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Background and aims Anagrelide is a drug effective in reducing platelet counts in essential thrombocythemia (ET) and Ph1-negative myeloproliferative neoplasms. The aim of this study was to evaluate the real-life use of anagrelide in patients with ET followed over 25 years at the Haematological Institutes belonging to "Ph1-negative Myeloproliferative Neoplasms Latium Group." Patients and methods Eligibility criteria were diagnosis of ET and treatment with anagrelide. Data were collected through an ad hoc case report form. Results One hundred and fifty patients received anagrelide for a median time of 7.4 years (0.1-23.2). Anagrelide was administered as first-line therapy in 34.7% of patients, as second-line in 52% and as third-line in 13.3%: 85.4% responded to therapy. Sixty-eight/136 evaluable patients reported side effects: palpitations, peripheral vasodilation, anaemia, diarrhoea and gastric distress. Fourteen thrombotic (arterial 10, venous 4) and 51 bleeding events (minor 48, major 3) occurred. Sixteen/150 (10.6%) patients developed secondary myelofibrosis and 3/150 (2%) an acute myeloid leukaemia. Conclusions In our experience, anagrelide is an effective drug in reducing platelet levels in a high percentage of patients with ET. It is especially addressed to younger people. A careful assessment of the thrombotic risk and monitoring of cardiac function, at diagnosis and during follow-up, is mandatory.

Deferasirox (DFX) is used for the management of iron overload (IOL) in many haematological malignancies including myelofibrosis (MF). The ‘RUX-IOL’ study retrospectively collected 69 MF patients treated with ruxolitinib (RUX) and DFX for IOL to assess: safety, efficacy in term of iron chelation response (ICR) and erythroid response (ER), and impact on overall survival of the combination therapy. The RUX–DFX therapy was administered for a median time of 12.4months (interquartile range 3.1–71.2). During treatment, 36 (52.2%) and 34 (49.3%) patients required RUX and DFX dose reductions, while eight (11.6%) and nine (13.1%) patients discontinued due to RUX- or DFX-related adverse events; no unexpected toxicity was reported. ICR and ER were achieved by 33 (47.8%) and 32 patients (46.4%) respectively. Thirteen (18.9%) patients became transfusion-independent. Median time to ICR and ER was 6.2 and 2months respectively. Patients achieving an ER were more likely to obtain an ICR also (p=0.04). In multivariable analysis, the absence of leukocytosis at baseline (p=0.02) and achievement of an ICR at any time (p=0.02) predicted improved survival. In many MF patients, the RUX–DFX combination provided ICR and ER responses that correlated with improved outcome in the absence of unexpected toxicities. This strategy deserves further clinical investigation.

Spleen enlargement, present in 10-20% of Essential Thrombocythemia (ET) patients at diagnosis, is a feature clinically easy to assess, confirmable by echography with a very low chance of misinterpretation. Nonetheless, the clinical and prognostic role of splenomegaly has been seldom evaluated. From 1979 to 2013, 1297 ET patients retrospectively collected in the database of the Lazio Cooperative Group and Bologna University Hospital were evaluable for spleen enlargement at diagnosis and included in the analysis. On the whole, spleen was enlarged in 172/1297 (13.0%) patients; in most cases (94.8%) splenomegaly was mild (≤5 cm). Patients with splenomegaly were younger, predominantly male, presented higher platelet count and JAK2V617F allele burden and had a lower incidence of concomitant cardiovascular risk factors. At least one thrombotic event during follow-up occurred in 97/1,125 (8.6%) patients without spleen enlargement compared to 27/172 (15.7%) patients with spleen enlargement (P = 0.003). Despite comparable use of cytoreductive/antiplatelet therapies in the two groups, the cumulative risk of thrombosis at 5 years was significantly higher in patients with baseline splenomegaly (9.8% versus 4.4% in patients without splenomegaly, P = 0.012). In multivariate analysis exploring risk factors for thrombosis, splenomegaly retained its negative prognostic role, together with previous thrombosis, leucocyte count and male gender. Baseline splenomegaly seems to be an independent additional risk factor for thrombosis in nonstrictly WHO-defined ET patients. This data could be useful in the real-life clinical management of these patients.

Introduction: Deferasirox (DFX) is the currently available iron-chelation therapy (ICT) for the management of iron overload (IOL), mainly in myelodysplastic syndromes; recently, two retrospective independent studies (Di Veroli, 2018; Elli, 2019) demonstrated that a treatment with DFX is feasible and effective also in the setting of myelofibrosis (MF). However, no data are still available regarding the concomitant use of DFX in patients (pts) treated with Ruxolitinib (Rux). Aims and Methods: We retrospectively collected in 16 Italian Centers 59 pts (M: 37; F: 22) with primary MF (n=41) or post-Polycythemia Vera (n=9) and post-Essential Thrombocythemia (n=9) MF, treated with Rux and DFX for the management of IOL secondary to transfusion-dependent anemia. Primary endpoint of the study was to evaluate the efficacy of DFX in terms of reduction of ferritin levels and hematological improvement (HI). Additional endpoints were the safety of DFX associated to Rux treatment and the impact on survival and leukemic evolution. Results: The main features of pts at diagnosis and at baseline of DFX treatment are reported in Table 1 (column A). Pts started DFX after a median time from MF diagnosis of 26.7 months [Interquartile range (IR) 2.6-240.9] and from transfusion dependency of 13.5 months (IR 1.5 - 145.3). Forty-eight pts started DFX when already under Rux treatment, while 11 pts before Rux treatment. The median ferritin level (FL) at baseline was 1675 ng/mL (IR 646-6447). The median starting dose of DFX was 1000 mg/day (12.5 mg/kg/day). All pts were evaluable for DFX response (> 3 months of DFX), with a median time of DFX and Rux exposure of 14.5 months (IR 3.2-73.3) and 40 months (2.1-88.6), respectively; the median period of concomitant DFX-Rux treatment was 11.1 months (3.7-58.4). As to ICT efficacy, 24 pts (40.7%) obtained an iron chelation response (ICR), defined as a stable reduction of FL < 1.000 ng/mL or a reduction ≥ 50% of FL respect to baseline. The main variables analyzed in pts with ICR or no ICR were reported in Table 1 (Column B and C, respectively). At univariate analysis, pts who obtained ICR did not presented significant differences compared to pts without ICR, except for a significantly lower median FL at diagnosis (251 vs 496 mcg/l, p=0.008). As expected, ICR pts showed a progressive significant reduction of FL at 3, 6, 12 and 18 months, respect to baseline, in contrast to pts without ICR (p < 0.0001). The median time of exposure to DFX was higher in ICR vs no ICR group (22.0 vs 12.9 months, p=0.03), as well as the median time of concomitant DFX-Rux treatment (14.2 vs 9.7 months, p=0.019). The International Working Group criteria (Cheson, 2006) were applied to assess HI during ICT. Erythroid response (ER) was defined as complete (CR: achievement of transfusion independency), partial (PR: reduction in the transfusion requirement ≥ 50% and/or increase of haemoglobin levels) or no response (NR). ER was observed in 25 pts (42.4%) with ten (17%) obtaining CR, 15 (25.4%) PR and 34 (57.6%) NR. Obtainment of ICR predicted for the achievement of ER: 17 (70.8%) pts with ICR achieved CR or PR compared to 8 (22.8%) without ICR (p =0.0007). DFX-related toxicities occurred in 30 pts (50.8%) and consisted mainly in renal impairment (32.2%), liver enzymes alterations (6.7%) or epigastric pain (8.4%): however, only in one case was observed a grade 3 toxicity. Overall, a dose reduction/temporary discontinuation related to DFX-toxicity was reported in 14 (23.7%) pts; however only 5 (8.4%) pts completely discontinued ICT because of grade ≥ 2 toxicity. After a median follow-up from diagnosis of 58.6 months (IR 7.1-282.9), 19 pts (32.2%) died [13 of them (22%) for leukemic evolution or disease progression]. The 3-year cumulative overall survival (Figure 1) and the 3-year cumulative incidence of leukemic evolution (Figure 2) from DFX initiation were 75.1% (95%CI 55.6 - 94.6) and 20.2% (95%CI 2.1 - 38.3) in pts who obtained ICR compared to 54.5% (95%CI 31.9 - 77.1) and 36.1% (95%CI 13.1 - 59.1) in pts without ICR, respectively (p=0.13 and p=0.153). Conclusions: The present multicenter study showed that ICT with DFX is effective and safe also in this setting of pts receiving concomitant Rux treatment. HI with ER seems occur in a significant proportion of pts and correlates with the achievement of ICR. Further larger and prospective investigations are required in order to evaluate the impact on survival and leukemic evolution of this combination. Disclosures Elli: Novartis: Membership on an entity's Board of Directors or advisory committees. Iurlo:Novartis: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria. Benevolo:Novartis Pharmaceuticals: Consultancy. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Bonifacio:Novartis: Honoraria; Amgen: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Cilloni:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Tiribelli:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Trawinska:Novartis: Consultancy, Honoraria. Breccia:BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Palumbo:Janssen: Honoraria; Celgene: Honoraria; Teva: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Hospira: Honoraria. Latagliata:Celgene: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Pfizer: Honoraria.

Background and Objectives While tyrosine kinase inhibitors (TKIs) have transformed CP-CML management, limited data exist on their use in clinical practice. Methods SIMPLICITY (NCT01244750) is an observational study in CP-CML patients, exploring first‑line (1L) TKI use and management patterns in the US and Europe. Over half of the patients recruited in Europe are from Italy (n=266). This is an analysis of the Italian cohort and a comparison with the rest of the European SIMPLICITY population. Baseline demographic, factors influencing choice of first-line TKI, response monitoring patterns and predictors of monitoring, and treatment interruptions, discontinuations and switching by index TKIs are presented for the Italian cohort in the first year of treatment and compared with that for the overall European SIMPLICITY cohort. Results Italian patients received 1L imatinib (IM; retrospective [(n=31]; prospective [n=106]), dasatinib (DAS; n=56) or nilotinib (NIL; n=73). Documented cytogenetic response monitoring by 12 months was lower than expected, but almost all patients had documented molecular response monitoring. Fewer patients discontinued first-line TKI by 12 months in Italy compared with the rest of the European SIMPLICITY population (p=0.003). Of those with ≥12 months follow-up since start of 1L TKI, only 7.1% (n=19) of Italian patients switched to a second-line TKI, a third less than in the rest of the European SIMPLICITY population. Of interest, intolerance as opposed to resistance, was the main reason for switching. Conclusion This analysis provides valuable insights into management and treatment patterns in Italian patients with CML within routine clinical practice.

To identify prognostic factors affecting thrombosis-free survival (TFS) and overall survival (OS), we report the experience of a Regional cooperative group in a real-life cohort of 1,144 patients with essential thrombocythemia (ET) diagnosed from January 1979 to December 2010. There were 107 thrombotic events (9.4%) during follow-up [60 (5.3%) arterial and 47 (4.1%) venous thromboses]. At univariate analysis, risk factors for a shorter TFS were: age >60 years (P 60 years (P 15 × 109/l (P = 0.0370) were independent risk factors. Previous thrombotic events in ET patients are crucial for TFS but their importance seems related not to the occurrence per se but mainly to the interval between the event and the diagnosis. Am. J. Hematol. 89:542–546, 2014. © 2014 Wiley Periodicals, Inc.

Aim of this study is to explore the role of different treatments on the development of secondary malignancies (SMs) in a large cohort of essential thrombocythemia (ET) patients. We report the experience of a regional cooperative group in a real‐life cohort of 1026 patients with ET. We divided our population into five different groups: group 0, no treatment; group 1, hydroxyurea (HU); group 2, alkylating agents (ALK); group 3, ALK + HU sequentially or in combination; and group 4, anagrelide (ANA) and/or α‐interferon (IFN) only. Patients from groups 1, 2, and 3 could also have been treated either with ANA and/or IFN in their medical history, considering these drugs not to have an additional cytotoxic potential. In all, 63 of the 1026 patients (6%) developed 64 SM during the follow‐up, after a median time of 50 months (range: 2–158) from diagnosis. In univariate analysis, a statistically significant difference was found only for gender (P = 0.035) and age (P = 0.0001). In multivariate analysis, a statistically significant difference was maintained for both gender and age (gender HR1.7 [CI 95% 1.037–2.818] P = 0.035; age HR 4.190 [CI 95% 2.308–7.607] P = 0.0001). The impact of different treatments on SMs development was not statistically significant. In our series of 1026 ET patients, diagnosed and followed during a 30‐year period, the different therapies administered, comprising HU and ALK, do not appear to have impacted on the development of SM. A similar rate of SMs was observed also in untreated patients. The only two variables which showed a statistical significance were male gender and age >60 years.

To evaluate the prognosis of patients with Essential Thrombocythemia (ET) in the first decade of the century we assessed retrospectively the thrombosis free survival (TFS) and the overall survival (OS) of the patients diagnosed from 01/01/2000 to 31/12/2009 and collected in the database of our group. The diagnosis of ET was performed with PVSG, WHO 2001 or WHO 2008 criteria, according to the period of the first observation. The whole population of 757 patients was then divided in two groups: the first (group I) with the diagnosis performed between 01/01/2000 to 31/12/2005 (334 patients) with a median follow-up of 111,9 months, the second (group II) diagnosed between 01/01/2006 to 31/12/2009 (385 patients) with a median follow-up of 58,2 months. The main clinical features of the two groups of patients are reported in the Table 1. No difference was observed between the two groups as to age, gender, platelet and WBC count, Hb level, Cardio-Vascular Risk Factors (CVRF), spleen enlargement and occurrence of previous thrombotic events. The frequency of the JAK-2 V617F mutation resulted significantly different (49.1% vs 68.4%) but in the group I the search of the mutation was never performed at the diagnosis. The TFS and OS were calculated from the date of diagnosis to the date of any appropriate event or to the date of last follow-up with Kaplan-Meier product limit method; the comparison of proportions and median values was computed with the Chi-squared and the Mann-Withney tests, as indicated. No significant difference emerged neither for TFS (p= 0,09, HR 1,42, 95% C.I. 0.89-2.30) nor for OS (p= 0,15, HR 1,34, 95% C.I. 0,87-2,06). We also considered the type of treatment used in the two groups to assess the potential link between the therapy and TFS or OS. No difference emerged between the two groups as to anti-aggregating treatment (mainly ASA), equally utilized in both groups [287/369, 77,8%, and 330/383, 78,3%, respectively (p = 0,95)]. As for the cyto-reductive therapy, Hydroxyurea was used in 74.8% vs 67.9% (p= 0.60) and alkylating agents in 1.9% vs 2.1% (p= 0.85), whereas Anagrelide was used in 10,6% vs 3,9% (p= 0,001) and Interferon in 9,5% vs 5,2% (p= 0,037), respectively. This more frequent use of Anagrelide and Interferon in the first group (2000-2005) did not modify TFS and OS of the patients. In conclusion, no improvement was observed in the prognosis of ET patients in the recent years: thus, new efforts to identify patients at risk and the introduction of new drugs as JAK-2 inhibitors are warranted to improve the prognosis of these patients. Table Table. Disclosures Breccia: Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Honoraria; Ariad: Honoraria. Cimino:Celgene: Honoraria; Bristol-Mayer: Honoraria. Lo Coco:Pfizer: Consultancy; Baxalta: Consultancy; Novartis: Consultancy; Lundbeck: Honoraria, Speakers Bureau; Teva: Consultancy, Honoraria, Speakers Bureau. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria.

Dasatinib (DAS) has been licensed for the frontline treatment in chronic myeloid leukemia (CML). However, very few data are available regarding its efficacy and toxicity in elderly patients with CML outside clinical trials. To address this issue, we set out a "real-life" cohort of 65 chronic phase CML patients older than 65 years (median age 75.1 years) treated frontline with DAS in 26 Italian centers from June 2012 to June 2015, focusing our attention on toxicity and efficacy data. One third of patients (20/65: 30.7%) had 3 or more comorbidities and required concomitant therapies; according to Sokal classification, 3 patients (4.6%) were low risk, 39 (60.0%) intermediate risk, and 20 (30.8%) high risk, whereas 3 (4.6%) were not classifiable. DAS starting dose was 100 mg once a day in 54 patients (83.0%), whereas 11 patients (17.0%) received less than 100 mg/day. Grade 3/4 hematologic and extrahematologic toxicities were reported in 8 (12.3%) and 12 (18.5%) patients, respectively. Overall, 10 patients (15.4%) permanently discontinued DAS because of toxicities. Pleural effusions (all WHO grades) occurred in 12 patients (18.5%) and in 5 of them occurred during the first 3 months. DAS treatment induced in 60/65 patients (92.3%) a complete cytogenetic response and in 50/65 (76.9%) also a major molecular response. These findings show that DAS might play an important role in the frontline treatment of CML patients >65 years old, proving efficacy and having a favorable safety profile also in elderly subjects with comorbidities.

At present, very few data are available on deferasirox (DFX) in the treatment of patients with Philadelphia-negative myeloproliferative neoplasms in fibrotic phase (FP-MPN) and transfusion dependence. To address this issue, a retrospective analysis of 28 patients (22 male and 6 female) with FP-MPN and iron overload secondary to transfusion dependence was performed, based on patients enrolled in the database of our regional cooperative group who received treatment with DFX. DFX was started after a median interval from diagnosis of 12.8 months (IR 7.1-43.1) with median ferritin values of 1415 ng/mL (IR 1168-1768). Extra-hematological toxicity was reported in 16 of 28 patients (57.1%), but only two patients discontinued treatment due to toxicity. Among 26 patients evaluable for response (≥6 months of treatment), after a median treatment period of 15.4 months (IR 8.1-22.3), 11 patients (42.3%) achieved a stable and consistent reduction in ferritin levels1000 ng/mL. As for hematological improvement, 6 of 26 patients (23%) showed a persistent (3 months) rise of Hb levels1.5 g/dL, with disappearance of transfusion dependence in four cases. Treatment with DFX is feasible and effective in FP-MPN with iron overload. Moreover, in this setting, an erythroid response can occur in a significant proportion of patients.

Thrombotic events are major complications in patients (pts) affected by Essential Thrombocytemia (ET) and Polycytemia Vera (PV). To compare thrombotic risk in these 2 groups, we evaluated retrospectively our database of 1249 ET and 623 PV pts diagnosed and followed in 11 hematological centers in the Latium region between 1/1980 and 12/2010: the diagnosis was done according to PVSG, WHO 2001 and 2008criteria based on the time of first observation. Baseline features of ET pts: 797F/452M,median age 62.9 yrs (range 19-96),median WBC count 8.8 x 109/L (range 1.2-57.7), median PLT count 812 x 109/L (range 457-3582), median Hb level 14.0 g/dl (range 6-20.5), JAK-2V617F positivity 59.7% with a median allele burden of 19,6% (range 0.2- 99.9), spleen enlargement in 18.7% of pts, previous thrombosis223/1239 evaluable pts (17.9%) [arterial 176/223 (14.1%), venous 47/223 (3.8%)]. Baseline features of PV pts: 289F/334M, median age 63.0yrs (range 21-91), median WBC count 10.1 x 109/L (range 3.5-37.6), median PLT count 457 x 109/L (range 169-1790), median Hb level 18.2 g/dl (range 10.5-24.8), JAK-2V617F positivity 94.3% with a median allele burden of 59.1% (range 0.3-99.9), spleen enlargement in 42% of patients, previous thrombosis 146/617 evaluable pts (23.7%)[arterial 114/617 (18.5%), venous 32/617 (5,2%)].in the ET cohort, after a median follow-up of 7.7 yrs, thrombotic complications were seen in 107/1141 evaluable pts (9.4%) [arterial60 (5.25%), venous 47 (4.11%)]; in the PV cohort, after a median follow-up of 8.5 yrs, thrombotic complications were seen in 107/623pts (17.2%) [arterial 67 (10.8%),venous 40 (6.4%)].All common risk factors for thrombosis were evaluated in multivariate analysis, searching the cut-off number for continuous variables with ROC curves. The significant variables at multivariate analysis for ET and PV pts are shown in the table; age, previous thromboses and spleen enlargement were risk factors in ET pts, while previous thromboses and JAK-2V617F allele burden were risk factors in PV pts. PLT count above ROC value seemed to be a protective factor in both cohorts. In conclusion, in contrast with the tendency to evaluate in a similar manner the thrombotic risk of PV and ET, data from our retrospective database showed that these 2 groups should be considered populations with different risk factors for thrombosis. Table 1.Putative prognostic factorsPolycythemia VeraEssential ThrombocythemiaHR95% C.I.pHR95% C.I .pPrevious thromboses2,311,13 - 4,740,021,871,08 -3,230,026Age ≥ 60 y1,540,79 - 2,990,211,901,18 - 3,060,009JAK2V617FPV: allelic burden ≥ 81% ET: pos1,951,03 - 3,710,040,760,48 - 1,210,25Plt countPV ≥ 452.109/L ET ≥ 944.109/L0,490,25 - 0,950,040,520,31 - 0,890,017Spleen enlargement0,670,34 -1,310,241,711,02 - 2,890,04CV risk factors (at least 1)0,920,41 - 2,030,830,870,51 - 1,490,62WBCPV ≥ 10,175.109/L ET ≥ 9,630.109/L1,090,57 - 2,080,801,410,89 -2,260,15 Disclosures No relevant conflicts of interest to declare.

INTRODUCTION: Essential Thrombocytemia (ET) is the most common of the myeloproliferative neoplasms, vascular complications contribute mostly to both morbidity and mortality. The ability to identify thrombotic risk of the individual patient is necessary for a correct therapeutic management. Traditionally, risk stratification for thrombosis in ET pts was based on the respective absence and/or presence of either age >60 years or history of thrombosis. Recently, the IPSET score (International Prognostic Score Of Thrombosis for ET) was developed to better predict the occurrence of thrombotic events in ET patients. Risk factors included in the new score were: age, cardiovascular risk factors, previous thrombosis, presence of JAK 2 V617F mutation. AIM: to evaluate the validity of IPSET-thrombosis score in a cohort of ET patients from "Gruppo Laziale for Myeloproliferative Ph negative Neoplasms" in predicting thrombosis incidence. METHODS: from January 1978 to December 2011 we observed 1249 ET patients, median follow up was 105 months (range 12.1-417.7). We were able to retrospectively evaluate all the IPSET risk factors in 680 ET patients and estimated the clinical implication of the IPSET-thrombosis score system. According to the score 27.3 %, 19.1% and 53.5% of pts were stratified in low, intermediate and high risk group respectively. RESULTS: median age at the time of diagnosis was 61.8 yrs (range 19.9 -94; 64% females), median hemoglobin was 14 g/dl (range 6-20); median leukocyte count was 8.8 x 109/L (range 1,2-57); median platelets count was 812x 109/L (range 108-3582). We observed, during a median follow-up of 200 months, 82 thrombotic events (total incidence 17,89 %). According IPSET-thrombosis risk, in our ET population was documented a statistically different thrombosis free survival (TFS) (Gray test 0.1316): 85%, 78%, 77% in low,intermediate and high risk group respectively. During all the observation period the intermediate and high risk group showed a similar probability of thrombotic events. CONCLUSIONS: in our retrospective study the IPSET score was able to differentiate the rate of thrombosis events in low-risk (0-1 risk factors) from that of intermediate (>= 2 risk factors) and high risk (>= 3 risk factors) ET pts. Unfortunately the intermediate and high risk groups show a similar incidence of thrombotic events during the whole observation period. We were not able to verify the clinical benefit resulting from the different treatment strategies. Because treatment options in ET pts are tailored according to thrombotic risk, and since we have specified therapeutic indications for patients with low and high risk, it is necessary to validate the score IPSET in a large prospective, long term study to discriminate a true "intermediate" subset of patients for which there are no currently defined therapeutic guidelines. Disclosures No relevant conflicts of interest to declare.

The protective effect of higher platelet count at diagnosis of Essential Thrombocythemia (ET) was reported in some papers (Carobbio A. 2011, Palandri F. 2012, Montanaro M., 2014). As at our knowledge, there is no study specifically addressing this point; in this retrospective analysis we have examined 1201 ET patients (pts) followed in 11 Hematological centers of our region from 1/1978 to 12/2010. The diagnosis of ET was made with PVSG, WHO 2001 and WHO 2008 criteria, respectively, according to the period of 1st observation. The main features of our cohort were as follows: median age 62,9 yrs (19-96), male/female 435/766 (36.2%/63.8%), median WBC count 8,8 x 106/L (1.2-57.7), median Hb level 14.0 g/dl (6.0-20.5), median platelet count 813 x 106/L (457-3582), JAK-2V617F mutation in 498/834 performed pts (59,7 %) with a median allele burden of 19.6% (0.2-99.9%), spleen enlargement in 226 pts (18.7%), previous thrombosis in 17.9% of pts (arterial 14.1%, venous 3.8%). The median follow-up of the entire cohort was 7.75 yrs. Thrombosis-free survival curves were plotted according to Kaplan-Meier method and independent risk factors were identified with the Cox proportional-hazards method. At the multivariate analysis, negative prognostic factors for TFS resulted: previous thrombotic events (p= 0.012), age ≥60 yrs (p= 0.008) and spleen enlargement (p= 0.039): on the contrary, platelet count ≥ 944.109/L resulted a protective factor for TFS [p= 0.031 with an HR 0,57 (C.I. 95% 0,35-0,95)]. Receiver operating characteristic (ROC) analyses based on thrombotic events during follow-up were used to identify the baseline platelet count of 944 x 109/L as the best threshold for predicting thrombotic events. Thrombotic events according to this cutoff were 40/384 (10.3%) in pts with platelet count ≥ 944 x 109/L and 109/817 (13.3%) in pts with platelet count < 944 x 109/L. The sites of thrombosis are reported in the table. A comparison of the main features in these two populations showed that pts with PLT count < 944 x 109/L were older (median age 60.4 yrs vs 57.1 yrs, p= 0.016), had a lower median WBC count (8.8 x 109/L vs 10.6 x 109/L, p< 0.0001), an higher median Hb level (14.1 g/dL vs 13.6 g/dL, p< 0.0001) and an higher rate of JAK-2V617F mutation (67.2% vs 41.6%, p< 0.0001); no differences were observed between the two groups as to thrombotic events before diagnosis, spleen enlargement and cardiovascular risk factor (p=NS). As to the treatment, both groups resulted equally treated with anti-aggregant agents (84,6% vs 87,4%, p= 0,76) while in pts with platelet count Disclosures No relevant conflicts of interest to declare.

To predict leukemic transformation (LT), we evaluated easily detectable diagnostic parameters in 338 patients with primary myelofibrosis (PMF) followed in the Latium region (Italy) between 1981 and 2010. Forty patients (11.8%) progressed to leukemia, with a resulting 10-year leukemia-free survival (LFS) rates of 72%. Hb (

Background Dasatinib has been recently licensed for first line treatment of patients with chronic myeloid leukemia (CML). However, very few data are available as to toxicity and efficacy of dasatinib in unselected elderly CML patients. Aim To address this issue, we revised a “real-life” cohort of 43 CML patients in chronic phase aged > 65 years treated with frontline dasatinib in 19 Italian Centers from 6/2012 to 6/2014 focusing on toxicity and efficacy data. Methods The main clinical features of the patients at diagnosis were as follows: M/F 20/23 (46.5%/53.5%), median age 75.2 years [interquartile range (IQR) 70.3 – 79.8), median Hb 12.5 g/dl (IQR 11.0 – 13.7), median WBC 57.7 x 109/l (IQR 29.5 – 100.0), median PLTS 466 x 109/l (IQR 249 – 758). According to Sokal risk classification, 3 patients (6.9%) were low risk, 26 (60.4%) intermediate risk, 10 (23.2%) high risk while 4 (9.5%) were not classificable. 20/43 patients (46.5%) had ≥ 2 comorbidities requiring concomitant therapies: according to ECOG scale, performance status at baseline was 0 – 1 in 36 patients (83.7%) and 2 in 7 patients (16.3%). Results Median interval from diagnosis to dasatinib start was 23 days (IQR 14 – 32). Dasatinib starting dose was 140 mg/day in 1 patient (2.3%), 100 mg/day in 33 patients (76.7%) and < 100 mg/day in 9 patients (21.0%), respectively. After a median period of treatment of 9.7 months (IQR 4.3 – 17.5) all patients were evaluable for toxicity; on the whole, grade 3 – 4 hematological and extra-hematological toxicities were reported in 4 (9.3%) and 6 (13.9%) patients, respectively. Overall, 7 patients (16.2%) permanently discontinued dasatinib due to toxicity (2 patients in the first 3-month period of treatment and 5 beyond that period). Pleural effusions of all WHO grades occurred in 7 patients (16.2%): in 2 of them the pleural effusion occurred during the first 3-month period of treatment. As to treatment efficacy, 6 patients were considered too early to be evaluated (< 3 months of treatment) and 37 were evaluable for cumulative response; on the whole, 33/37 patients (89.1%) achieved complete cytogenetic response (CCyR) and 23/37 (62.1%) also a major molecular response (MMolR). Response to treatment at different time-points is shown on | | 3rd month | 6th month | 12th month | | ------------------------------------------------------ | -------------------- | --------------------- | --------------------- | | Not evaluable: Too early Not performed | 11 6 5 | 13 11 2 | 19 19 0 | | Evaluable | 32 | 30 | 24 | | Discontinuation | 2 (6.2%) | 4 (13.3%) | 6 (25%) | | Less than CCyR | 6 (18,7%) | 2 (6.7%) | | | CCyR only | 17 (53.1%) | 5 (16.6%) | 4 (16.6%) | | MMolR | 7 (21.9%) | 19 (63.3%) | 14 (58.4%) | Table. Conclusions Present data shows that dasatinib could have a major role in the treatment of unselected patients aged > 65 years; indeed, dasatinib seems very effective and has a favourable safety profile also in elderly subjects with comorbidities. Disclosures Latagliata: Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Shire: Consultancy. Gugliotta: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Breccia: novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy.

Background Deferasirox (DFX) is an oral iron chelator widely employed to reduce iron overload in patients with myelodysplastic syndromes; in this subset, an unexpected hematological improvement (HI) has been reported in about 20% of cases by several groups. At present, only few case reports showed a similar HI in patients with Ph- Myeloproliferative Neoplasms (MPN) and transfusional requirement receiving DFX treatment. Aim To address the incidence of HI during DFX treatment in MPN patients, we revised all patients with MPN and iron overload secondary to transfusional requirement enrolled in the database of our regional cooperative group who received a treatment with deferasirox. Methods Twenty-eight patients [M/F 22/6, median age at diagnosis 68.8 years, interquartile range (IQR) 63.2 – 74.3] were reported in the database. Of them, 25 had a primary Myelofibrosis, 2 a post Essential Thrombocythemia myelofibrotic phase (MP) and 1 a post Polycythemia Vera MP. An HI was considered as a rise in Hb values ≥ 1.5 g/dl and/or a reduction in the transfusional requirement ≥ 50% lasting at least 3 months. Results Treatment with DFX was started after a median interval from diagnosis of 12.8 months (IR 7.1 – 43.1) and from transfusion requirement of 10.0 months (IR 5.7 – 15.9). Median Hb and ferritin values at baseline were 7.8 g/dl (IQR 7.2 – 8.4) and 1,415 ng/ml (IQR 1,168 – 1768), respectively. Starting DFX dose was 1,500 mg/day in 13 patients, 1,250 mg/day in 5 patients, 1,000 mg/day in 9 patients and 3 months) rise of Hb levels > 1.5 g/dl, with disappearance of transfusional requirement in 4 cases and reduction ≥ 50% in the remaining 2 cases. The main clinical features of these 6 patients at DFX initiation and at HI are reported in the Table. Table 1.GenderAge (yrs)Months from diagnosisMonths from transfusionsHb (g/dl)Ferritin (ng/ml)Hb at HI (g/dl)Ferritin at HI (ng/ml)Months to HI# 1M68.7101.545.28.21,59010.127218# 2M67.513.313.28.7130911.265912# 3M77.29.86.08.017909.6168212# 4F76.721.715.39.1121410.5104112# 5M71.86.94.66.8264110.884924# 6M67.179.46.78.070610.05006 The HI was achieved together with a reduction of ferritin levels in 4 cases, while it was independent by ferritin response in the remaining 2 cases. To identify factors predicting the achievement of HI, many features at baseline (age, gender, Hb and ferritin levels, interval from diagnosis to DFX treatment) were compared between patients obtaining or not HI: however, none of them showed a significant role. Conclusions Treatment with DFX is feasible and effective in MPN with iron overload. Moreover, it is worth of note and deserves further biological and clinical insights that also in this setting an hematological improvement can occur in a sizeable rate of patients. Disclosures Latagliata: Novartis: Consultancy; Bristol Myers-Squibb: Consultancy; Celgene: Consultancy; Shire: Consultancy. Breccia:Celgene: Consultancy; BMS: Consultancy; novartis: Consultancy.

Polycythemia Vera (PV) is a myeloproliferative neoplasm characterized by trilinear marrow expansion and an increased susceptibility to thrombo-embolic complications. Data of 623 patients (pts) followed in 11 Hematological centers of our region from 1978 to December 2010 were collected in our database. The diagnosis was made according to PVSG criteria, WHO 2001 and 2008 criteria, respectively, based on the year of diagnosis. The main epidemiological and clinical features of all pts are reported in table. Of 623 pts, 161( 25,8%) died, 87 (13,9%) were lost to follow up and 375 (73,1%) were alive at the time of evaluation. The median follow up was 8.5 years. The thrombotic events during follow-up were 107 (17,2% of 622 evaluable pts): the arterious events were 67 (10.8%), the venous were 40 (6,4 %). The rate of thrombosis (patients/year) was 1,71 %. At the univariate analysis, the risk factors for thrombosis-free survival (TFS) at diagnosis that resulted statistically significant were: age (> 60 yrs, p= 0,036), WBC (> 10.2 x 109/L, p= 0,034), previous thrombosis (p< 0,0001). The presence of cardiovascular risk factors, Hb (>18.2 g/dL), PLT count (either > 457 x 109/L or >1000 x 109/L), JAK2V617F allele burden > 59.15% and spleen enlargement, did not reach the cut-off value of significance. At multivariate analysis with the Cox proportional hazards model method, age (> 60 yrs, p= 0,049) previous thrombotic events (p< 0.0001) and platelet count < 457 x 106/L (p= 0.019) maintained an independent prognostic value (p< 0,05), while WBC count (> 10.2 x 109/L, p =0,065) did not. The risk factors significant for overall survival (OS) at univariate analysis were: age > 60 yrs (p 10.2 x 109/L (p< 0,0001), previous thrombosis (p< 0,0001). diabetes (p= 0,0008), platelet count< 457 x 109/L (p= 0.013) and spleen enlargement (p= 0.02); Hb level < 18,2 gr% showed only a trend of significance (p= 0.056), while allele burden of JAK2 > 59.15% and the presence of at least 1 CV risk factor did not reach the cut-off value of significance. At multivariate analysis, age (p< 0,0001), WBC count > 10.2 x 109/L (p< 0,0001), previous thrombosis (p= 0,0004), diabetes (p= 0.0035) and Hb level < 18,2 gr% (p= 0.0078) maintained their independent prognostic value on OS; in contrast platelet count < 457 x 109/L and spleen enlargement lost their prognostic significance. In conclusion our retrospective analysis of a large series of PV confirm the prognostic value of age and previous thrombosis on TFS and OS, while seems to exclude any impact of spleen enlargement and high Hb level. Interesting, PLT count and Hb below median value resulted as independent risk factors for TFS and OS, respectively. Table CARACTERISTICS Evaluable N. VALUE Number of patients 623 Age years: median, (range) 63 (21 - 91) Gender, F/M : number, (%) 289 (46,4) / 334 (53,6) WBC x 109/L: median, (range) 582 10,2 (3.5-37.6) Hb g/dL: median, (range) 580 18,2 (10,5-24,8) Htc ; median, range (%) 581 56 (36-78) Plt x 109/L: median, (range) 587 457 (169-1790) JAK2 V617F : mutated / performed, (%) 386 364/386 (94,3%) JAK2 V617F quantitative (%): median, (range) 252 59,15 (0,3-99,9) Splenomegaly: number, (%) 588 247/588 (42 %) Epatomegaly: number, (%) 606 167/606 (27,5%) Disclosures Breccia: novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy.

In this study, we confirm the validity of the proposed Hammersmith score, which identifies three risk categories of patients and establish its strength on a large group of 128 chronic myeloid leukemia patients treated with second-generation tyrosine kinase inhibitors (TKIs) after being resistant to imatinib. Sixty-one patients were identified as good risk group, 27 patients as intermediate risk group, and 40 patients as poor risk group. The 1-year cumulative incidence of complete cytogenetic response was 73% in good risk patients, 40% in intermediate risk patients, and 22% in poor risk patients (P = 0.0001). Event-free survival at 3-year was 89% in good risk group, 70% in intermediate group, and 54% in poor risk group (P = 0.0001); the estimated 3-year progression-free survival was 95% in good risk category, 93% in intermediate risk category, and 87% in poor risk category (P=0.05). Kaplan-Meier estimated that the 3-year overall survival was 100% in good risk category, 93% in intermediate risk category, and 82% in poor risk category (P=0.04). In conclusion, some prognostic factors before starting second-generation TKIs might predict cytogenetic response and outcome. The so-called Hammersmith score was not yet validated in large series of patients: we demonstrated that this score is able to discriminate patients at high risk of failure and consequent progression before treatment with second-generation TKIs.

Abstract 4445 Imatinib advent has provided for old CML patients too a chance for an effective treatment, aimed at complete cytogenetic and major molecular response. Indeed, a few studies reported in patients more than 65 year old a response rate comparable to that observed in younger ones. However, fluid retention, a common side effect of imatinib therapy, seems to occur more frequently in elderly patients. Indeed, periorbital and ankle oedema are common patients’ complaints, whereas pleural effusions have not been usually observed in imatinib-treated patients. Conversely, pleural effusions (usually mild to moderate) occur in about 14% of patients treated with the second generation tyrosine-kynase inhibitor (TKI) dasatinib at the optimal dosage of 100 mg by single daily administration. We conducted a retrospective survey of 181 Italian CML patients, above the age of 75, treated with imatinib for chronic phase CML. Among sixty-five patients who were more than 80 year old we observed 5 cases (7.7%) who displayed a severe (grade 3: 4 patients) or moderate (grade 2: 1 patient) pleural effusion. Conversely, such a side effect was not observed in any of the 101 slightly younger (75–80 year old) patients. The 5 patients displaying a pleural effusion were all males, 80.3 – 88.7 year old at the time of imatinib start. One patient was in late chronic phase, and had received hydroxyurea for more than 2 years before imatinib start, whereas the other 4 started imatinib therapy within 2 months from diagnosis. All 5 patients had at least one cardiovascular co-morbidity. Pleural effusion developed after 3–8 months of imatinib therapy. Pericardial effusion and peripheral oedema were also evident in two and one of the 5 patients, respectively. Imatinib was definitely discontinued in 2 patients (one of them had cytogenetically resistant disease) whereas the drug could be resumed, after a few months of interruption, in the other 3, in one case after intolerance to second generation TKI nilotinib. Three patients died: two of myocardial infarction and one for CML blastic phase at 45, 31 and 54 months, respectively, from diagnosis. Two patients are alive, one in major cytogenetic response with resumed imatinib treatment, at 12 and 30 months from diagnosis. Our survey evidenced a significant percentage of very old patients who developed a pleural effusion during imatinib treatment. Although our casistic of patients with pleural effusion is small, some differences are evident, compared to the more common dasatinib-induced pleural effusions. In the case of dasatinib, most of pleural effusions are mild, unrelated to peripheral oedema, and may have an immune-related aetiology. In our imatinib-treated patients pleural effusions were more severe and frequently accompanied by pericardial involvement. Moreover, they were restricted to very old patients and possibly correlated to cardio-vascular co-morbidities. In conclusion, although imatinib still represents the best CML treatment for most of very old patients too, these should be strictly monitored for fluid retention and possible appearance of a pleural and or pericardial effusion. Disclosures: Russo Rossi: Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Rosti:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria.

Abstract 5065 The Latium is a region of central Italy that counts approximatively 5.600.000 of residents. We reported herein a preliminary analysis of 1572 patients affected by MPN diagnosed in the last 20 years and treated in 9 of the Centers belonging to our group. Our centers are mainly located in Rome (7 centers) and neighboring districts (2 centers, Latina and Viterbo). The diagnosis was performed according to PVSG criteria until 2001 and then according to the WHO criteria: the majority of the patients underwent bone marrow biopsy. 218 patients were affected by primary myelofibrosis (PMF), 779 by Essential thrombocytemia (ET) and 575 by Policytemia Vera (PV). Epidemiological and clinical findings of all patients at diagnosis as well as thrombotic complications and evolution are reported in the table:ET (779 pts)PV (575 pts)PMF (218 pts)M/F288/491350/225134/84Age (yrs)59 (r: 20-93)60 (r: 19-91)67 (r: 30-86)WBC (x109/L)9192 (+/− 3483 SD)10423 (+/− SD 4307)13313 (+/−5220)Hb (g/dL)13, 9 (+/− 1,8)18,1 (+/− 2,3)11,7 (+/− 2,8)Plts (x 109/L)877 (+/− 353)445 (+/−247)457 (+/− 358)Splenomegaly (%)193579Bone marrow biopsy (performed/total))557/779 (71,5%)254/575 (44,2%)207/218 (95%)JAK-2 V617F mut (%)284/484 (59%)256/369 (69,4%)69/116 (59,5 %)Jak-2 allele burdenPerformed in 188/284 cases 26,49% (SD +/− 24)Performed in 199/256 cases: 59,4 % (SD +/−30,9)Performed in 51/69 cases 57,5% (SD +/− 29,4)Median Follow-up (years)7,157,863,89Thrombosis pre-diagnosis of MPNN. of patients (%)108/779 (13,8%)100/575 (17,4%)29/218 (13,3%)(arterial+venous)74+3476+2424+5Thrombosis post diagnosis of MPNN. of patients (%)71/779 (9,1%)66/575 (11,5%)20/218(9,17%)(arterial+venous)42+2942+2412+8EvolutionMyelofibrosis9/779 (1,1%)24/575 (4,1%)AML9/779 (1,1%)13/575 (2,3%)17/143 (11,8%) Comments: In our opinion, this casistic of patients with different types of MPNs reflects clinical presentation and evolution of three variants of the same disease. Many clinical findings in our unselected cohort of patients are similar to those reported in literature; in particular, thrombotic events were seen in about 13 – 17% of patients, without any correlation with Jak-2 status in both pre-diagnosis and follow-up. However, 2 main differences were noted: a lower incidence of JAK-2 V617F mutation among our PV patients and a lower rate of evolution in myelofibrosis and AML among our ET and PV patients. Both these features warrant further insights to be fully elucidated. Disclosures: No relevant conflicts of interest to declare.

BACKGROUND: Elderly patients with Relapsed/Refractory (R/R) aggressive Large B-cell lymphoma (LBCL) and Peripheral T-cell lymphomas (PTCL), are commonly treated with intravenous conventional chemotherapies, which are often poorly tolerated and of short-lasting efficacy. Therefore only few fit-elderly patients might undergo intensive treatments with curative intent. Metronomic chemoterapy (MTN-CHT) is a new way of administering old drugs at low doses with only short chemotherapy free intervals. MTN-CHT may be combined with new targeted molecules, immunotherapies and radiotherapy. Although very few reports on MTN-CHT in LBCL and PTCL have been published existing data suggest that these lymphomas might respond to this approach. AIM: We aimed at demonstrating the efficacy and safety of MTN-CHT in a retrospective series of elderly patients with LBCL and PTCL, unfit for conventional treatments. PATIENTS AND TREATMENTS: From October 2008 up to May 2015 we treated elderly patients with R/R LBCL, Follicular Lymphoma(FL) and PTCL with MTN-CHT based regimen. Eligible patients should have given written informed consent, have a Performance Status=0-3, a life expection >2 months, be able to take oral therapy and have a care-giver. We used three different MTN schedules: 1] Provecip; 2] Vinblastine+Endoxan+Etoposide+Prednisone (VEED) and in the last two years an all-oral schedule 3] Navelbine+Endoxan+Etoposide+Prednisone (DE-VEC). All three schedules of MTN-CHT consisted of an induction phase of six months followed by a maintenance phase administered until progression or excessive toxicity. Rituximab was added to the induction phase for those patients characterized by CD20 expression. Thrombosis prophylaxis was carried out with aspirin or LMWH. RESULTS Patients features: LBCL=21; PTCL=7, FL=3; Age=77y (median, range 62-90), Previous CHT=2 (median, range 0-5) refractory to last CHT= 43%. MTN-CHT: 8 pts were treated with schedule 1], 8 pts with schedule 2] and 15 pts with schedule 3]. Outcome: in aggressive B and T-cell lymphomas (n=28pts) with all schedules Overall Response Rate = 62%, Complete Remission rate = 36%; Progression Free Survival = 8 months, Median Duration of Response (DOR)= 10 months. Overall Response Rate and Complete Remission in the subset treated with the all-oral DE-VEC schedule were 66% and 50% respectively. Serious adverse events: Extra hematologic toxicity grade 3-4: pulmonary embolism in 1pts; hematological toxicity of grade 3-4 and/or neutropenic infections in 6 patients 5 of whom had >2 previous conventional chemotherapies. The use of DE-VEC all-oral schedule reduced the number and the durations of day-hospital admissions. CONCLUSION Although our series is limited, these results suggest that MTN-CHT in elderly patients with R/R LBCL, PTCL and FL might achieve favorable results in terms of activity, toxicity and costs due to hospital admissions. With MTN-CHT most of the patients did not need G-CSF. Notably, patients who had had >2 lines of chemotherapies may be at very high risk of prolonged cytopenia and infections during MTN-CHT. Since the all-oral DE-VEC schedule was particularly manageable and active we believe that this combination deserve further investigation in aggressive lymphomas. Disclosures No relevant conflicts of interest to declare.

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 DFX 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 5062 Thrombotic events occurring before or at diagnosis of Essential Thrombocythemia (ET) are a worldwide recognized prognostic factor for the incidence of thrombosis during the follow-up of ET patients: however, these previous thrombotic events have been considered on the whole in the vast majority of studies, without further characterization. Among 1063 ET patients collected in the retrospective database of the “Gruppo Laziale SMPC Ph-”, we revised 186 cases with a previous thrombosis and a known data of occurrence, to evaluate the role of the interval from previous thrombotic episode and the diagnosis of ET. In 95 patients (51. 1%) previous thrombotic event occurred < 24 months before diagnosis of ET (group A) while in 91 patients (48. 9%) thrombosis occurred ≥ 24 months before diagnosis of ET (group B). Clinical features of patients at diagnosis are shown in the Table: GROUP A GROUP B p Gender (M/F) 40/55 42/49 0.636 Median age (yrs) (Interquartile range) (IR) 64.1 (52.7–71.8) 70.9 (61.0 – 78.0) 0.001 Hb median (g/dl) (IR) 13.9 (12.5 – 14.7) 14.2 (13.0 – 15.2) 0.136 PLT median (x 109/l) (IR) 800 (669 – 1066) 778 (652 – 926) 0.453 WBC median (x 109/l) (IR) 9.2 (7.8 – 11.3) 8.6 (7.1 – 10.8) 0.121 Median interval diagnosis – CHT (mos) (IR) 0.9 (0 – 7.0) 1.7 (0.4 – 5.6) 0.194 *CV risk factors (n°/%): 0.454 0 20 (21.0) 17 (18.6) 1 42 (44.2) 44 (48.3) ≥ 2 33 (34.8) 30 (33.1) Type of previous thrombosis (n°/%): 0.873 Arterial 78 (82.1) 67 (73.6) Venous 17 (17.9) 24 (26.4) * Cardiovascular (CV) risk factors at diagnosis were considered the presence of arterial hypertension, diabetes, smoking attitude, and hypercholesterolemia. In the group A, 9 out 95 patients (9. 4%) reported thrombotic episodes (5 arterial and 4 venous) during follow-up compared to 23 out 91 patients (25. 2%) (13 arterial and 10 venous) in the group B (p=0. 004). Consequently, patients of group B had a significantly higher cumulative risk of thrombosis compared to patients of group A (p=0. 0029, CI95% 1. 5 – 6. 1, RR 3. 04). In addition, it is worth of note that there was no difference in the cumulative risk of thrombosis between the patients of group A and the 877 patients without previous thrombotic events (p=0. 303, CI95% 0. 64 – 3. 21, RR 1. 24) In conclusion, the prognostic role of a previous thrombotic event in ET patients seems to be related not to the occurrence per se of the event but mainly to the interval between the event and the diagnosis of ET. Disclosures: Tafuri: Sigma Tau Pharmaceuticals: Research Funding.

Abstract 4504 INTRODUCTION POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes) is a rare multi-system disease characterized by chronic progressive polyneuropathy and plasma-cell dyscrasia. A major diagnostic criterion for POEMS is elevation of circulating vascular endothelial growth factor (VEGF), which is believed to play a pathogenic role in this disease. We report 3 cases of POEMS syndrome treated with high-dose melphalan and autologous peripheral blood stem cell transplantation (PBSCT). PATIENTS AND METHODS CASE 1 A 32-year-old woman presented with a progressive gait difficulty, weakness in limb muscles, skin hyperpigmentation, axillar and laterocervical lymphoadenopathies, peripheral edema. Neurophysiological testing showed a motor and sensory axonal polyneuropathy. At laboratory testing, thrombocytosis and monoclonal gammopathy IgA-λ were detected. A biopsy of laterocervical lymphonode was positive for Castleman’s disease. Initial treatment with intravenous immunoglobulin (IVIg) failed to result in clinical benefit. After cyclophosphamide 2 g plus G-CSF priming a total of 7.1×106/kg stem cells were collected from peripheral blood and used to perform double autologous transplantation at interval of 5 months following conditioning with melphalan 140 mg/sq/m. CASE 2 A 48-year-old woman presented with numbness and paresthesias in foot soles, weakness in lower limbs and axillar lymphoadenopathy. Nerve conduction studies showed motor and sensor demyelinating polyneuropathy. A monoclonal gammopathy IgG K-λ was present and bone marrow biopsy was unremarkable. She was treated with prednisone and plasma exchange with progressive improvement and clinical stabilization for two years. Unfortunately she presented a relapse of neurological symptoms responding to the same therapeutic strategy. A second relapse occurred after 3 months with appearance of sensory ataxia, xerotic skin, hepatomegaly. Laboratory analysis revealed biclonal gammopathy IgG k-λ and IgA-λ and Bence Jones proteinuria (λ light chain). Radiologic studies showed lytic lesions with sclerotic rim in homerus, VII rib and iliac bone and mediastinal, axillary and iliac lymphadenopathies. The patient received cyclophosphamide 2 g and G-CSF for mobilization. Melphalan 200 mg/sq/m was administered intravenously as conditioning regimen followed by reinjection of the cells collected. CASE 3 A 44-year-old woman presented with asthenia, scleroderma-like skin changes, weight loss, limb paraesthesia and weakness. Neurophysiological testing showed a motor and sensor demyelinating polyneuropathy. She presented thrombocytosis and a monoclonal IgG-λ protein at laboratory tests. Radiologic studies showed laterocervical, axillary, mediastinal lymphoadenopathies, multiple thyroid nodules and a mixed sclerotic and lytic lesion in the pelvis and in the right humeral head. Biopsy of this lesion demonstrated a plasmacytoma with λ light chain restriction. Initial treatment with IVIg was unsuccesful. She received oral therapy with melphalan and prednisone for 3 years obtaining clinical stabilization, then she was treated with monthly zoledronic acid infusion only. After 3 years she presented a relapse of neurological symptoms, appearance of hepatomegaly, axillar and laterocervical lymph nodes enlargement, peripheral edema. She therefore underwent PBSC harvesting following cyclophophamide priming (2 g), than she received melphalan (200 mg/sq/m) with CD34-selected PBSC rescue. RESULTS The post-transplant course was uneventful other than the development of febrile neutropenia in 2 cases. Patients 1 and 2 presented a progressive improvement in strength, physical skills and peripheral neuropathy after few months. They are well with clinical stabilization after 4 and 6 years, respectively, from PBSCT. At 3 months from PBSCT, patient 3 presents progressive neurological improvement and reduction of organomegalies. CONCLUSIONS Although treatment for POEMS is not standardized, disseminated disease require systemic therapy. No randomized controlled trials have been conducted, but patients with POEMS have been successfully treated with PBSCT since 1998. Our cases confirm its usefulness and safety and support the idea that, although delayed intervention maintains its efficacy, PBSCT could be considered early during the disease course to obtain the best response. Disclosures: No relevant conflicts of interest to declare.

Abstract 4303 INTRODUCTION Invasive fungal infections (IFI) represent an important cause of mortality and morbidity in patients with Acute Myeloid Leukemia (AML) undergoing intensive chemotherapy. A prophylactic antifungal therapy is often administered during intensive chemotherapy, however the optimal antifungal prophylaxis protocol is still unknown. Amphotericin B lipid complex (Abelcet®) has been commonly used as a standard treatment for IFIs caused by Aspergillus and Candida, but its effectiveness in prophilaxis has not been clearly estabilished. METHODS From September 2010 to April 2011 we treated six patients with newly diagnosed AML using low dose amphotericin B lipid complex as antifungal prophilaxis. Patients observed were three females and 3 males, median age was 54 years (range 21–74 years) and they were all fit to receive intensive chemotherapy. Three patients older than 60 years received Fludarabine based chemotherapy regimen during both induction and consolidation. Three patients aged less than 60 years old were treated using a chemotherapy protocol based on Citarabine, Daunorubicin and Ethoposide association. One patient in this group also underwent BuCy conditioned autologous stem cell transplant. Amphotericin B lipid complex was administered intravenously at 100 mg once a day. Antifungal prophilaxis was started when the absolute neutrophil count was ≤ 500 cells/μ l and was continued until neutrophils recovery was ≥ 500 cells/μ l, without any evidence of IFI. RESULTS Five patients did not experience any proven fungal infection during all treatment. Anyway one patient died during induction due to a severe bacterial lung infection. One patients discontinued antifungal prophylaxis due to extensive skin rash during the second infusion of the drug. Amphotericin B lipid complex was otherwise well tolerated by patients. One patient was diagnosed with lung aspergillosis infection by evidence of galattomannan positivity on BAL and a lung CT scan showing a single nodular escavated lesion on left upper lobe; subsequentely he was successfully treated with voriconazole. CONCLUSIONS In our experience, Amphotericin B lipid complex showed to be an effective and safe antifungal prophylaxis for newly diagnosed AML patients. Further clinical studies are certainly required to obtain definitive data. Disclosures: No relevant conflicts of interest to declare.

Abstract 3854 Increasing age is a well-recognised risk factor for thrombotic events in patients with Essential Thrombocythemia (ET): however, few data exist on the role of other clinical and biological features in different age groups. To address this issue, we analysed retrospectively 1090 ET patients (M/F 403/687, median age 63 years, IR 17 – 96) diagnosed at 11 Hematological Institutions in the Lazio region from 1980 to 2010 and with a median period of follow-up of 84 months (IR 1 – 371). Based on the commonly adopted age threshold, 480 patients (44 %) were < 60 years (Group A) and 610 (56 %) were ≥ 60 years (Group B). Clinical and biological features as well as cardiovascular risk factors analyzed for the impact on the thrombotic risk in the two age groups are reported in the Table.Group A < 60 yearsGroup B ≥ 60 yearsPutative risk factorsRisk ratio (95% CI)P valueRisk ratio (95% CI)P valueM/F167/3132.68 (1.03–6.94)0.0029236/3741.12 (0.17–2.59)0.73WBC median (range) x 109/l8.9 (4.29–22.35)0.387 (0.149–1,004)0.06458.9 (1.2–57.7)0.79 (0.41–1.47)0.445PLTS median (range) x 109/l837 (451–3582)0.37 (0.258–1.70)0.66802 (450–3104)0.52 (0.28–0.99)0.0052Hb median, g/dL (range)14.1 (6.0–18.4)0.86 (0.33–2.24)0.76914.0 (7.0–17.8)0.87 (0.45–1.67)0.674*JAK-2 mutational status: wild type/mutated (%)53.2/46.81.57 (0.50–4.87)0.4434.1/65.90.498 (0.17–1.48)0.209Previous thrombotic events: n° (%)· All events72 (15)2.18 (0.59–7.96)0.12149 (24.4)3.01 (1.38–6.57)0.0004· within 24 months from diagnosis48 (10)1.43 (0.19–10.4)0.7464 (10.5)0.506 (0.18–1.39)0.189· within 60 months from diagnosis60 (12.5)NA0.5191 (14.9)0.323 (0.11–0.95)0.023Cardiovascular risk factors: Y/N %○ Arterial hypertension41.7/58.31.68(0.64–4.36)0.2880.7/19.30.96 (0.36–2.57)0.935○ Diabetes10.2/89.81.11 (0.23–5.15)0.8925.0/75.01.09 (0.38–3.11)0.86○ Smoking attitude45.6/54.42.78 (1.01–7.65)0.06758.3/41.71.04 (0.35–3.09)0.94○ Hyperlipidemia31.0/69.03.11(0.917–10.592)0.03951.6/48.42.31 (0.70–7.55)0.203 In Group A, 39 patients (8.1%) had at least one thrombotic event during follow-up; there were 20 (51.3%) arterial thrombosis and 19 (48.7%) venous thrombosis. In Group B, 63 patients (10.3%) had at least one thrombotic event during follow-up; there were 38 (69.4%) arterial thromboses and 25 (39.6%) venous thromboses. In group A univariate analysis for thrombosis-free survival performed by Kaplan-Meier method, disclosed a significant impact of male gender (p=0.0029, CI 1.03–6.94, HR 2.68), > 2 cardiovascular risk factors (p=0.0002, CI 1.87 – 190, HR 18.94) and isolated hyperlipidemia (p=0.039, CI 0.917 – 10.59, HR 3.11), while previous thrombotic events had no significant impact (p=0.27). By contrast, the presence of a previous thrombotic event was the only feature with a significant impact on thrombotic risk in Group B (p=0.0004, CI 1.38 – 6.55, HR 3.01). WBC and PLTS values at different cut-off levels as well as JAK-2 mutational status did not have any impact on thrombosis in either age groups. However, in group B, we observed a trend (p=0.052, CI 0.28–0.99, HR 0.52) towards a protective effect of higher PLTS values (> 800 × 109/l). In conclusion, our data seem to reinforce the need of a different thrombotic risk assessment in distinct age groups: in particular, younger patients could benefit from early recognition and treatment of well-known cardiovascular risk factors. Disclosures: No relevant conflicts of interest to declare.

Abstract 4507 Background. Inflammatory myopathies are primary diseases of the striated muscles caused by an underlying autoimmune dysfunction. Dermatomyositis and polymyositis are the most common diseases of the striated muscle, skin and surrounding connective tissue. Usually the presentation includes proximal muscle weakness, inflammatory changes, creatine kinase elevation and skin rash. Although the cause of polymyositis/dermatomyositis is unknown, an autoimmune pathogenesis is strongly implicated and this provides the rationale for using immunosuppressant treatment. In the presteroid era prognosis was very poor, currently the mainstay treatment is based on high dose prednisone followed by different immunosuppressant and immunomodulating drugs as second and third line treatment for non responder patients. Autologous haemopoietic stem cell transplantation (HSCT) has been successfully employed in autoimmune diseases becoming a curative option for conditions with very poor prognosis, such as severe forms of systemic sclerosis, multiple sclerosis, and systemic lupus erythematosus. To our knowledge, 14 patients with polymyositis have been successfully treated with autologous bone marrow transplantation. The goal of PBSCT in polymyositis is to achieve remission of the systemic manifestations. Thus, we describe a case of dermatomyositis treated with high-dose chemotherapy and autologous peripheral blood stem cell transplantation (PBSCT), after a long history of conventional immunosuppressive therapy without advantage. Aims and methods: In our centre, member of the Rome Transplant Network, we observed a 60-year old man with seronegative dermatomyositis, which began in 1996 with symmetric proximal muscle weakness. Dermatomyositis was diagnosed according to Bohan and Peter criteria with a 5/5 score. Despite the administration of five lines of different immunosuppressive treatments between 1996 and 2010, disease progressed with pharingo-laryngeal involvement causing dysphagia and aphonia and EMG evidence of severe myopathic changes. HSCs were successfully mobilized with cyclophosphamide 2 g and G-CSF 5 mg/kg/day. Time from diagnosis to transplantation was 15 years. Tiothepa 70 mg on day -5 and cyclophosphamide 3.5 g on day -3 and -2 were administered intravenously as conditioning regimen followed on day 0 by reinjection of the cells collected by leukapheresis. The number of CD34+ cells infused was 2.9 × 106 /Kg. All the procedures for PBSCT were well tolerated and the post-transplantation period was uneventful, except for an episode of neutropenic fever without bacteriological documentation that resolved under broad-spectrum antibiotics. Results. After the PBSCT, we observed slow but progressive improvement in neurological symptoms and performance status. Currently, three months after transplantation, the patient is able to perform daily activities autonomously. Conclusions. Our case confirms the usefulness and safety of PBSCT in dermatomyositis. We are not able to tell which role high dosage of CSF have played in the clinical response. However our case reinforces the idea that PBSCT should be considered in the treatment of severe forms of dermatomyositis, even early during the disease course in order to reach the best response. Disclosures: No relevant conflicts of interest to declare.

Abstract 1229 In the “real world” of clinical practice, many very elderly CML patients have been treated with imatinib (IM), but there are few data on the results and the best initial dosage in such patients. To highlight peculiar aspects of toxicity and efficacy of IM in this subset which accounts for at least 10–15% of all CML cases, we retrospectively revised 156 CML patients in chronic phase treated with IM when aged > 75 years from 23 haematological Institutions in Italy; there were 85 males and 71 females, median age at IM start was 78.4 years (IR 76.1 – 81.4), Sokal Risk at diagnosis was low in 2 patients, intermediate in 90, high in 50 and not evaluable in 14. One or more concomitant diseases requiring specific treatments were present in 144/156 patients (92.3%), with 94 patients (60.2%) assuming 3 or more concomitant drugs. Thirty patients (19.2%) were in late chronic phase (≥ 12 months from diagnosis) and pretreated (25 with HU and 5 with IFN) before starting IM; on the whole, median time from diagnosis to IM was 1.2 months (IR 0.5 – 3.6). Starting dose of IM was 400 mg/day in 117 patients (75.0%) and 300 mg/day or less in 39 patients (25.0%); overall, 59 patients (37.8%) (52/117 at 400 mg starting dose and 7/39 at 3 300 mg starting dose) needed a dose reduction and 18 (11.5%) discontinued IM for toxicity (early toxicity in 13 and late toxicity in 5). Excluding the 13 patients who discontinued IM due to early toxicity, maximum tolerated daily dose during treatment was 400 mg in 63 patients, 300 mg in 51 patients and < 300 mg in 29 patients. According to CTC-AE, grade 3 – 4 hematological and extra-hematological toxicities were observed in 34 (21.7%) and 34 (21.7%) patients, respectively; 5 patients (3.2%) presented a pleural effusion during IM treatment. After a median treatment period of 29.4 months (IR 7.9 – 54.4), 8 patients (5.1%) are still too early (< 6 months of treatment), 13 (8.3%) discontinued IM due to early toxicity, 3 (1.9%) were resistant and 1 (0.7%) died from unrelated cause early after IM initiation: the remaining 131 patients (84.6%) achieved a complete haematological response (CHR). Among these 131 patients in CHR, 11 refused any other karyotipic or molecular evaluation (1 lost CHR and shifted to hydroxyurea, 4 are still alive in CHR, 6 died in CHR from unrelated causes), 17 achieved CHR only and 103 (66.0% of all 156 patients) achieved a cytogenetic response (CyR), which was major in 11 patients and complete (CCyR) in 92 (58.9% of all 156 patients). In addition, among the 92 patients in CCyR, 62 (39.7% of all 156 patients) achieved a molecular response (major molecular response in 40 patients and complete molecular response with an undetectable BCR/ABL hybrid gene at qualitative nested PCR in 22 patients). After a median follow-up of 34.0 months (IR 12.9 – 60.0), 36 patients have died (5 from disease progression and 31 from unrelated causes), 4 patients were lost to follow-up and 116 are still alive: 2-year and 4-year overall survival were 90.2% (CI95% 84.8 – 95.6) and 76.8% (CI95% 68.6 – 85.0), respectively. In conclusion, results from this large unselected cohort of patients show that should be definitely considered unethical to avoid IM therapy to any elderly patient; no upper age limit should be given but also very elderly (and with concomitant severe diseases) patients should have this chance of cure. The role of a reduced starting dose of IM warrants further studies. Disclosures: No relevant conflicts of interest to declare.

Abstract 2211 Poster Board II-188 Dasatinib is a 2nd generation tyrosine-kinase inhibitor active in CML patients resistant or intolerant to Imatinib; at present there is no data on its toxicity and efficacy in unselected elderly patients. To highlight this issue, 97 patients treated with Dasatinib when aged > 60 years were retrospectively evaluated from 16 Italian Centers on a “real-life” basis, including all patients treated at each Center independently from enrolment or not in controlled clinical trials.There were 52 males and 45 females, median age at Dasatinib start was 69.5 years (IR 65.0 – 73.3), Sokal Risk at diagnosis was low in 26 patients, intermediate in 37, high in 15 and not valuable in 19. Forthy-five patients (46.4%) were primarily resistant, 11 (11.4%) were intolerant and 41 (42.2%) had secondary resistance to Imatinib; all patients were in CP when Dasatinib was started. Median time from diagnosis to Dasatinib treatment was 85.0 months (IR 44.8 – 120.0); 53/97 patients (54.6%) had been pretreated with IFN ± Ara-C before Imatinib, all patients received Imatinib at standard dose (400 mg/day) followed in 50/97 (51.5%) by increased dose (600 – 800 mg/day) with an overall median period of Imatinib treatment of 48.6 months (IR 26.9 – 67.0). In addition, 28/97 patients (28.8%) received other 2nd line treatment (10 Nilotinib, 14 HU +/- other drugs, 3 Imatinib + HU or IFN and 1 allogeneic transplant) before Dasatinib. Starting dose of Dasatinib was 140 mg/day in 47 patients, 100 mg/day in 44 patients and ≥ 50 mg/day in 6 patients, respectively. After a median period of treatment of 15.6 months (IR 7.6 – 23.0) all patients were evaluable for toxicity; on the whole, grade 3 – 4 hematological and extra-hematological toxicities were reported in 36/97 (37.1%) and 27/97 (27.8%) patients, respectively. A grade 3 – 4 hematological toxicity occurred in 25/47 (53.1%) patients receiving 140 mg as compared to 10/44 (22.7%) patients receiving 100 mg (p 60 years resistant/intolerant to Imatinib; in particular, when employed at the current recommended dose of 100 mg/day, it is very effective and has a favourable safety profile also in heavily pretreated elderly subjects. Disclosures: Vitolo: Roche: . Pane:Novartis: Research Funding; Ministero dell'Università/PRIN: Research Funding; Regione Campania: Research Funding; Ministero della Salute/Progetto integrato Oncologia: Research Funding.