronic Data Capture (REDCap) system. Patients were managed at 20 Italian centers and received at least one dose of ibrutinib. Clinical data were reported by the treating physicians. Results. The median age of patients was 69.9 years (range 49.8-83.3); 53% were in Rai stage III-IV, 32% in stage II and 15% in stage 0-I. Sixty-two percent of patients had relapsed disease, 38% were refractory to prior treatment. The presence of a 17p deletion and/or TP53 mutations was recorded in 51 R/R patients. Eighty-six percent of patients had an unmutated IGHV gene profile. The median number of prior treatments was 3 and included allogeneic stem cell transplantation in 4 cases. Two or more comorbidities were reported in 57 patients (52%) and included atrial fibrillation (AF) in 10 (9.1%) and hypertension in 40 (36.4%). After a median follow-up of 12.1 months (range, 1.6-24.6), 87 patients (79%) were still on ibrutinib. A response to ibrutinib was reported in 98/110 patients (89.1%). The best recorded response was a CR/CRi in 19 patients (17.3%), while a PR was reported in 79 patients (72%; PR-L 21.1%). Similar response rates were observed in patients with unmutated IGHV genes (91.9%) and in those with 17p deletion/TP53 mutations (90.3%). At 12 months, the progression-free survival (PFS) and overall survival (OS) were 92.9% (95%CI: 87.9-98.2) and 95.2% (95%CI: 91.1-99.4), respectively. PFS at 12 months of patients who achieved a response was 96.3%, 98.9% in unmutated IGHV patients, 90.7% in those with 17p deletion/TP53 mutations. Five patients (4.5%) died during the NPP program (1 patient each for sepsis, heart failure, ileus perforation, cancer, unknown cause). Adverse events (AE) were recorded in 75 patients (68.2%); in 47 (42.7%) they were grade ≥3. Any grade AEs recorded in ≥5% of patients were: infections (35%; grade ≥3, 22%), granulocytopenia (18.8%; grade ≥3, 17.2%), bleeding (15.5%; grade ≥3, 2.7%), fever of unknown origin or febrile neutropenia (12%; grade ≥3, 5.4%), AF (10.9%; grade ≥3, 4.5%), diarrhoea (8.3; grade ≥3, 2%), hypertension (7.2%; grade ≥3, 5.4%). A new event of AF occurred in 1/10 patients with a prior history of AF. Warfarin was required in 1 patient with AF and this was the reason for ibrutinib discontinuation. Conclusions. The results of the first interim analysis of this retrospective, real life study confirms that ibrutinib, as a single agent, is an effective treatment for patients with poor-prognosis CLL. Our data also suggest that ibrutinib given to unselected patients, in a compassionate-use program, shows a clinical activity and a safety profile comparable to those reported in prospective trials. Data collection is ongoing in order to complete the analysis of this large NPP cohort in Italy. Disclosures Marasca: Roche: Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria. Coscia:Karyopharm: Research Funding; ROCHE: Honoraria, Other: Advisory board; Janssen: Honoraria; Gilead: Honoraria; Mundipharma: Honoraria. Zinzani:Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees. Molica:Jansen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche Italy: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Speakers Bureau. Orlandi:Ariad: Honoraria; BMS: Honoraria; Novartis: Honoraria. Ghia:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; Adaptive Biotechnology: Consultancy; Roche: Honoraria, Research Funding. Foà:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; BMS: Consultancy; Genentech: Consultancy; Pfizer: Speakers Bureau; Ariad: Speakers Bureau.

Abstract: Background. The stomach is the most frequent site of intestinal lymphomas. However, few data are available on the clinical-endoscopic presentation of gastric lymphoma as well as on possible differences in clinical pattern and endoscopic features between low-grade (LG) and high-grade (HG) lymphomas. In this study, we evaluated such aspects on consecutive primary gastric lymphoma patients observed in the last 12 years (1993–2004) in four Italian Hospitals (1 North, 2 Centre, 2 South). Methods. Clinical, histological, and endocospic records of consecutive patients diagnosed with LG or HG gastric lymphoma were retrieved and accurately evaluated. Symptoms were categorized as “alarm” (anaemia/melaena/heamorrage, persistent vomiting, weight loss) or “no alarm” (epigastric/abdominal pain, heartburn, dyspepsia/bloating). The endoscopic findings were classified as “normal” (no macroscopic lesions) or “abnormal” (ulcer, erosions, nodular pattern, hypertrophic folds, polypoid mass). Statistical analysis was carried out by using the Chi squared test. Results. During the study period, 143 patients with primary gastric lymphoma were detected. Overall, 61 patients were observed in the first 6 years and 82 in the last 6 years. The main results of the study are summarized in the table 1. Conclusions. The incidence of primary gastric lymphoma seems to be increasing. The overall prevalence of alarm symptoms is quite low, and they may be absent in near 75% of LG lymphoma patients. Moreover, contrarily to HG, LG lymphoma may present as a normal endoscopic finding and it is more frequently associated with H. pylori infection. At diagnosis, HG lymphoma is more frequently detected in an advanced stage as compared to LG lymphoma. Overall (143 patients) LG lymphoma (73 patients) HG lymphoma (70 patients) P value Age (mean ± SD) yrs 59.5 ± 14.2 59.4 ± 13.3 59.7 ± 15.1 0.4 Sex (M /F) 83/60 44/29 39/31 0.6 Alarm symptoms 57 (40%) 19 (26%) 38 (54%) 0.0009 Normal endoscopy 15 (10%) 15 (20%) 0 (0%) 0.0004 H. pylori infection 66 (73%) 47 (86%) 27 (39%) 〈 0.0001 Stage (IA / 〉 IA) 78/65 58/15 20/50 〈 0.0001