ALBERT

Description: Key Points Previously untreated patients with severe hemophilia A caused by F8 null mutations show a more severe phenotype than previously untreated patients with non-null mutations. The phenotypic differences are modest, and as such not likely to affect decisions regarding when and how to start prophylaxis.

Description: Introduction The standard treatment for elderly untreated diffuse large B-cell lymphoma (DLBCL) is RCHOP21, however up to 40% of patients experienced failures. Lenalidomide showed activity in heavily pretreated DLBCL and in vivo and in vitro data demonstrated a synergism with rituximab. In the phase I trial REAL07 (Chiappella et al, Haematol 2013), FIL demonstrated that the association of LRCHOP21 was feasible in elderly untreated DLBCL and identified 15 mg lenalidomide from day 1 to day 14 as the maximum tolerated dose in combination with RCHOP21. Patients and methods. The phase II trial REAL07 was designed based on Simon's two stage design to demonstrate an improvement of overall response rate (ORR) of 15% in LRCHOP21 compared to 70% of standard RCHOP21. Secondary endpoints were progression-free survival (PFS), overall survival (OS), event-free survival (EFS) and to correlate outcome with cell of origin (COO) profile. Response was evaluated according to 2007 Cheson criteria. Inclusion criteria were: age 60-80 FIT at the comprehensive geriatric assessment; untreated CD20+ DLBCL; Ann Arbor stage II/III/IV; international prognostic index (IPI) at low-intermediate/intermediate-high/high (LI/IH/H) risk. Treatment plan was: RCHOP21 plus 15 mg lenalidomide from day 1 to 14 for 6 courses. All cases were centrally reviewed by expert pathologist; COO profile analysis was conducted with immunohistochemistry according to Hans' algorithm and with gene expression profile (DASL assay). Results. From April 2010 to May 2011, 49 patients were enrolled. Clinical characteristics were: median age 69 years (range 61-80); stage III/IV 43 (88%), IPI IH/H 30 (61%). At the end of 6 LRCHOP21, ORR was 92%. Complete remissions (CR) were 42 (86%) and partial remission 3 (6%); 3 patients (6%) did not respond and one (2%) died for homicide. At a median follow-up of 28 months, 2-year OS was 92% (95% CI: 79-97), 2-year PFS was 80% (95% CI: 64-89) and 2-years EFS was 70% (95% CI: 55-81); 2-year PFS for IPI LI was 89% (95% CI: 62-97) and for IPI IH 76% (95% CI: 47-90) and for IPI H 72% (95% CI: 36-90). Hematological and extra-hematological toxicities were mild, with no grade IV extra-hematological events and no toxic deaths during treatment. Of the 294 planned courses of LRCHOP21, 277 (94%) were administered; median dose of lenalidomide delivered was 1185 mg (94% of the planned dose); at least 90% of the planned dose of each drug was administered in 91% of the RCHOP21 courses. Median interval time between RCHOP21 courses was 21 days (range 19-48). All 49 cases underwent central pathology review and diagnosis of DLBCL was confirmed. Regarding COO analysis, tissue block or stained slides were collected in 40/49 (82%), of which 32 were adequate for analysis. At the time of this abstract, COO analysis was reported according to immunohistochemistry data; DASL analysis is ongoing. Clinical characteristics between germinal center (GCB, 16 patients) and non-GCB (16 patients) were superimposable, excepted for a majority of H IPI risk in non-GCB group (p 0.067). ORR for GCB and non-GCB were 88% (CR 81%) and 88% (CR 88%), respectively. At a median follow-up of 28 months, 2-year PFS was 71% (95% CI: 40-88) in GCB-group and 2-years PFS was 81% (95% CI: 51-93) in non-GCB-group (Figure 1). Conclusions. In conclusion, LRCHOP21 is effective, also in poor risk patients, namely in non-GCB subgroup. These encouraging data warrant a future phase III randomized trial comparing LRCHOP21 vs. RCHOP21 in untreated non-GCB DLBCL. Disclosures: Off Label Use: lenalidomide in first line DLBCL is off lable. drug provided free by Celgene. Vitolo:Roche: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau.

Description: BACKGROUND Essential Thrombocythemia (ET) is a Philadelphia-negative chronic myeloproliferative neoplasm characterized by haemorrhagic and thrombotic complications. Haemorrhagic events and arterial and venous thrombosis, including microcirculation transient occlusions, are the major causes of morbidity in ET patients. The control of these events represents the goal of standard therapeutic approaches. MATERIALS AND METHODS We retrospectively analysed data about 107 ET patients who received diagnosis between January 1980 and June 2014. Median follow-up was 80 months,16 patients were lost during follow-up. The medium age at diagnosis was 60 years, with a prevalence of female (66 patients).We recorded adverse cardiovascular events at diagnosis and during follow-up, assessing whether cytoreductive ad antiplatelet therapy could reduce such events and improve quality of life. Finally, we evaluated the impact of additional cardiovascular risk factors. OBJECTIVES to observe incidence and kind of thrombotic events in patients affected by ET at diagnosis and during follow-up. RESULTS 30 patients (27.7%) had a history of thrombosis at diagnosis (8 transient cerebral ischemia, 7 myocardial infarction/unstable angina, among them 7 patients experienced a rethrombosis during follow-up. 16 patients (15%) developed a first thrombotic event, all patients were under cytoreductive treatment. 21 patients with a history of thrombosis had more than 60 years at diagnosis, 19 patients (63%) had at least one additional cardiovascular risk factor among arterial hypertension, dyslipidemia, diabetes, obesity, hyperuricemia and smoking. Median platelet count was 813000/mm3, leukocyte count greater was more than 10000/mm3 in half of patients. Evolution to acute leukemia/myelofibrosis occurred in 3 (2,7%) and 7 (6,5%) patients of total. CONCLUSIONS The occurrence of thrombotic events even in patients with good hematologic response of disease and during antiplatelet and cytoreductive therapy, indicates the presence of a residual risk of thrombosis. This risk is not yet fully clarified by retrospective studies published until now. Prospective studies will be useful to evaluate the role and the importance of comorbidity in these patients with long-prognosis, in order to optimize therapy, reduce cardiovascular events and improve quality of life Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Myelodysplastic syndromes (MDS) are a highly heterogeneous group of clonal disorders, with very different prognosis in given individuals, overall survival (OS) ranging from more than 10 years (y) for the more indolent conditions to only few months (m) for the forms approaching AML; beside of the well-established disease-related prognostic systems (classical IPSS or its revised form [IPSS-R], the prognostic implication of comorbidities is emerging as a relevant patient-related factor influencing clinical outcome. Aim of our study was to evaluate the clinical impact of comorbidities in a series of MDS patients whatever treated in a “real-life” setting. Methods: this retrospective cohort study involved the MDS patients consecutively registered between Jan 2011 and Dec 2013 into the Registro Ligure delle Mielodisplasie database, a regional registry established within the framework of the Italian Network of regional MDS registries. Data of 318 patients (pts) with available complete assessment of comorbidities at diagnosis were included into the study. The clinical characteristics and comorbidities were all considered into the analysis. Comorbidities were evaluated according to both hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and MDS-specific comorbidity index (MDS-CI). All survival analyses were made from the date of diagnosis to last follow-up, death, or progression to AML. Unless specified, survival analyses were Cox models using continuous variables accounting for interactions. Results: Our cohort mainly consisted of older (median age 75y (range 40-98) “lower-risk” MDS pts: according to IPSS stratification, 151 (54.7%) pts were classified as low-risk, 86 (31.2%) as intermediate-1, 32 (11.6%) as intermediate-2 and 7 (2.5%) were in the high-risk group. One or more comorbidity of any grade of severity was seen in 177 (55.7%) pts at diagnosis. The more common comorbidity was cardiac (26.5%). At least a single comorbidity was present in 61.2% of pts older than 75y and in 50.6% of younger pts (p=0.07). Cardiovascular disorders were more frequent among older (32.9% for 〉75y vs 15.1% for ≤ 75y, p75 y (48% vs. 28.9% for 〈 75 y (p=0.001). A lower comorbidity score impacted on the clinical choice for active forms of therapy, while pts with an higher burden of comorbidities were preferentially treated with supportive care, even if difference did not reach significance (p=0.07). Overall survival and risk of non-leukemic death (NLD) were analyzed (median f.u. 26.9 m (range 1-220). HCT-CI did not significantly correlated with OS nor NLD (p= 0.1 and p= 0.07, respectively), while MDS-CI was found to be of prognostic significance both for OS (mean 136.6 (95%CI 116-157) m for the low-risk group, 81.3 (95%CI 61-102) m for the intermediate group and 48.1 (95%CI 30-66) m for the high-risk group, p=0.001) and for NLD (mean 159.6 (95%CI 139-180) m for the low-risk group, 96.5 (95%CI 72-121) m for the intermediate group and 49 (95%CI 31-67) m for the high-risk group (p

Description: Background The majority of myelodysplastic syndrome (MDS), primary myelofibrosis (MPN) and aplastic anemia (AA) patients during the course of the disease develops a symptomatic anemia requiring transfusions of packed red blood cells (PRBC), each of them containing approximately 200 mg of elementary iron. Because of the fact that human beings are unable to actively eliminate iron from the body, secondary emosiderosis yet becomes evident when body iron content is above 7-14 grams, an amount easily reached after receiving as few as 15-30 PRCB units.From a pathophysiologic point of view, long-term transfusion therapy is certainly the most important cause of iron overload (IOL) in these patients; nevertheless, others mechanism account for this phenomenon, and in particular the role of the ineffective erythropoiesis.Deferasirox (DSX) is the principal option currently available for iron chelation therapy in the management of IOL due to transfusion dependent anemia. DSX is also a potent NF-kB inhibitor, and this effect may explain in part the phenomenon of hematological improvements reported in different clinical trials and in case reports. Materials and Methods We analyzed 21 patients,16 male and 5 female, with transfusion dependent anemia and with a transfusional history of almost 10 packed PRBC, treated with DSX from 1 February 2013 to 1 February 2014. Median age was 80 years (65-88). 20 patients (95%) have almost a comorbidity, 7 of them (30%) have more than 3 comorbidities. Heart disease was the most common comorbidity. At baseline median creatinine clearance was 76 ml/min; in 12 patients was 〈 60ml/min but 〉40 ml/min, according to NCCN Guidelines. All patients (16 MDS, 3 MPN, 1 AA, 1 hemolytic anemia) were evaluated for IOL by serum ferritin (SF), while only 7 with RM T2*.Median SF at baseline was 1750 μg/L and median PRBC was 32.The starting dose of DSX was 10 mg/kg/day; the dosage should be adjusted up to 20–30 mg/kg/daily according to the transfusional regimen, SF and IOL, if tolerated. Objectives To observe safety, tolerability, and efficacy of iron chelation therapy with DSX in older patients with transfusion dependent anemia. Results The SF decreased of 50% and 66% after 3 and 6 months respectively. The SF was normalized (SF

Description: Background: HSCT has greatly improved the prognosis of patients affected by hematological malignancies leading to more long-term survivors. However, long-term survivors are at increased risk of developing complications; cardiovascular complications are relatively rare but, on the other hand, it seems quite common to develop cardiovascular risk factors like: arterial hypertension (AH), diabetes, dyslipidemia. Aims of the study: to observe the incidence and outcome of patients developing cardiovascular risk factors (CVRF) and cardiovascular events (CVE) after allo-HSCT, eventually identifying patient and HSCT-related risk factors for CVE (CVE predictors). Materials and methods: We retrospectively analyzed 300 patients undergoing allo-HSCT from January 2006 to December 2009. Patients were considered long-term survivors and suitable for the analysis if they were alive at 2 years after HSCT. Following variables were recorded: diagnosis, sex, age at time of HSCT, comorbidities and pre-existing risk factors, BMI, previous chemotherapy with anthracyclines, donor type, disease status at time of HSCT, conditioning regimens with or without total body irradiation (TBI), onset of acute or chronic graft versus host disease (aGVHD and cGvHD), treatment with high doses corticosteroids after HSCT. We observed incidence and outcome of early (within 2 years) and late (after 2 years) CVRF and CVE in long-term survivors; CVE were divided in non-serious (grade1-2) and serious (grade 3-4) if they required or not hospitalization. Dichothomius variables were compared with Chi-Square test or Fisher's exact test. Continuous variables were compared with Student's T-Test. Median Follow-Up duration was estimated with Kaplan Meier reverse survival method. Multiple linear regression models were built for multivariate analysis of CVE incidence. A two-sided p value

Description: Abstract 5123 Vertebral compression fractures occur in approximately 60% of MM patients and can cause pain, persistent disability and dismail quality of life. Appropriate therapy of MM or radiotherapy can lead to improvement of symptoms in a significant percentage of patients, but these positive effects can take time to be perceived. Vertebral agumentation techniques have been recently proposed as suitable options to relieve bone pain from vertebral compression fractures in patients with benign osteoporosis or neoplastic diseases such as MM. Aim of this study was to analyze the clinical course and outcome of 40 consecutive MM patients (23M, 17F, median age = 67.6yrs) treated in the Centers referring to GER, who underwent percutaneous vertebroplasty from 2006 to 2010. Seventeen patients (43%) were newly diagnosed while 23 patients were relapsed or refractory after 1–3 lines of therapy. All the patients were treated because of severe pain, the extent of vertebral fractures was assessed by nuclear magnetic resonance imaging. Sixty-nine procedures were performed at C2-L5 levels, 51% of the patients were treated at a single level, a maximum of three levels were treated in 6 patients, 13 procedures (32%) were performed at L1 level. Thirty seven patients (92%) experienced reduction of pain, with 55% showing complete disapperance of symptoms prior to any further treatment, 3 patients reported no or little improvement. Responses were durable, after a median follow-up of 14 months no further collapse of the treated vertebrae was observed. After vertebroplasty, first line or salvage therapy was administered to 35 patients, 10 newly diagnosed patients were scheduled to receive autologous stem cell transplant, and peripheral blood stem cell collection was not affected by the procedure. In conclusion, percutaneous vertebroplasty appears to be useful in MM patients with painful vertebral fractures as it allows rapid and durable achievement of pain control, without interfering with further therapeutic programs Work supported in part by RiminiAIL Disclosures: No relevant conflicts of interest to declare.

Description: The incidence of thrombosis in the purely obstetric form of antiphospholipid syndrome is uncertain. We performed a 10-year observational study of 1592 nonthrombotic women who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal death at or beyond the 10th week of gestation. We compared the frequencies of thrombotic events among women positive for antiphospholipid Abs (n = 517), women carrying the F5 6025 or F2 rs1799963 polymorphism (n = 279), and women with negative thrombophilia screening results (n = 796). The annual rates of deep vein thrombosis (1.46%; range, 1.15%-1.82%), pulmonary embolism (0.43%; range, 0.26%-0.66%), superficial vein thrombosis (0.44%; range, 0.28%-0.68%), and cerebrovascular events (0.32%; range, 0.18%-0.53%) were significantly higher in aPLAbs women than in the other groups despite low-dose aspirin primary prophylaxis. Women carrying 1 of the 2 polymorphisms did not experience more thrombotic events than women who screened negative for thrombophilia. Lupus anticoagulant was a risk factor for unprovoked proximal and distal deep and superficial vein thrombosis and women in the upper quartile of lupus anticoagulant activity had the highest risk. Despite data suggesting that aPLAbs may induce pregnancy loss through nonthrombotic mechanisms, women with purely obstetric antiphospholipid syndrome are at risk for thrombotic complications.

Description: A precise identification of adult human hemangioblast is still lacking. To identify circulating precursors having the developmental potential of the hemangioblast, we established a new ex vivo long-term culture model supporting the differentiation of both hematopoietic and endothelial cell lineages. We identified from peripheral blood a population lacking the expression of CD34, lineage markers, CD45 and CD133 (CD34−Lin−CD45−CD133− cells), endowed with the ability to differentiate after a 6-week culture into both hematopoietic and endothelial lineages. The bilineage potential of CD34−Lin−CD45−CD133− cells was determined at the single-cell level in vitro and was confirmed by transplantation into NOD/SCID mice. In vivo, CD34−Lin−CD45−CD133− cells showed the ability to reconstitute hematopoietic tissue and to generate functional endothelial cells that contribute to new vessel formation during tumor angiogenesis. Molecular characterization of CD34−Lin−CD45−CD133− cells unveiled a stem cell profile compatible with both hematopoietic and endothelial potentials, characterized by the expression of c-Kit and CXCR4 as well as EphB4, EphB2, and ephrinB2. Further molecular and functional characterization of CD34−Lin−CD45−CD133− cells will help dissect their physiologic role in blood and blood vessel maintenance and repair in adult life.

Description: Abstract 903 Introduction. R-CHOP21 is the standard treatment for untreated elderly DLBCL, however up to 40% of patients fail. There is a need to improve the efficacy of R-CHOP21; an option may be the addition of novel drugs in first line induction therapy. Lenalidomide has a complex mechanism of action as immunemodulation, antiangiogenesis, restoration of immunesynapses and direct antitumor effects. Lenalidomide monotherapy exhibits significant activity in patients with relapsed aggressive B-cell NHL and has in vitro synergy with rituximab and cytotoxic therapy. This rationale prompted FIL to conduct a prospective multicenter dose finding phase I-II trial aimed at evaluating toxicity and activity of lenalidomide plus R-CHOP21 (LR-CHOP21) in elderly untreated DLBCL (NCT00907348). In the dose-finding phase I study, 21 patients were enrolled, and 15 mg lenalidomide from day 1 to day 14 was identified as the maximum tolerated dose (MTD) in combination with R-CHOP21 (Vitolo, Ann Oncol 2011;22(4):331a). Patients and Methods. Based on the phase I results, 15 mg of lenalidomide in combination to R-CHOP21 was tested in a phase II study. Phase II was designed according to Simon's two stage design; primary endpoint was an improvement of overall response rate (ORR) of 15% in LR-CHOP21 compared to 70% of standard R-CHOP21 and the study would be considered of interest if at least 16/23 in step 1 and 39/49 in step 2 responses occurred. Response was evaluated according to 2007 Cheson criteria. PET scan was mandatory at the end of the treatment; patients in partial remission (PR) who underwent radiotherapy were considered as failure in progression free survival (PFS) analysis. Inclusion criteria were: age 60–80 FIT at the comprehensive geriatric assessment; untreated CD20+ DLBCL; Ann Arbor stage II/III/IV; IPI at LI/IH/H risk. Treatment plan was: R-CHOP21 plus 15 mg lenalidomide from day 1 to 14 for 6 courses. Mandatory supportive care included: GCSF or PegGCSF, cotrimoxazole as Pneumocystis Jiroveci prophylaxis and low molecular weight heparin or low dose aspirin as deep venous thrombosis prophylaxis. Results. From April 2010 to May 2011, 49 patients were enrolled in the phase II study including 9 patients treated at the MTD during phase I. Clinical characteristics were: median age 69 years (range 61–80); stage III/IV 43 (88%), performance status 〉1 31 (63%), IPI IH/H 30 (61%). The step-1 of the trial showed an ORR of 22/23. At the end of 6 LR-CHOP21, ORR was 45/49 (92%). Complete remissions (CR) were 42 (86%) and PR 3 (6%); 3 patients (6%) did not respond and one (2%) died for violent death. At a median follow-up of 18 months, overall survival (OS) was 94% (95% CI: 82–98) and PFS was 75% (95% CI: 57–86). (Figure 1). Of the 294 planned courses of LR-CHOP21, 277 (94%) were administered, of which 221 (75%) with lenalidomide as planned, 40 (14%) with dose and/or day reduction and 16 (5%) without lenalidomide. Median dose of lenalidomide delivered in 49 patients was 1185 mg (IQR 900–1260), i.e. 94% of the planned dose (1260 mg). The most frequent cause of lenalidomide reduction or withdrawal was neutropenia. At least 90% of the planned dose of doxorubicine, cyclophosphamide and vincristine were administered, in: 91%, 95% and 83% of the R-CHOP21 courses, respectively. Median interval time between R-CHOP21 courses was 21 days (range 19–48). Hematological toxicity was mild: grade III/IV thrombocytopenia occurred in 13% of courses, anemia in 5% and neutropenia in 33%, with only 4% of febrile neutropenia. No grade IV extra-hematological toxicities were observed. Grade III non-hematological toxicities were reported in 7 patients: cardiologic, gastroenteric and renal in one patient respectively, grade III neurological toxicities, sensory and motorial neuropathy in two, thromboembolic event in one not receiving anti-thrombotic prophylaxis, and skin rash in one. No toxic deaths occurred during treatment. One patient died three months off therapy while in CR, due to aeromonas hydrophila sepsis and multi-organ failure. Conclusions. The addition of 15 mg lenalidomide on days 1–14 to R-CHOP21 is safe, feasible and effective in elderly untreated DLBCL. The primary objective of the phase II study was met, with 92% of ORR of which 86% CR and promising PFS rates. The addition of lenalidomide did not impair the administration of R-CHOP21. Based on these data, the efficacy of LR-CHOP21 needs to be investigated in a large phase III randomized trial in elderly DLBCL. Disclosures: Off Label Use: Trial partially supported by a research grant by Celgene. Lenalidomide was provided free by Celgene. The use of Lenalidomide is off-label in untreated DLBCL. Dreyling:Roche: Membership on an entity's Board of Directors or advisory committees. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees.