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Abstract 3953 Oral bexarotene, a novel retinoid that selectively activates retinoid × receptors, is approved for the treatment of cutaneous manifestations of refractory or relapsed cutaneous T cell lymphomas (CTCL) as monotherapy. Phase II/III trials have demonstrated a greater than 50% response rate in patients with all stages of CTCL who were refractory or intolerant to the previous therapy but the recommended bexarotene dose of 300 mg/m2/day is associated with significant side-effects. Novel studies are looking for synergistic therapies combining lower bexarotene doses in order to reach the same or even better outcomes while avoiding a negative impact on the quality of life. Early studies with bexarotene and psoralen plus ultraviolet A photochemotherapy (PUVA) show promise. Synergy between bexarotene and PUVA may derive from retinoid-induced reductions in epidermal thickness, which consequently improves UVA penetrations, and/or from retinoid-specific enhancement of immune functions. The aim of this study was to assess the efficacy and safety of a 2 stage-protocol (induction and maintenance) with low dose bexarotene (Targretin) and PUVA in refractory and/or resistant patients with Mycosis Fungoides (MF) and Sézary Syndrome (SS). A prospective, phase 2 clinical study was conducted between February 2007 and May 2010 by two Italian academic hospital centers. We enrolled 15 patients with stages I through IV MF/SS; all patients had failed PUVA or several systemic regimens. Response to treatment was assessed with clinical endpoints such as remission of symptoms (pruritus, pain, sleep disturbance) and signs (erythema, scaling, thickness of plaques, presence of nodules, tumours, peripheral lymphadenopathy). Complete remission (CR) was defined as the disappearance of all clinical evidence of disease for at least 4–6 weeks, partial remission (PR) as 50% or more decrease in extent or severity of disease. Overall response (OR) rate was defined as the combination of CR/PR. Patients with MF/SS were started with bexarotene (150 mg/day) and PUVA (three times weekly). Increments of bexarotene to a maximum of 300 mg/day were scheduled. Patients who achieved CRs and PRs during the induction remained on the same dose in the maintenance period, whereas the frequency of PUVA was gradually reduced. A preventive therapy to lower triglycerides and elevated thyroid hormone levels in the blood, was administered in all cases; therapeutic dietary and lifestyle changes were often recommended. Primary endpoint were OR rate at the end of induction and maintenance; secondary endpoints were safety and event-free survival (EFS). Kaplan-Meyer method and long-rank test was used for statistical analysis. All 15 patients (8 M and 7F) were evaluable for response; ten patients had early-stage (IB) and 5 had advanced stage (2 IIB, 1 IIIA, 1 IIIB, 1 IV). The median age was 68 years (34-81). The OR rate was 93% with 33% CR after induction period and 93% with 47% CR at the end of the protocol. A response was observed even in 1 case with SS and in 2 cases with MF in large cell transformation. Significantly, patients treated previously with PUVA monotherapy achieved better and faster CR compared with those treated with more than one systemic therapy (83% and 22% respectively; χ2 test, P=0.041; median time to maximal response 4 weeks and 8 weeks respectively, P=0.007). Median EFS at 37 months, for the whole group was 27 months. All patients have been closely monitored for adverse events during treatment; 2 of 15 patients (13%) had mild grade I-II asthenia, hypercholesterolemia and central hypothyroidism, 2 patients developed elevations of CPK (grade 3). With regard to hematologic toxicity, leukopenia was mild (grade I) and occurred in 3 patients (20%). In conclusion, our study have demonstrated a greater than 90% response rate in patients with all stages of CTCL refractory or intolerant to the previous therapies; the efficacy is more pronounced in patients previously treated with PUVA monotherapy. Starting treatment at lower dose of bexarotene followed by dose escalation may improve the efficacy and safety of both bexarotene and PUVA. Moreover the additional maintenance phase seems to improve the OR and length of remissions. Disclosures: Leoni: Celgene: Honoraria.

Abstract 3072 Thromboembolic disease (TE) is a major cause of morbidity and mortality in Essential Thrombocythemia (ET). Recently JAK2V617 mutational status and allele burden seem to add prognostic significance to standard risk factors; furthermore it was reported an interesting but not confirmed association between baseline leukocytosis and thrombosis. The aim of the study was to evaluate such factors in a series of patients with ET. Study subjects were recruited from the Ancona Hematology Clinic database of ET patients; clinical and laboratory data were collected at time of diagnosis and correlated with the occurrence of TE. In addition, qualitative and quantitative PCR for JAK2V617F was performed on stored samples of peripheral blood or bone marrow in a subset of study patients. Qualitative JAK2V617F analysis was done according to standard PCR-based methods and quantitative JAK2V617F was determined with a commercially available Taqman assay. Standard statistical methods were applied to test significance of associations between thrombosis and other variables. A total of 218 ET patients were included in the study (median age 59, range 18–90; 71 males and 147 females). At diagnosis the median of platelets, hemoglobin and leukocytes were 776×109/L, 13.9g/dL, and 8.4 ×109/L respectively. At diagnosis a history of remote thrombosis was recorded in 27 patients (12,4%). Of the 122 patients analysed for JAK2 mutational status, 70 (57.4%) were JAK2 wild-type and 52 (42.6%) were JAK2V617F positive. Quantitative analysis was carried out in 48 cases: 6 patients (11.5%) were homozygotic and 42 (80.8%) were heterozygotic. At diagnosis, a total of 17 patients (7.8%) had TE: 8 (3.7%) arterial thrombosis (AT) and 9 (4.1%) venous thrombosis (VT). the AT included acute coronary syndromes (ACS; n=4), transient ischemic attack/cerebrovascular accidents (TIA/CVA; n=3), and peripheral arterial thrombosis (PAT; n=1). The VT included deep vein thrombosis/pulmonary embolism (DVT/PE; n= 4), abdominal vein thrombosis (AVT; n=4) and dural sinus thrombosis (n=1). During follow-up 25 patients experienced TE: 13 VT (6%) and 12 AT (5.5%). Post diagnosis VT included.: DVT/PE (n= 4), AVT (n=4), superficial vein thrombosis (TVS; n=3), retinal vein thrombosis (n=1) and dural sinus thrombosis (n=1). Post diagnosis AT included TIA/CVA (n=6), ACS (n=3) and PAT (n=3). Gender, age, hemoglobin, platelets, leucocyte count, splenomegaly, increased cellularity of bone marrow, bone marrow fibrosis and common vascular risk factors did not affect the probability of thrombotic events at diagnosis and during follow-up. On univariate analysis a significant increase of thrombosis as presenting manifestations, was registered in patients with a history of remote thrombosis (OR= 10.0, 95% CI 4,1-24,5; p Subjects with both JAK2 mutation and a history of remote thrombosis have a OR of 24.44 (95% CI 3.07–194.66; p=0.01) in comparison with wild-type patients without a history of thrombosis. During follow-up, the probability of vascular events was predicted only by a history of remote thrombosis (OR=2.3, 95% CI 1.01–5.35; p=0.05), and neither by JAK2V617F mutational status (OR=1.24, 95% CI 0.43–3.62; p=0.76). The present analysis suggests that the thrombotic risk is higher in JAK2V617F positive patients and is further increased by a past history of thrombosis. The opportunity of combine such criteria must be defined in prospective trials. Disclosures: Leoni: Celgene: Honoraria.