Abstract: Background Deferasirox (DFX) is an oral iron chelator widely employed in the treatment of iron overload during thalassemic syndromes and myelodysplastic syndromes. Aim At present, very few data are available on the treatment with DFX in patients with Ph- Myeloproliferative Neoplasms(MPN) and transfusional requirement. Methods To address this issue, we report here on 41 patients (M 31; F 10) with MPN and iron overload secondary to transfusional requirement enrolled in the database of our regional cooperative group who received a treatment with DFX. Of them, 36 had a primary Myelofibrosis, 4 a post Essential Thrombocythemia myelofibrotic phase and 1 a post Polycythemia Vera myelofibrotic phase. Results According to IPSS classification, 8 patients (19.5%) resulted low/intermediate-1 risk, 14 (34.1%) intermediate-2 risk and 19 (46.4%) high-risk. The main features of the patients at diagnosis and at baseline of DFX treatment are reported in the Table. Treatment with DFX was started after a median interval from diagnosis of 13.3 months [interquartile range (IR) 7.3 - 41.1] and from start of transfusion dependence of 11.5 months (IR 5.8 - 20.2), with a median of 27 packed red cells units received (IR 18 - 37). The starting DF X dose was 20 mg/Kg in 16 patients (39.1%), 15 mg/Kg in 20 patients (48.8%) and 10 mg/Kg in 5 patient (12.1%). All patients were evaluable for toxicity:extra-hematological toxicity of all WHO grades was reported in 20/41 patients (48.8%) and consisted of gastro-intestinal symptoms in 7 patients, transient renal impairment in 10 patients and skin reactions in 3 patients: however, only 3 patients (7.3%) needed a permanent discontinuation for toxicity. Thirty-nine out 41 patients were evaluable for response ( 〉 6 months of treatment). As to chelation efficacy, after a median treatment period of 15.4 months (IR 8.1 - 22.3), 4 patients achieved ferritin levels 〈 500 ng/ml, 10 patients ferritin levels 〈 1,000 ng/ml and 2 patients presented a reduction 〉 50% of basal ferritin but with levels 〉 1,000 ng/ml, with a global response rate of 16 out 39 patients (41.0%): among the remaining 23 patients, 2 discontinued for early toxicity, 20 did not have any ferritin reduction and 1 had an early unrelated death ( 〈 6 months of treatment). As to hematological improvement, 7/39 patients (17.9%) showed an unexpected and persistent rise of Hb levels 〉 1.5 g/dl, with disappearance of transfusional requirement in 5 cases. The median overall survival of the whole cohort from DFX initiation was 20.7 months (95% CI 16.0 - 25.3): the median overall survival from DFX initiation in patients with chelation response was 46.9 months (95% CI 10.7 - 83.0) compared to 14.0 months (95% CI 5.6 - 22.3) in patients without chelation efficacy (p=0.002). Conclusions Treatment with DFX is feasible and effective in MPN with iron overload. Moreover, also in this setting an hematological improvement can occur in a sizeable rate of patients. Disclosures Breccia: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria.

Abstract: Polycythemia vera (PV) is associated with high morbidity and mortality for thrombosis. We hypothesized that in PV altered sensitivity to aspirin might be related to dysfunction of the endothelial repair and/or of the nitric oxide (NO) system. Urinary thromboxane (TX) A2 metabolite (TXM), endothelial colony-forming cells (ECFCs), plasma asymmetric dimethylarginine (ADMA) and von Willebrand factor (VWF) were measured in 37 PV patients on low-dose aspirin and 12 healthy controls. Patients showed an approximately 2-fold increase in median TXM and plasma ADMA levels (P 〈 .001), while ECFC numbers were reduced by approximately 7-fold (P 〈 .001) as compared with nonaspirinated control. These differences were more pronounced in patients with previous thrombosis. An 8-week course of aspirin did not affect ECFCs in 6 controls. VWF and TXM correlated directly with ADMA, and inversely with ECFCs. By multiple regression analysis, lower ECFC quartiles (beta = −0.39; SE = 0.17; P = .028) and higher VWF levels (beta = 0.338, SE = 0.002, P = .034) were independent predictors of higher TXM quartiles (R2 = 0.39). Serum TXB2, measured in 22 patients, was approximat-ly 10-fold higher than aspirin-treated controls. PV patients appear to have an unbalanced ECFC/NO axis, and an apparent altered sensitivity of platelet TXA2 production, all potentially contributing to aspirin-insensitive TXM formation. Thus, additional antithrombotic strategies may be beneficial in PV.

Abstract: Introduction: Oral iron delivery is attractive due to the ease of administration and is mainly based on immediate release formulations of ferrous iron. Commonly used ferrous iron salts are poorly absorbed. Overcoming gastrointestinal barriers, is a great challenge and there is a need for new absorption and protective enhancers. Iron DeficiencyAnemia (IDA) is a presenting symptom in approximately 40% of patients with Hodgkin's Lymphoma (HL). Usually with hemoglobin (Hb) between 10 and 12 g/dL. When considering oral iron therapy in cancer patients one must take into account the impact of worsening of existing clinical conditions due to oral iron as intolerance and non-compliance. For these reasons, effective management of iron deficiency anemia is mandatory and iron supplementation is often necessary. To avoid constant exposure of intestinal cells to insoluble iron and consequent side effects, we have developed a new oral Iron formulation named Sucrosomial¨ Iron. This oral formulation is an innovative preparation of ferric pyrophosphate, covered by a phospholipids plus sucrester matrix, with high bioavailability and tolerability and has been showed to improve Hb concentration similarly to intravenous iron but without any gastrointestinal side effects. Objective: to showpre-clinical and clinical evidences of the absorption, effectiveness and tolerability of Sucrosomial¨ Iron. Methods: to study the absorption pathway of Sucrosomial¨ Iron, gastro-resistance and permeation experiments have been performed using in vitro simulated gastric pH digestion, and isolate rat intestine ex vivo models, respectively. To show the efficacy and compliance of Sucrosomial¨ Iron (Sideral¨ Forte) in IDA patients with Hodgkin's Lymphoma (HL), 25 patients were retrospective analyzed, (median age, 35 years; range 26 to 44 years). All patients were staged 2B or higher, according to Ann Arbor classification, none of them showed bone marrow infiltration. A continued treatment with oral Sideral¨ Forte (30 mg/die) was performed for the whole period of chemotherapy administration and iron parameters were tested at the end of the planned treatment. Results: In vitro gastro-resistance experiment displays the ability of Sucrosomial¨ Iron (SRM), to avoid release of Ferric Iron from the matrix compared to phospholipid only-containing iron formulation (PCC, Figure 1). These results showed the gastro-resistance features of SRM.We have performed ex-vivo permeability experiments using Hussing chamber-like experimental model and measured ferric iron concentration in presence of bivalent iron chelator (BPDS) too. Thanks to this model we have showed that SRM is able to cross the intestinal tissue through a passive transport in respect to the other iron formulations (Figure 2). Moreover we have observed that Sucrosome components ratio is pivotal for kinetics properties of Sucrosomial¨ Iron. Data from the clinical study showed that Sideral¨ Forte is well tolerated and effective in patients with HL in advanced stage. At baseline (T0) medium Hb level was 10.2 g/dL, median serum iron and total iron-binding capacity (TIBC) were 35 μg/dL and 244 μg/dL respectively. Ferritin levels showed a wide variation with a median of 90 ng/mL. At the end of treatment (T1 6 months) medium Hb level was 12.8 g/dL (+2,2 g/dL) the median serum iron and total iron-binding capacity increased up to 95 μg/dL and 264 μg/dL and Ferritn levels increased with a median of 277 ng/mL (Figure 3). Thanks to the high compliance and tolerability, all patients were able to continue Sucrosomial¨ Iron supplementation up to the end of the chemioterapy period. CONCLUSIONS: these results showed that Sucrosomial technology is able to protect ferric iron from the gastric pH conferring the ability to reach covered the intestine for absorption and to cross intestinal epithelium through a passive route; thus minimizing the conventional oral iron side effects and increasing Hb and Ferritin levels in HL patients. SRM Iron pyrophosphate, Lecithin, Sucrester PCC phospholipid-containing carrier BPDS Bivalent Iron chelator PYR Iron pyrophosphate SLP pyr, Lecithin, low phospholipid concentration, Sucrester SRMS pyr, Lecithin, high Sucrester concentration Results are expressed as median values *p 〈 0,05 Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Brilli: Pharmanutra S.p.A.: Employment. Tarantino:Pharmanutra S.p.A.: Employment.

Abstract: The DASISION and ENESTnd controlled clinical trials have changed the front-line treatment of Chronic Myelogenous Leukemia (CML) leading to the advent of dasatinib and nilotinib in this setting: however, both these company-sponsored trials had many exclusion criteria, with a possible selection bias compared to the real-life CML population. To address the impact of these exclusion criteria on the 1st line treatment in the current clinical practice, we revised 207 unselected newly diagnosed chronic phase CML patients [M/F 108/99, median age 58.8 years, interquartile range (IR) 42.3 – 70.2] treated with front-line imatinib from June 2002 to June 2013 at our Institution and evaluated how many of them would have been excluded from enrolment in the 2 trials. Among these 207 patients, 28 patients should have been excluded by both trials due to polycomorbidities (12 cases), severe cardiopathy (5 cases), age 〉 80 with frailty (3 cases), drug abuse (2 cases), severe liver impairment, Rendu-Osler disease, active prostatic cancer, chronic obstructive broncopulmonar disease (COPD) + peripheral arterial obstructive disease (PAOD), COPD + arrhythmia, refusal to any marrow examination (1 case each). In addition, 8 patients should have been considered not eligible only for the DASISION due to isolated COPD and 19 patients should have been considered not eligible only for the ENESTnd due to isolated diabetes (10 cases), arrhythmia (4 cases), acute myocardial infarction 〉 6 months before CML diagnosis (2 cases), chronic pancreatic disease (2 cases), PAOD (1 case). On the whole, 36/207 patients (17.4%) would have been considered not eligible for the DASISION trial and 47/207 (22.7%) for the ENESTnd trial. As expected, these patients potentially not eligible for DASISION and ENESTnd were significantly older and with the imatinib treatment had a worse follow-up in terms of Complete Cytogenetic Response (CCyR), Major Molecular Response (MMolR) and Overall Survival (OS) compared to patients potentially eligible, as shown in the Table. In conclusion, our data highlight that an important fraction of newly diagnosed patients in a real-life setting would have been excluded by the 2 controlled trials whose results are the current mainstay of the 1st line treatment in CML: thus, an automatic transposition of those results into the current clinical practice should be regarded with caution. Disclosures: No relevant conflicts of interest to declare.

Abstract: BACKGROUND Multiple myeloma (MM) is a B-cell malignancy critically dependent for survival and proliferation on signals coming from its inflammatory microenvironment in which toll-like receptors (TLR) may be potential linking elements between inflammation and cancer. It has been recently demonstrated that TLR4 pathway provides a protective effect against bortezomib (BTZ)-induced endoplasmic reticulum (ER) stress and pre-treatment of MM cells with LPS significantly reduces BTZ-induced apoptosis. AIM Since the acquisition of BTZ resistance is accompanied by an increased reliance on mitochondrial respiration, we investigated the role of TLR4 as stress-responsive mechanism that protect mitochondria during BTZ-induced ER stress as potential mechanism of drug resistance. RESULTS The activation of TLR4 signaling by LPS increased mitochondrial mass in human MM cell lines (HMCL: U266, MM1.S, OPM2, NCI-H929) and induced up-regulation of mitochondrial biogenesis markers (PGC1a, PRC and TFAM). After treatment with BTZ for 24h, all HMCL over-expressed TLR4 and its signaling was functional as suggested by up-regulation of MyD88 and MAPK activation. Compared to BTZ-sensitive cells (U266-S), U266-R showed higher levels of TLR4, p-p38 and p-ERK proteins and higher mitochondrial mass. Using a selective TLR4 inhibitor (TAK-242), we next treated U266-R cells with either 15nM BTZ, 20 μM TAK-242 or their combination. Combinatorial treatment significantly induced cell apoptosis (about 52%; p 〈 0.001) that appeared to result from the deleterious effects of oxidative stress. Indeed, BTZ-induced intracellular ROS returned to normal levels after 3h and cells were able to up-regulate two anti-oxidant enzymes (GPX1 and GSTP1). On the contrary, TAK-242/BTZ activated a strong pro-oxidant status incresing ROS and RNS (reactive nitrogen species) levels, decreasing GSH ones and down-regulating GPX1 and GSTP1. Analyzing the effect of each treatment on mitochondrial polarization status, we observed about 6,7% of depolarized mitochondria after BTZ treatment, while TAK-242/BTZ combination induced a mitochondrial depolarization of about 69,3% (p 〈 0.001). Moreover, cells treated with BTZ alone showed a compensatory up-regulation of the OXPHOS- (NDUFA-6 and MT-ND4) and mitochondrial fusion-related genes (mitofusin and OPA1) and TFAM. On the contrary, all these genes were down-regulated by TAK-242/BTZ combination. Also a dramatic drop in mitochondrial respiration was observed with a marked decrease in ATP production, consequent accumulation of AMP and a decreased NAD+/NADH and NADP+/NADPH ratio. Since high levels of oxidative stress and mitochondrial impairment activate mitophagy sensitizing cells to apoptosis, we evaluated co-localization of mitochondria (stained with MitoTracker) with the autophagosome marker LC3 using confocal microscopy. BTZ and TAK-242/BTZ increased Mitotracker/LC3 co-localization respectively of about 4,5 and 50 fold compared with control (BTZ vs combination: p 〈 0.001). To evaluate whether TLR4 inhibition resensitizes resistant primary cells, CD138+ cells derived from 5 refractory/relapsed MM patients were treated with 5nM BTZ, 10mM TAK-242 or their combination. Compared to BTZ alone, combination treatment induced higher mitochondrial depolarization after 24h and significantly decreased viability of CD138+ cells after 48h. TLR4 inhibitor alone or in combination did never show cytotoxicity toward CD138- cells. CONCLUSION Taken together, these findings indicate thatTLR4 signaling is involved in the acquisition of bortezomib resistance protecting mitochondria during BTZ exposure and sustaining mitochondrial dynamics in BTZ-resitant cells. Inhibition of TLR4 may overcome bortezomib resistance in patients with relapsed/refractory MM. Disclosures Conticello: Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Palumbo:Celgene: Honoraria; Amgen: Honoraria; Hospira: Honoraria; Teva: Honoraria; Novartis: Honoraria; Janssen: Honoraria. Di Raimondo:Takeda: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Abstract: Introduction Lenalidomide (Len) and low-dose Dexamethasone (dex) (Rd) in continuous is a new standard of care for elderly newly-diagnosed multiple myeloma (NDMM) patients (pts), as established by FIRST trial (Facon et al, Blood 2018). Methods and results This is a retrospective, multicentric study conducted in Italy with the aim of evaluating efficacy and tolerability of Rd in a real-life population. Thirty-seven centers were involved and data of 429 pts are available. Pts were considered eligible for the study when completing at least 2 cycles of Rd regimen. Table 1 summarizes the characteristics of pts at time of MM diagnosis. Median age was 78 years (range 57-92), 36.6% had an ECOG PS≥2, creatinine clearance (ClCr) was 〈 30 ml/min in 7.1% of pts. 16, 30 and 54% resulted respectively fit, unfit and frail by IMWG Frailty score. ISS was respectively I, II and III in 27.5, 40.5 and 32% while R-ISS was I, II and III in 31.8, 42.4 and 25.8% of pts. t(4;14), t(14;16), del(17p) or amp(1q) by FISH were respectively found in 9.2%, 5.5%, 5.8% and 36.6% of pts. Extramedullary disease (EMD) was documented in 11% of pts. After a median follow-up of 11 months, most pts are still on treatment (60,4%), the median number of administered cycles was 7 (range 2-33). Overall response rate (ORR, ≥PR) was 74.5% with 34.1% of pts obtaining at least a VGPR. Clinical Benefit Rate (CBR, including minimal responses) was 83.3%. Responses were rapid with median time to first and to best response respectively of 1.8 (range 1-8) and 5 (1-26) months. Median OS and PFS were not reached with a 1-y and 2-y OS of 84.8 and 73.8% and a 1-y and 2-y PFS of 78.6 and 65%. Median EFS was 19.8 months. In univariate analysis, factors significatively impairing ORR were frailty (fit/unfit/frail 91.2/77/55.9%, p 〈 0.001), ECOG (0-1/ 〉 2 81.7/61.6%, p 〈 0.001), presence of t(4;14) (52.9 vs 76.7%, p=0.033) and amp(1q) (53.4 vs 83.5, p 〈 0.001), R-ISS (3 vs 2-1 55.3 vs 72.6%, p=0.027), LDH 〉 upper level of normal (ULN) (65.8 vs 77%, p=0.034). 1-y PFS is significantly shorter in pts with lower ECOG (0-1 vs 2, 66.5 vs 84.8%, p 〈 0.001), higher frailty score (fit/unfit/frail 100/86.4/66.6%, p=0.01), higher ISS (I-II-III 88.4-79.1-68.5%, p=0.002) and R-ISS (I-II-III 75.5-88-50.5% p=0.02), LDH 〉 ULN (66.4 vs 83.2%, p=0.02), lower ClCr ( 〈 30/30-50/ 〉 50 57.2/81.3/80.1%, P=0.01), presence of t(14;16) (42.9 vs 80.4% p=0.01) and amp(1q) (63.5 vs 85.6%, p=0.01); factor impairing OS are ECOG (0-1/ 〉 2 93.4 vs 69.4%, p 〈 0.001), frailty (fit/unfit/frail 100/90.5/75.3% p=0.001), higher ISS (I-II-III 93.6/87.8/74.6%, p=0.006) and R-ISS (I-II-III 87/93/72%, p 〈 0.001)), LDH 〉 ULN (75.1 vs 97.1, p=0004), impaired ClCr ( 〈 30/30-50/ 〉 50 64/83.7/88.2%, p 〈 0.001); EFS was affected by ECOG (0-1/ 〉 2 74.2 vs 47.3%, p 〈 0.001), frailty (fit/unfit/frail 83.4/74.5/52% p=0.09), R-ISS (I-II-III 61.4/74.9/37.5% p=0.006), presence of t(14;16) (35.5 vs 67.8% p=0.08) or amp(1q) (50.1 vs 69% p=0.02). In multivariate analysis ORR is significantly correlated with ECOG 〉 2 (p=0.05), LDH 〉 ULN (p=0.005) and presence of amp1q (p=0.006); PFS was significantly affected by R-ISS III (p=0.04), LDH 〉 ULN (P=0.01) and ClCr 〈 30 (p=0.006) and EFS by R-ISS III (p=0.002); only ECOG 〉 2 still impact on OS (p 〈 0.0001) Dose reduction of Len or dex was required respectively in 20.7% and 22.1% and 39.2% needed cycle delay for adverse events (AEs). Grade 3-4 (G3-4) AEs occurred in 52% of pts with 30.9 and 36.6% having at least a hematological or extra-hematological G3-4 AE. In particular, 17.9 and 16.6% of pts had severe neutropenia and anemia while the most common non-hematological AEs were infections (25.8%, G3-4 12.2%), mainly involving respiratory tract (71.2%). Gastroenteric and cutaneous AEs were quite common (22.1 and 19.2%), mainly diarrhea and itching, but in the vast majority were mild. G3-4 asthenia was present in 22.8% of pts. Although 99% of pts was given antithrombotic prophylaxis, 8.5% had a thromboembolic event, a third of severe entity. G-CSF and EPO analogs were required in 27.4 and 26% of pts. Conclusion Real-life data confirm efficacy and tolerability of Rd in elderly NDMM pts. Performance status by ECOG and IMWG frailty score and severe renal impairment but not age itself act as limiting factors affecting outcome. These data must be confirmed by longer follow-up. Disclosures Conticello: Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Mangiacavalli:Janssen cilag: Consultancy; celgene: Consultancy; Amgen: Consultancy. Zambello:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Belotti:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Molteni:Celgene: Membership on an entity's Board of Directors or advisory committees. Aquino:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Del Fabro:Janssen: Consultancy. Galli:Leadiant (Sigma-Tau): Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria.

Abstract: Differences in baseline features and follow-up among patients with chronic myeloid leukemia (CML) according to age at diagnosis have been recently reported in cohorts from clinical controlled trials (Castagnetti F et al, 2015). To evaluate this issue in a real-life setting, we revised 207 consecutive CML patients treated at our Institution with imatinib frontline from 6/2002 to 6/2013, dividing them in young adults ( 〉 20 〈 45 years) (YA), middle-aged adults (≥45 〈 65 years) (MA) and elderly (≥65 years) (EL). The main features at baseline of the whole cohort and of the 3 age groups are reported in the Table. Table.ALLYAMAELpN° of patients207617274M/F108/8930/3140/3238/360.752Median WBC (x 109/l)IQR66.1 (32.7 - 119.0)109.8 (65.9 - 148.0)59.5 (31.3 - 126.6)40.1 (26.5 - 81.4) 〈 0.001Median Hb (g/dl)(IQR)12.5 (11.0 - 13.5)11.7 (9.8 - 12.7)12.7 (11.0 - 14.2)12.8 (11.3 - 13.7)0.002Median PLT (x 109/l)IQR414 (275 - 616)445 (291 - 597)378 (262 - 546)457 (271 - 732)0.287Spleen enlargement ( 〉 5cm) N° (%)17 (8.3)11 (18.3)4 (5.6)2 (2.7)0.003Sokal score (N°)Low/Int/High89/93/2047/9/338/27/54/57/12 〈 0.001Comorbidities ≥ 2, N° (%)77 (37.2)5 (8.1)26 (36.1)46 (62.1) 〈 0.001 The rates of complete cytogenetic response (CCyR) were similar (86.4% in YA, 95.5% in MA and 91.0% in EL, p=0.227) while the rate of major molecular response was higher in the MA group (89.7% vs 63.8% in YA and 75.8% in EL, p=0.001). The number of events (permanent discontinuation due to toxicity, primary or secondary resistance, any death for CML related or unrelated causes) was lower in the MA group [8 (11.1%) vs 21 (34.4%) in YA and 28 (37.8%) in EL, p=0.001]: no difference was observed in the rate of evolution to blastic phase [3 (4.9%) in YA, 1 (1.4%) in MA and 2 (2.7%) in EL, p=0.478] . The number of deaths was higher in the EL group [12 (16.2%) vs 2 (3.2%) in YA and 0 in MA, p 〈 0.001]: it is worth of note, however, that 11/12 deaths in the EL group were not related to CML progression. The 4-year event-free survival (EFS) for the whole cohort was 73.5% (95%CI 67.0 - 80.0): the 4-year EFS in the MA group [92.0% (95%CI 85.1 - 98.9)] was significantly higher than in YA group [67.3% (95%CI 55.1 - 79.5)] and in EL group [61.1% (95%CI 49.5 - 73.7)] (p=0.001). The 4-year overall survival (OS) for the whole cohort was 94.4% (95%CI 90.9 - 97.9): the 4-year OS in the EL group [72.4.% (95%CI 56.9 - 87.9)] was significantly lower than in YA group [96.3% (95%CI 91.2 - 100)] and in MA group (100%) (p 〈 0.001). In conclusion, age at diagnosis influences significantly the course of CML patients treated with imatinib: the MA group has the best follow-up with an excellent OS and EFS, while the relatively lower OS and EFS in the EL group are clearly related to the incidence of unrelated deaths like in the general aged population. A possible explanation of the counterintuitive worse course of YA group is the delayed diagnosis in these patients (higher WBC counts, lower Hb levels, higher rate of spleen enlargement 〉 5 cm) compared to aged patients, who have often concomitant diseases and make routinely blood analyses: however, a more aggressive biology of CML in YA could not be excluded and warrants further investigations. Disclosures No relevant conflicts of interest to declare.

Abstract: From November 2012 to July 2014, brentuximab vedotin (BV) was available in Italy for patients with relapsed systemic anaplastic large cell lymphoma (ALCL) outside a clinical trial context based on a local disposition of the Italian Drug Agency (AIFA) issued according to a national law (Law 648/96: "medicinal products that are provided free of charge on the national health service"). A large Italian observational retrospective study was conducted on the use of BV in the everyday clinical practice to check if clinical trial results are confirmed even in a real life context. Primary endpoint was the best response; secondary endpoints were the overall response rate at the end of the treatment, duration of response, survival and the safety profile. BV was infused intravenously at the dose of 1.8 mg/kg every 3 weeks for a maximum of 16 cycles. A total of 40 ALCL (18 anaplastic lymphoma kinase [ALK] negative and 22 ALK-positive status) patients were treated with BV in 40 Hematology Centers. All patients had histologically documented CD30+ ALCL; 16 (40%) had relapsed and 24 (60%) had refractory disease. Patients were heavily pretreated with a median of 2 previous therapies (including autologous transplant in the 32.5% of cases). Best response was observed after a median of 4 cycles in 31 patients (77.5%): 19 (47.5%) patients obtained a complete response (CR) and 12 (30%) achieved a partial response (PR); overall response rate at the end of the treatment was 62.5% (18 CR and 7 PR). The best response rate was higher in the elderly subset ( 〉 60 years): 9 (64.2%) CR and 3 (21.4%) PR, achieving a total of 85.6%. At the latest follow up 15/18 patients are still in CR (3 with consolidative procedure). Global progression free survival was 39.1% at 29 months and disease free survival 54% at 23.9 months (median not reached). Median duration of response was 12 months (range 9-24 months). We identified 5 long term responders (patients with a response ≥ 12 months), all were still in CR at the latest follow up (1 underwent allogeneic transplant). Particularly, all the long term responders were aged 〈 30 years at first BV infusion. All patients were included in the safety profile for the analysis; in general, the treatment was well tolerated even in this real life context and the toxicity profile was closely similar to the previously published data; no death has been linked to BV toxicity. Toxicity was primarily neurological and rarely so serious as to require treatment reduction or interruption; furthermore, neurological toxicity always reversed completely after end of treatment. No long-term toxicity was assessed during the follow-up period, even in patients later subjected to transplant consolidation. BV induces clinical responses quite rapidly, i.e. within the first 4 cycles in most responders, thus permitting the timely application of the transplantation phase. Furthermore, BV displays a favorable toxicity profile, without overlapping toxicities with most of the agents employed in high-dose conditioning regimens. For patients ineligible for transplant or for who transplant failed, BV may represent a feasible effective therapeutic option in everyday clinical practice. Disclosures Rusconi: Takeda: Consultancy; Teva: Consultancy, Other: Congress attendance; Janssen: Consultancy, Other: Congress attendance. Spina:Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Zinzani:Abbvie: 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; Roche: Membership on an entity's Board of Directors or advisory committees.