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Background. Use of 2nd generation tyrosine kinase inhibitors (2G-TKIs) dasatinib (DAS) and nilotinib (NIL) in chronic phase (CP) chronic myeloid leukemia (CML) patients failing imatinib (IM) results in around 50% of sustained cytogenetic response, and around 40% major molecular response (MMR). However, these are historical data and it's unclear if there's a significant difference in efficacy of the two 2G-TKIs, especially in the long-term. Aims and methods. We retrospectively analysed 163 CP-CML patients resistant or intolerant to IM that received either DAS (n=95) or NIL (n=68) as second-line therapy. We compared the characteristics of the two groups at the time of CML diagnosis and at the time of IM failure, including the cause of switch to 2G-TKI, duration of IM therapy, IM dose escalation and Hammersmith score to predict the probability of response to 2G-TKIs. Cytogenetic and molecular responses were evaluated according to the ELN recommendations. Sustained deep molecular response (DMR) was defined as MR4 or better lasting ≥ 2 years, ongoing at the last contact, and with at least a Q-PCR test every 6 months. Time to treatment failure (TTF) was calculated from the start of 2G-TKI to any of the followings: progression to accelerated or blast phase (ABP), death for any cause at any time, treatment discontinuation for primary or secondary resistance or intolerance. Progression free survival (PFS) was calculated from the start of 2G-TKI to ABP or death. Overall survival (OS) was calculated from the start of 2G-TKI to death. Results. DAS and NIL cohorts were comparable for age, sex and risk score (Sokal and EUTOS) at diagnosis. Median duration of IM therapy was similar (DAS 19 months, NIL 14 months), but 27/95 patients (28%) had IM dose escalation before DAS compared to only 9/68 (13%) before NIL (p=0.03). There was a higher rate of switch to DAS than to NIL for secondary resistance (26/95, 27% vs 7/68, 10%; p=0.01) while more patients changed from IM to NIL due to intolerance (31/68, 46%, vs 21/95, 22% for DAS; p=0.002). Rates of primary resistance did not differ (47/95, 49% for DAS vs 28/68, 41% for NIL; p=0.37), as well as other causes of switch (1/95, 1% for DAS vs 2/68, 3% for NIL; p=0.77). Hammersmith score was almost identical in the two groups. Complete cytogenetic response (CCyR) was attained in 53/73 (73%) patients not in CCyR at the time of DAS start, and in 31/48 (65%) patients not in CCyR at the time of NIL start (p=0.46). Mean time to CCyR was similar (7.1 months for DAS and 5.3 months for NIL; p=0.30). MMR was achieved in 55/89 (65%) patients not in MMR at the time of DAS start and in 39/61 (65%) patients not in MMR at the time of NIL start (p=0.82). Again, mean time to MMR was not different in the DAS e NIL cohorts (12.4 vs. 8.5 months; p=0.14). DMR was obtained in 39/88 (44%) patients not in DMR at the time of DAS start and in 30/65 (46%) patients not in DMR at the time of NIL start (p=0.95). Sustained DMR was evaluable in 127 patients: 37 patients (29%) achieved sustained DMR, without difference between DAS (24/82, 29%) and NIL (13/45, 29%; p=1.00). With a median follow-up of 44 months (range 1-124), 5-year TTF was similar for DAS (65%, 95%CI 52-75%) and NIL (61%, 95%CI 43-74%; p=0.40) [Figure 1a]. Thirty-two of 95 patients (34%) stopped DAS due to toxicity (19/32, 59%), resistance (11/32, 31%) or other causes (3/32, 10%); 22/68 patients (32%) interrupted NIL for toxicity (11/22, 50%), resistance (8/22, 36%) or other causes (3/22, 14%). Probability of survival and progression were almost identical, with a 5-year PFS of 84% (95%CI 68-89%) for DAS and 92% (95%CI 79-97%) for NIL (p=0.27) [Figure 1b] and a 5-year OS of 89% (95%CI 78-95%) and 96% (95%CI 85-99%) (p=0.31), respectively. Conclusions. With the limits of a retrospective analysis, our data suggest similar efficacy of DAS and NIL after IM failure in CP-CML, with rates of cytogenetic and molecular responses higher than those previously reported and excellent long-term survival. Around 30% achieved sustained DMR with second-line therapy, thus being potentially candidate for TKI discontinuation. Disclosures Tiribelli: Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau. Bonifacio:Ariad Pharmaceuticals: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Amgen: Consultancy. Fanin:Novartis: Speakers Bureau.

Background In essential thrombocythemia (ET) patients, history of thrombosis and age over 60 y are validated risk factors for occurrence of thrombosis during the follow-up. Leukocytosis, JAK2 V617F mutation, cardiovascular (CV) general risk factors, and male gender are candidate risk factors for thrombosis. The thrombocytosis, a constitutive abnormality in ET, is associated with both thrombotic and hemorrhagic complications. Aim To evaluate in a large cohort of ET patients the potential relationship between the thrombosis history and the main clinical and biological characteristics at diagnosis, i.e. before any interference of cytoreductive treatment. Methods A cohort of ET patients (PVSG or WHO criteria) of the Registro Italiano Trombocitemie (RIT) was retrospectively analyzed through logistic regression models. Results A total of 977 patients, 387 males and 590 females, presented at diagnosis: median age 56 y (43% with age >60 y), median PLT count 783 x 109/L (33% with low thrombocytosis, 10 x 109/L), median HCT 42.6% (high HCT: >47% in 24% of the males and >44% in 23% of the females), CV general risk factors in 69% of cases (one of smoking, hypercholesterolemia, hypertriglyceridemia, hypertension, diabetes, obesity, CV disease, familiarity for thrombosis), bone marrow fibrosis grade 0 in 67% of cases, JAK2 V617F mutation in 56% of the 399 tested patients. The history of thrombosis (arterial in 74% of cases) was reported in 194 (19.9%) patients. The history of thrombosis in univariate analysis was significantly related to: age >60 y (p 0.001), male gender (p 0.009), CV general risk factors (p 0.002), low thrombocytosis (p 0.000), leukocytosis (p 0.003), high HCT (p 0.004), and JAK2 V617F mutation (p 0.008). No relationship was found with bone marrow fibrosis. In multivariate analysis a relationship was confirmed between thrombosis history and age >60 y (p 0.023), male gender (0.046), CV general risk factors (0.039), low thrombocytosis (p 0.004), leukocytosis (0.019), and JAK2 V617F mutation (p 0.033). The rate of thrombosis history in the patients without both low thrombocytosis and leukocytosis (11%, 49/428) resulted significantly lower (p 0.0001) than in the patients with leukocytosis (24%, 54/224), the patients with low thrombocytosis (27%, 71/266), and the patients with both low thrombocytosis and leukocytosis (34%, 20/59). Conclusion In this cohort of ET patients the rate of thrombosis history in multivariate analysis is significantly related to various clinical and biological characteristics at diagnosis, including low thrombocytosis (PLT 10 x 109/L), JAK2 V617F mutation, age >60 y, male gender, and CV general risk factors. Acknowledgment this study was partially supported by the GIMEMA Foundation (Promotor of the RIT) and by the AIL Foundation. Disclosures: Gugliotta: SHIRE Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Abstract 2839 Patients affected by low-risk essenthial thrombocythosis (ET) may develope thrombotic/haemorragic events at a lower rate compared to high-risk ET patients. So far, it has not be possible to identify useful markers to predict which of these patients are more likely to have an event. Previous authors [Carobbio A et al, Blood 2007] have shown that leukocytosis at diagnosis is associated with a high hazard risk (HR) of developing a thrombotic event, while high platelets count is not. Subsequently other authors [Gangant N et al, Cancer 2009] have contradicted this findings and instead shown that in low-risk ET, the increase in leukocyte count over time correlates with thrombotic events [Passamonti F et al ISTH 2009]. For these reasons we decided to evaluate risk parameters in a dynamic manner with the aim of identifying those patients who are more likely to have an event and might benefit from preventive treatment. We performed a large multicentre retrospective study that included several North Italian Haemathology centres and a large Austrian university hospital. Patient data was analysed using random effect linear regression model and a dedicated Cox model with dynamic proportional risk. We studied 136 patients with low risk ET. Out of those, 45 had a thrombotic/haemorragic event and 91 never had an event (events included: stroke, TIA, IMA, PE, PAD, epystaxis and gastrointestinal bleeding). Overall, the median age was 42 years (IQR 20; range 18–60), the median Hb was 14.0 g/dL (IQR 2.3; range 4.4–18), the median WBC was 8.1 ×103/Â μL (IQR 3.3; range 3.3–23.8), the median PLT was 701 ×103/ÂL (IQR 404; range 206–1806). Gender was M 33% (n=45), F 67% (n=91); smokers were 24% (n=18/N=74); hypercholesterolemia was 18% (n=17/N=92). The FBCs of both groups were recorded from the date of diagnosis (entry time) and up to 3 years of follow up or to the development of a thrombotic/haemorragic event (exit time). A total number of 1294 FBCs were provided by the group with event and compared to a total of 4487 FBCs from the group without event. The follow-up Hb values showed a decreasing linear pattern linear from baseline values. The PLT-count showed a trend similar to Hb over the period of follow-up in both the group without events and in the group with events. The WBC showed a decrease during follow-up in the group with events and an increase in the group without events. Surprisingly, the risk of developing an adverse event after 60 months of follow-up was reduced by 20% for each increase of 1 g/dL Hb (p =0.007), was increased by 8% for each WBC increase of 1 103/uL (p =0.026) and was decreased by 6% for each PLT increase of 100 × 103 /uL (p =0.434). No differences were seen between venous or arterious thrombotic events (Log rank test, p=0.842). In conclusion, this study confirms that baseline FBCs values are not predictive of events within the ET low risk group. The emerging new finding is that the risk of developing an event is higher when Hb is reduced. This strongly suggests a protective role of Hb in the low-risk ET group. Previous studies have shown that red cells might store and generate nitric oxide (NO), a key endothelial modulator [Kim-Shapiro DB et al 2006]. The presence of NO would keep PLT in resting state, would reduce endothelial cell adhesion and in turn reduce thrombosis rate. However this needs to be confirmed. Disclosures: Steurer: Amgen: Consultancy, Honoraria. Pizzolo:Hoffmann-La Roche: Consultancy, Honoraria.

Background: the Registro Italiano Trombocitemia, that is a GIMEMA project, has been activated to registry Italian Essential Thrombocythemia (ET) patients, to improve the diagnosis appropriateness (WHO criteria), to verify the prognostic value of the clinical and biological parameters, to evaluate the compliance to the therapeutical Italian guidelines (1), and to create a network for activation of new studies. Objective: this analysis is mainly devoted to describe the ET patients registered in the RIT and to evaluate the therapeutic approach adopted in the 102 participating hematological centers. Material and methods: two thousand and fifteen ET patients have been registered after the written informed consent was obtained, and data validation by various expert panels is in progress. This preliminary report considers 1785 patients, diagnosed mainly (1078, 60.4%) since the publication in the year 2004 of the ET therapy Italian guidelines (1). Results: the patients, 678 (38%) males and 1107 (62%) females, showed at diagnosis: age 60.3 ± 16.8 years with higher values in males than in females (61.7 ± 15.3 vs. 59.4 ± 17.7, p Conclusion: in the analyzed patients of the ET Italian registry the diagnosis appropriateness resulted improved in the cases observed since the year 2004 respect those observed before, with an increase of bone marrow biopsies from 51% to 68% of patients. Moreover, in accord with the ET therapy Italian guidelines, the use of the cytoreductive drugs was less frequent in the patients diagnosed since the year 2004 than before (particularly for BUS, IFN, and ANA) and the more safe molecules IFN and ANA were preferentially deserved to the younger patients.