Passamonti, Francesco

Abstract Abstract 3846 INTRODUCTION There is strong evidence indicating that the clear-cut separation of prefibrotic primary myelofibrosis (PMF) from essential thrombocythemia (ET) by consequent application of the World Health Organization (WHO) 2008 criteria is reflected in different, well defined clinical pictures and divergent prognoses (Barbui et al, JCO 2011,Thiele et al, Blood 2011). Very recently the specific risk profile for arterial and venous thrombosis in WHO- diagnosed ET was published (Carobbio et al, Blood 2011). In PMF so far all published data on vascular events were exclusively based on overt disease manifestations until now there are no data available regarding prefibrotic stages. Consequently, we aimed to evaluate the corresponding risk profile of patients with WHO-diagnosed prefibrotic PMF. METHODS A total number of 264 patients with WHO-defined prefibrotic PMF derived from either the Medical University of Vienna or an International Database (Barbui et al, JCO 2011) were studied. Nonfatal thrombotic events considered in this study were reported as rates per 100 patient-years and included transient ischemic attacks, thrombotic cerebrovascular accidents, coronary artery disease, myocardial infarction, peripheral arterial disease, deep vein thrombosis of peripheral vasculature, pulmonary embolism, and abdominal large vein thrombosis. Cardiovascular risks factors considered, comprised of arterial hypertension, diabetes mellitus and tobacco use. To evaluate risk factors for total thrombosis and for arterial and venous events in particular multivariate Cox- regression analysis including the co-variables sex, age, previous thrombotic event, laboratory parameters measured at diagnosis and need for cytoreductive and/or antiplatelet therapy during follow-up was calculated. P values less than 0.05 were considered as statistically significant. RESULTS After a median follow- up of 5.8 years (range0.0 – 27.2), the total rate of non fatal thrombotic events was 2.1% patient-years (95% CI, 1.5–2.8); the incidence of arterial events was higher (1.7% patient- years) than of venous events (0.6% patient-years).Considering thrombosis in general a higher white blood cell (WBC) count enhances the risk significantly (p=0.005; HR 1.15). This is also true in arterial events in particular (p=0.047; HR 1.12). A lower platelet count is associated with a higher risk for thrombotic events; for thrombosis in general this association is of borderline significance (p=0.056; HR 0.99), for arterial thrombosis in particular of significance (p= 0.042; HR 0.99). A lower hemoglobin level is associated with a higher risk for venous thrombosis (p=0.007; HR 0.59). CONCLUSION Leukocytosis appears as a risk factor for thrombosis in general and also for arterial thrombosis in particular in WHO-diagnosed prefibrotic PMF. Moreover, higher platelet counts seem to decrease significantly the risk for thrombotic events in general and arterial thrombosis in particular. Anemia is associated with a higher risk for venous thrombosis. These observations are partly in line with recently published findings in WHO-diagnosed ET (Carobbio et al,2011) and might indicate the existence of a specific risk profile for thrombotic events in prefibrotic PMF. This is the first study reporting data on the risk profile for thrombosis in WHO-diagnosed prefibrotic PMF. Certainly these findings ask for validation in a larger patient population. Disclosures: Gisslinger: Novartis: Speakers Bureau; Celgene Austria: Research Funding, Speakers Bureau; AOP-Orphan Pharmaceuticals AG: Speakers Bureau. Vannucchi:Novartis: Honoraria.

Abstract Abstract 3833 Background: Survival in primary myelofibrosis (PMF) is assessed by the Dynamic International Prognostic Scoring System (DIPSS) (Blood 2010;115:1703) and DIPSS-plus (JCO 2011;29:392). The latter is based on eight risk factors including age>65 years, constitutional symptoms, hemoglobin <10 g/dL, red blood cell transfusion need, leukocyte count >25 × 109/L, platelet count <100 × 109/L, peripheral blood (PB) blasts ≥1% and unfavorable karyotype. Recent studies have highlighted the prognostic significance of monosomal karyotype (MK) (Blood 2011;117:5612), unfavorable karyotype (Leukemia 2011;25:82) and platelet count <100 × 109/L ((JCO 2011;29:392), for leukemic transformation (LT) in PMF. Methods: A combination of multivariable and receiver operating characteristic (ROC) analyses were applied to a Mayo Clinic database of 884 karyotypically-annotated patients with PMF, in order to define karyotype-dependent and karyotype-independent risk models for LT. The karyotype-independent model was further validated in a separate cohort of 525 PMF patients from an international database (Blood 2010;115:1703). Patients in the Mayo cohort were evaluated at time of referral and those of the international database at time of initial diagnosis. Results I: Sixty cases of LT were documented. Karyotype (categorized into MK, inv(3)/i(17q) abnormalities, other unfavorable, and favorable), PB blast percentage (as a continuous variable), and platelet count (as a continuous variable) were the most reliable (p<0.01) in predicting leukemia-free survival (LFS). The best discriminant levels for inferior LFS were MK (HR 6.2, 95% CI 2.2–17.1), inv(3)/i(17q) abnormalities (HR 7.6, 95% CI 1.8–33.3), PB blast ≥2% (HR 2.4, 95% CI 1.4–4.2) and platelet count ≤41 × 109/L (HR 2.6, 95% CI 1.3–5.1). MK and inv(3)/i(17q) abnormalities were subsequently consolidated into one “very high risk” cytogenetic category (n =27), with a corresponding HR of 6.6 (95% CI 2.7–16.0). HR-based risk scores were assigned to “very high risk” karyotype (2 points), PB blast ≥2% (one point) and platelet count ≤50 × 109/L (one point) to classify patients into low (no adverse points; n =522), intermediate (one adverse point; n =290) and high risk (two or more adverse points; n =72) groups; the corresponding 3-year LT rates were 3%, 10% (HR 2.6; 95% CI 1.4–4.6) and 35% (HR 9.4, 95% CI 4.7–18.7) (Figure 1). Results II: The karyotype-independent model was based on PB blast percentage and platelet count only; low-risk (no adverse points; n =525), intermediate-risk (one adverse point; n =311) and high-risk (two adverse points; n =48); the corresponding 3-year LT rates were 3%, 12% (HR 3.1, 95% CI 1.8–5.4; p<0.0001) and 25% (HR 6.0, 95% CI 2.6–14.1). The karyotype-independent model was validated in a separate cohort of 525 PMF patients with 70 documented cases of LT, from an international database (Blood 2010;115:1703). Conclusions: The current leukemia risk models are applicable at diagnosis or during follow-up, in the presence or absence of cytogenetic information, and complement DIPSS-plus in the comprehensive prognostication of patients with PMF. Disclosures: Vannucchi: Novartis: Honoraria.

Abstract Background Fedratinib (SAR302503) is a JAK2-selective inhibitor that has provided clinically meaningful reductions in MF-associated splenomegaly and symptoms in Phase I and II studies (J Clin Oncol 2011;29:789. Haematologica 2013;98:S1113). Here, we present efficacy and safety data from the Phase III JAKARTA study of fedratinib versus placebo in patients with MF (NCT01437787). Methods In this international double-blind, placebo-controlled, 3-arm study, patients aged ≥18 years with IPSS intermediate-2 or high-risk MF, platelet count ≥50 × 109/L, and splenomegaly were randomized (1:1:1) to receive placebo or fedratinib 400 mg or 500 mg, orally, once daily, in consecutive 4-week cycles. Patients who received placebo were eligible to cross-over to fedratinib (randomized 1:1 to 400 mg or 500 mg) following 6 cycles of treatment, or prior to Cycle 6 if the patient had disease progression. The primary endpoint was spleen response rate (RR) (≥35% reduction in spleen volume from baseline measured by MRI or CT at Week 24, and confirmed 4 weeks later). Secondary endpoints included symptom RR (≥50% reduction in total symptom score from baseline at Week 24, measured through a daily electronic eDiary using the modified Myelofibrosis Symptom Assessment Form [Cancer 2011;117:4869. Blood 2011;118:401]), and safety of fedratinib. Results A total of 289 patients were randomized: median age 65 years; 59% male; 63% primary MF; 48% high-risk MF; 67% JAK2V617F positive; 16% platelet count <100 × 109/L; median baseline spleen volume 2568 mL (range 316–8244); median baseline total symptom score 14.7 (0–57). Median (range) exposures for placebo, 400 mg and 500 mg groups were 24 (2–34), 30 (1–55) and 28 (1–60) weeks, respectively. Spleen RRs at Week 24 (placebo 1%; 400 mg 47%; 500 mg 49%), and confirmed at Week 28 (placebo 1%; 400 mg 36%; 500 mg 40%), were significantly (p<0.0001) higher in both fedratinib groups compared with placebo (Table). Nineteen patients had a spleen response at Week 24 not confirmed 4 weeks later (spleen reduction 25–35% [n=10]; image not available/evaluable [n=8]; image taken outside time window [n=1]). Spleen RRs by baseline platelet level are shown in the table. Patients treated with fedratinib had significantly (p<0.0001) greater improvements in MF symptoms compared with placebo (Table). The most common all grade non-hematologic treatment-emergent adverse event (TEAE) was diarrhea (16%, 66% and 56% of patients in the placebo, 400 mg and 500 mg groups, respectively). Grade 3/4 diarrhea was reported in 5% of patients in both the 400 mg and 500 mg dose groups. The most common hematologic TEAE was anemia (any grade 91%, 99% and 98%; Grade 3/4 25%, 43% and 60% in the placebo, 400 mg and 500 mg groups, respectively). Rates of Grade 3/4 thrombocytopenia were 9% (placebo), 17% (400 mg), and 27% (500 mg). Incidences of Grade 3/4 liver function tests (placebo/400 mg/500 mg) were: bilirubin, 2%/2%/1%; ALT, 0%/3%/3%; and AST, 1%/2%/2%. Overall treatment discontinuation rates up to 24 weeks of treatment were 25% (placebo), 22% (400 mg) and 32% (500 mg). Twenty-five patients died during the study (10, 5 and 10 in the placebo, 400 mg and 500 mg groups, respectively); the most common causes of death: disease progression (placebo [n=5]; 400 mg [n=3]; 500 mg [n=4]) and adverse events (placebo [n=4]; 400 mg [n=1]; 500 mg [n=4]). Conclusions In this Phase III, randomized, placebo-controlled, 3-arm study of 289 MF patients, treatment with fedratinib 400 mg or 500 mg once-daily demonstrated clinically meaningful and statistically significant reductions in splenic volume and MF-associated symptom burden versus placebo. Fedratinib had an acceptable safety profile, with the adverse events reported consistent with those observed in previous studies. This study was sponsored by Sanofi. Disclosures: Pardanani: Sanofi, Bristol Myers Squibb, PharmaMar and JW Pharma: Clinical trial support Other. Harrison:Novartis: Research Funding; Novartis, Sanofi, YM Bioscience, Celgene, SBio, Gilead: Honoraria; Novartis, Sanofi, Shire: Speakers Bureau; Novartis, Sanofi, YM Bioscience, SBio, Gilead: Membership on an entity’s Board of Directors or advisory committees. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Cervantes:Novartis: Speakers Bureau; Novartis and Sanofi: Membership on an entity’s Board of Directors or advisory committees. Mesa:Incyte, Genentech, Lilly, MS Pharma, Gilead: Research Funding. Jourdan:Sanofi: Honoraria. Vannucchi:Novartis: Membership on an entity’s Board of Directors or advisory committees. Drummond:Sanofi, Novartis, Celgene: Honoraria; TargeGen, Novartis: Speakers Bureau; Sanofi, Novartis, Celgene: Consultancy. Passamonti:Novartis, Celgene, Incyte, Sanofi, Roche: Honoraria. Neumann:Sanofi: Employment. Gao:Sanofi: Employment.

Abstract Background Myelofibrosis (MF) is a clonal myeloproliferative neoplasm (MPN) associated with a high degree of symptomatology, progressive cytopenias and potential to transform into acute myelogenous leukemia (AML). Thrombocytopenia amongst MF patients is a proven negative prognostic indicator and predictor of transformation to AML. Ruxolitinib is an effective JAK inhibitor for MF symptoms and splenomegaly, but is not indicated in patients with severe thrombocytopenia. Phase III trials of pacritinib have shown alleviation of the MF symptom burden amongst patients with thrombocytopenia (ASCO 2015 Mesa et. al.). In this study, we assessed the symptom burden of MF patients with significant thrombocytopenia who were naïve to pacritinib. Methods Data was assessed from a prospectively collected international database of MF patients in which demographics, disease features, and MF symptoms utilizing the myeloproliferative neoplasm symptom assessment form (MPN-SAF; Scherber et al, 2011). The MPN-SAF includes the patient's perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. Total symptom score (TSS) was computed based on symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. MF risk scores were calculated using the DIPSS criteria (Gangat, 2011). Thrombocytopenia was defined as a platelet count <100 x 10(9)/L, anemia was defined as hemoglobin<10 g/dL and leukopenia was defined as a white blood cell count <4.0 x 10(9)/L. Associations between the MPN-SAF individual symptoms were investigated using Pearson correlations. Results Demographic and Disease Features: A total of 418 patients with (n=89) and without (n=329) thrombocytopenia completed the MPN-SAF. Patients with thrombocytopenia were slightly younger (57.4 vs. 61.0, p=0.01) with longer disease durations (11.9 years vs. 8.8 years, p=0.0489) and had a higher prevalence of primary myelofibrosis (PMF; 82% vs. 66%, p=0.01). The presence of thrombocytopenia was associated with other laboratory abnormalities including anemia (60.7% vs. 25.3%, p<0.001) and leukopenia (34.8% vs. 52.3%, p<0.001), along with the need for red blood cell transfusions (34.8% vs. 14.6%, p<0.001). Patient cohorts did not differ by gender, DIPSS risk score, history of prior thrombosis or hemorrhage. In comparing patients with severe thrombocytopenia (<50 x 10(9)/L, n=43) to those with moderate thrombocytopenia (51-100 x 10(9)/L, n=46), severe thrombocytopenia patients were more likely to have anemia (74.4% vs. 47.8%, p=0.01) and require red blood cell transfusions (51.2% vs. 19.6%, p=0.002). Symptoms Scores for individual MPN-SAF items were assessed for each subgroup. Patients with thrombocytopenia had markedly higher total symptom scores than patients without thrombocytopenia (32.8 vs. 24.1, p<0.001). Individual scores were also higher for most items (fatigue, early satiety, inactivity, dizziness, sad mood, sexuality, cough, night sweats, itching, fever, weight loss, overall QOL)[Figure 1]. No significant differences in MPN SAF TSS or individual symptom scores were observed in comparing severe vs. moderate thrombocytopenia patients. Discussion MF patients with thrombocytopenia have distinctive clinical characteristics and face a significantly more severe symptom burden. Importantly, despite thrombocytopenia being a recognized risk factor for disease advancement, no correlations are noted between patient symptomatology and risk category. In addition, patients with severe thrombocytopenia do not differ symptomatically from patients with moderate thrombocytopenia despite having more severe anemia, leukopenia and transfusion requirements. This implies that the degree of symptomatology expressed by thrombocytopenic MF patients occurs independent from the exact platelet value. Conclusion The results of this study suggest that patients with thrombocytopenia will benefit from aggressive symptomatic control, potentially from targeted agents. Figure 1. MF Symptoms in Patients With and Without Thrombocytopenia Figure 1. MF Symptoms in Patients With and Without Thrombocytopenia Disclosures Kiladjian: Novartis: Consultancy; Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Incyte Corporation: Consultancy. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Shire: Speakers Bureau; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Gilead: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau. Cervantes:Novartis: Consultancy, Speakers Bureau; Sanofi-Aventis: Consultancy; CTI-Baxter: Consultancy, Speakers Bureau. Barbui:Novartis: Speakers Bureau. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Roy:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Vannucchi:Shire: Speakers Bureau; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis. Research- incyte, Gilead, cti, Genentech, promedior, NS Pharma: Consultancy.

Abstract Background: The Philadelphia chromosome negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) all have a time dependent risk of progression to either an advanced myelofibrotic state (post ET/PV MF) and/or to acute myeloid leukemia. The impact of disease duration upon the MPN symptom burden is not well understood, nor are the precise mechanisms of disease progression. We sought to better understand the impact of disease duration on MPN symptom burden. Methods: Symptom burden data was collected utilizing the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) amongst MPN patients, collected at the time of an office visit in an international cohort of MPN patients as previously described (Scherber et. al.). Symptom burden assessment was a previously validated 27-item symptom burden questionnaire scored on a 0-10 scale (0= as good as it can be, 10 = as bad as it could be). The patient or provider was asked to report the time since MPN diagnosis. MPN duration was determined to be early if the diagnosis was established between 0 to 5 years ago, intermediate if the diagnosis was established between 6 to 10 years ago, and late if the diagnosis was established 11 years ago or more. Anemia was defined as a red blood cell count less than 10 g/dL, leukopenia was defined as a white blood cell count was below 4 x 109, and thrombocytopenia if the platelet count was below 150 x109. Statistical significance was calculated using ANOVA f-test and chi squared. Results: Patient demographics and disease burden: A total of 1443 patients responded to the survey, including 592 (41%) ET, 549 (38%) PV, and 302 (21%) MF patients, including 181 (60%) primary MF, 67 (22%) post-ET MF, and 54 (18%) post-PV MF. Among MF patients, mean duration of MPN diagnosis was 9 years, and mean duration MF diagnosis was 4.7 years. Among respondents, 757 fit criteria for early disease duration, 353 fit criteria for intermediate disease duration, and 333 fit criteria for late disease duration. Respondent mean age was 62 years and approximately half of respondents were female (55%). Patients with longer diagnosis duration tended to be older (p=0.009) and were most likely to have anemia (0.02), leukopenia (p=0.01), or thrombocytopenia (p=0.03). These individuals were also most likely to have a history of hemorrhage (p=0.007) or require red blood cell transfusions (p<0.001). Combined cohort symptom burden: On average among the combined cohort of ET, PV and MF patients, symptoms tended to worsen with time with this effect being significant for symptom items of fatigue (BFI, p<0.04), concentration (p=0.007), insomnia (p=0.02), sexual difficulties (p=0.002), cough (p=0.03), night sweats (p=0.002), and pruritus (p=0.02). Symptoms of early satiety (p=0.004), concentration difficulties (p=0.01), insomnia (p=0.03), sexual difficulties (p=0.02), cough (p=0.01), and night sweats (p=<0.001) had significantly higher prevalence in those with longer disease duration. Similarly, the total calculated MPN-10 score (p=0.008) and quality of life assessment (0.03) demonstrated worsened outcomes with time (Table 1). No significant differences in symptoms for the combined cohort were observed among individuals diagnosed 0 to 1 years ago compared to those with a diagnosis established between 2 and 5 years ago. Symptom burden in MPN subtypes. When evaluating specific MPN types, patients with essential thrombocythemia experienced significantly greater sexual difficulties over time (p=0.03). The severity (p=0.01) and incidence (p=0.03) of pruritus and incidence of night sweats (p<0.001) were significantly increased over time for individuals with PV. For those with MF, the severity (p= 0.01) and incidence (p=0.009) of cough also significantly increased with longer diagnosis duration. Discussion Overall, significant worsening in symptom burden can be recognized over time for individuals diagnosed with MPNs. Diagnosis may not necessarily correlate with disease duration as the timing of diagnosis may be delayed from onset of disease. Given the intent of this abstract to evaluate changes with disease duration, we did not investigate correlations between symptom burden and cytopenias. We do know that risk factors for survival in the MPNs include older age and thrombosis, however, disease duration should be investigated as an alternative marker of burden in future survival studies. Disclosures Harrison: CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Shire: Speakers Bureau; Gilead: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Kiladjian:Incyte Corporation: Consultancy; Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Novartis: Consultancy. Zweegman:Celgene: Research Funding; Janssen: Research Funding; Takeda: Research Funding. Barbui:Novartis: Speakers Bureau. Etienne:Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; ARIAD: Consultancy, Honoraria, Speakers Bureau. te Boekhorst:CTI Biopharma: Consultancy; Novartis: Consultancy. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis. Research- incyte, Gilead, cti, Genentech, promedior, NS Pharma: Consultancy.

Abstract Abstract 4104 Background: The International Prognostic Scoring System (IPSS) for primary myelofibrosis (PMF) uses five predictors of inferior survival: age > 65 years, hemoglobin < 10 g/dL, leukocytes > 25 × 109/L, circulating blasts ≥ 1% and constitutional symptoms (Cervantes F et al. Blood 2009; 113: 2895). The dynamic IPSS (DIPSS) utilizes the same prognostic variables but can be applied at any time during the disease course (Passamonti F et al. Blood 2010; 115: 1703). IPSS-independent risk factors for survival have since been described and include unfavorable karyotype, red cell transfusion need and platelets < 100 × 109/L. Objectives: i) To determine if the aforementioned IPSS-independent risk factors for survival in PMF (i.e. unfavorable karyotype, red cell transfusion need and platelets < 100 × 109/L) are also DIPSS-independent. ii) To develop and validate a refined DIPSS model that incorporates DIPSS-independent prognostic factors for survival. iii) To establish a prognostic model for leukemia-free survival in PMF. Methods: The Mayo Clinic database for PMF was used to identify patients in whom bone marrow histologic and cytogenetic information was obtained at the time of their referral. WHO criteria were used for PMF diagnosis and leukemic transformation (Vardiman JW et al. Blood 2009; 114: 937). None of the patients in the current study were included in the original group of patients used to describe DIPSS (Passamonti F et al. Blood 2010; 115: 1703). Results: A total of 793 patients met the above-stipulated criteria. The study population was divided into two groups based on whether or not patients were seen at the Mayo Clinic within (n=428; training set) or beyond (n=365; test set) their first year of diagnosis. i) Objective 1: Multivariable analysis that included DIPSS risk category (low, intermediate-1, intermediate-2 and high risk), karyotype (favorable or unfavorable), platelet count (≥ or <100 × 109/L) and transfusion status (independent or dependent) was performed using the training set and all four variables were found to be significant as independent predictors of survival (p<0.0001, <0.0001, 0.0008 and 0.01, respectively). ii) Objective 2: Using the respective hazard ratios (HR) obtained during the multivariable prognostic analysis in the training set, HR-weighted adverse points were assigned: 3 points for high-risk DIPSS, 2 points for intermediate-2 risk DIPSS, and 1 point each for intermediate-1 risk DIPSS, unfavorable karyotype, platelets < 100 × 109/L or transfusion need. Accordingly, a refined DIPSS model (i.e. DIPSS-plus) was devised using the training set (Figure 1) and subsequently validated in the test set (Figure 2): low-risk (0 adverse points), intermediate-1 risk (1 adverse point), intermediate-2 risk (2-3 adverse points) and high-risk (4-6 adverse points). Considering the entire group of 793 study patients, the respective median survivals were 185, 78, 35 and 16 months (p<0.0001). ii) Objective 3: Multivariable analysis identified platelet count (p=0.0007) and karyotype (p=0.04) but not DIPSS or transfusion status as independent predictors of leukemia-free survival. We used these two variables to classify patients into a low (favorable karyotype and platelets ≥ 100 × 109/L) or high (unfavorable karyotype or platelets < 100 × 109/L) risk category for leukemic transformation; the respective 5- and 10-year risk of leukemic transformation were 6% and 12% vs. 18% and 31%, respectively (p<0.0001; HR 3.3, 95% CI 1.9–5.6). Conclusions: DIPSS-plus effectively incorporates prognostic information from karyotype, platelet count and transfusion status into the DIPSS prognostic model for PMF. Unfavorable karyotype or platelets <100 × 109/L is associated with a significantly higher risk of leukemic transformation in PMF. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 5060 Background: The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) is a concise instrument of patient reported outcomes (PRO) designed to assess the unique spectrum of symptoms present in the majority of patients (Mesa et. al. Cancer 2007). We sought to validate the Italian Translation of the MPN-SAF which addresses 19 separate symptoms reported by MPN patients. Methods: Translation: We utilized the standard practice of PRO translation in which 3 independent translations are created by 3 independent translators fluent in both languages. A fourth translator then discussed the translations with the other translators and a consensus translation was obtained. Validation: Patients self completed the MPN-SAF: Italian at the time of a physician office visit and the Italian EORTC-QLQ-C30 (a widely used instrument of PRO for cancer patients) was co-administered for validation purposes. Results: Patients and Symptomatic Burden: 186 patients were prospectively enrolled (ET (N=88; 47%), PV (N=69; 37%) and MF (N=29; 16%)) a median of 6 years (range:0-29) from their diagnosis. Patients were of a median age (62; range 29–91 years) and gender (56% females) typical of the disease. 72% (N=135) had received some form of non-aspirin medical therapy for their disease, and 68% were on therapy at the time of completing the questionnaire. Patients frequently had a history of either thrombotic events (31%) and/or hemorrhagic events (13%). The MPN-SAF measured 19 items in the enrolled patients (data summarized in Table 1). Validation Analysis: EORTC-QLQ-C30: Consistent with our experience with the MPN-SAF:English, Pearson correlations between MPN-SAF:Italian individual symptom scores and the Italian EORTC-QLQ C30 showed excellent correlations with co-validation questions including fatigue, pain, insomnia, (all p<0.001). Excellent correlations were demonstrated between EORTC-QLQ-C30 subscales and corresponding MPN-SAF measurements. Comparison with MPN-SAF:English: Comparison with 102 patients prospectively completing the MPN-SAF: English (ET=20, PV=23, MF=59) in the USA indicated very strong correlations (when controlling for MPN subtype) in the prevalence of all 19 items assessed and only subtle differences in terms of symptomatic severity for fatigue, itching and insomnia. Conclusions: The MPN-SAF:Italian is an easy to administer, clear, 19-item inventory of patient-reported outcomes that is specific to MPNs. Additionally, the instrument is validated by 1) comparison to previously validated Italian instruments and 2) the correlation with the MPN-SAF:English. Utilization of the instrument in Italian MPN clinical trials will allow for useful comparison to patients completing the MPN-SAF in other countries and will serve as a valuable clinical marker of disease symptom severity. Disclosures: Vannucchi: Novartis: Membership on an entity's Board of Directors or advisory committees. Mesa:SBio: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Incyte: Research Funding; Roche: Research Funding; eisai: Research Funding; telik: Research Funding.

Abstract Abstract 457 Introduction- The 2008 World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms (MPN) underscore the role of bone marrow (BM) morphology in distinguishing essential thrombocythemia (ET) from early, and at times prefibrotic, primary myelofibrosis (PMF) that clinically presents like ET. The value of such a distinction in predicting clinical outcome has been questioned by some investigators. Study Design- Clinician scientists and hematopathologists from seven international centers of excellence for ET convened to design a clinicopathologic database of patients locally diagnosed and treated as ET. Study eligibility criteria included availability of treatment-naïve BM specimens obtained within one year of diagnosis. All bone marrows subsequently underwent a central blinded re-review by the author of the pertinent WHO chapter (JT) who applied strict WHO guidelines to identify cases of early PMF that were spuriously diagnosed as ET. Results- Revision of the BM biopsies according to the WHO morphological criteria confirmed ET in 891 patients (81%). Diagnosis was revised to early, prefibrotic PMF in 180 patients (16%). The remaining 33 (3%) BM specimens were qualitatively inadequate for accurate classification or represented unclassified cases. i) At presentation, early PMF, as opposed to true ET, was characterized by higher leukocyte (p<0.0001) and platelet (p=0.002) counts, lower hemoglobin (p=0.01) and hematocrit (p=0.001) levels, higher serum lactate dehydrogenase level (p<0.0001), higher circulating CD34+ cell count (p=0.03) and higher rate of palpable splenomegaly. JAK2V617F mutational frequency was 60% in each of the two groups. ii) Median follow-up was 6.2 years for ET and 7.0 years for early PMF. During this period, the rates of arterial (1.2-1.4% patients/year) and venous (0.6 patients/year) thrombotic complications were similar in the two groups. However, patients with early PMF, as compared to those with ET, were more likely to develop overt myelofibrosis (1% vs. 0.5% patients/year; RR=2.0, p=0.04) or acute leukemia (0.6% vs. 0.1% patients/year; RR=5.2, p=0.001). Cumulative leukemic transformation rate at 10 and 15 years was 0.7% and 2.1% in true ET versus 5.8% and 11.7% in PMF Similarly, survival was significantly worse in patients with early PMF (mortality rate: 2.7% vs. 1.3% patients/year; RR=2.1, p=0.002).The 10 and 15-years overall survival rates were: 89% and 80% in true ET versus 76% and 59% in PMF. On multivariable analysis, other risk factors for poor survival were age > 60 years (HR=6.3, p<0.0001), a leukocyte count of > 11×109/L (HR=2.13, p<0.0001) and history of thrombosis (HR=3.0, p<0.0001). Conclusions- The current study validates the clinical relevance of strict adherence to WHO criteria in the diagnosis of ET and provides seminal information on the survival and risk of leukemic transformation in strictly WHO-defined ET, which appears to be substantially better than previously assumed. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 4095 Background: Symptomatic burden in myeloproliferative neoplasms (MPNs) is present in over 70% of MPN patients (Mesa et. al. Cancer 2007). We sought to validate a broadly applicable instrument (MPN-SAF) to assess symptoms in myelofibrosis (MF), essential thrombocythemia (ET) and polycythemia vera (PV). Methods: Using the previously validated MF-SAF as a base instrument, we added several key additional symptoms previously identified as present in all subtypes of MPNs including headaches, concentration, dizziness, extremity tingling, insomnia, sexual problems and mood changes on a 0 (absent) to 10 (worst-imaginable) scale. Validation: The MPN-SAF was administered jointly with the EORTC-QLQ-C30 as the co-validation instrument using prospective cohorts in the USA, Sweden and Italy. The translated MPN-SAF (Swedish and Italian) was created through a standard approach using teams of 4 translators working in concert. Results: Compiled MPN-SAF: Patient data: 402 MPN-SAF surveys were administered (English (25%), Italian (46%) and Swedish (28%)) in 161 ET patients (40%), 145 PV patients (36%), and 96 MF patients (24%), an average of 7.8 years (range 0 – 43 years) from their MPN diagnosis. Participants were of typical age (64.9, range 26 – 91 years) and gender (53% female) characteristic of disease. Prior hemorrhage (10%) and thrombosis (25%) were frequent. 68% of patients currently received cytoreductive therapy and 84% received cytoreductive therapy in the past. Patients and Symptomatic Burden: 19 items assessed in the MPN-SAF demonstrated consistently that the most common symptoms were fatigue (93%), decreased quality of life (84%), insomnia (65%), sad mood (65%), and sexuality problems (58%). The least common symptoms (<50% prevalence) were fevers (20%), weight loss (35%), abdominal pain (46%), cough (46%), headache (48%), and bone pain (49%). Symptoms were most severe in MF, followed by PV, then ET patients. Although symptoms are present in all 3 MPN subgroups, itching is notably more burdensome in PV patients (65%, median score of 2.8 out of 10). Additionally, abdominal pain, abdominal discomfort, early satiety and inactivity all are most prevalent and severe in MF. Interestingly, night sweats (present in 56%) overall had similar prevalence and severity across all 3 MPNs. The majority found the MPN-SAF easy to understand (98%) and “addressed most of my MPN symptoms” (96%). Comparison to EORTC-QLQ-C30: Strong correlations existed between individual items represented on both the MPN-SAF and the EORTC-QLQC30 including pain, fatigue, appetite and insomnia (all p<0.001). Additionally key symptomatic elements were highly correlated with the EORTC QLQ-C30 functional subscales. Comparison to Physician Perceptions: Comparison of the results of the MPN-SAF to enrolling physicians' blinded opinion of patients symptoms (6 assessed - night sweats, fevers, fatigue, weight loss, bone pain, and pruritus) showed excellent correlation with corresponding patients' responses except bone pain (all p<0.001). Comparison across Countries: When controlling for MPN subtype, responses between the three different countries (and 3 different languages the MPN-SAF was administered) demonstrated great consistency and correlation for all but 1 item, bone pain. Serial MPN-SAF Results: 51 patients in the USA (ET (17.6%), PV (25.5%), and MF (56.9%)), responded to a repeat MPN-SAF survey sent via US mail (50% response rate, mean time between surveys 190±63 days (range 43 – 257)). Pearson correlations indicate that most MPN-SAF items are well correlated (r >0.5, p<.001) upon repeat survey administration. Items characteristic of advanced disease, including weight loss, fever, and cough displayed lower Pearson correlations (r=0.46, -0.08, and 0.38 respectively). Intra-class correlations for test-retest reliability indicated that common features of disease, including mean BFI, inactivity, insomnia, and night sweats, were highly reproducible upon serial survey administration (ICC>0.7, 2, k model used). Conclusion: The MPN-SAF is comprehensive and reliable instrument which is available in multiple languages to evaluate MPN-associated symptoms. The MPN-SAF is recommended as a uniform symptom assessment tool for MPN patients participating in clinical trials globally. Disclosures: Vannucchi: Novartis: Consultancy. Samuelsson:Roche Sweden:. Harrison:Incyte: Honoraria; Novartis: Honoraria. Mesa:SBio: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Incyte: Research Funding; Roche: Research Funding; eisai: Research Funding; telik: Research Funding.

Abstract Abstract 1904 Poster Board I-927 BACKGROUND: Pomalidomide is an IMiDsó immunomodulatory drug that was created by chemical modification of thalidomide with the intent to reduce toxicity and enhance therapeutic activity. In a phase-2 randomized study of patients with myelofibrosis (MF), treatment with pomalidomide alone or in combination with a short course of prednisone was shown to be well tolerated and active in alleviating anemia ( JCO 2009). Herein, we report observations during the longer-term follow-up of those patients who had responded to a pomalidomide-containing treatment regimen. METHODS: Both primary and post polycythemia vera/essential thrombocythemia MF were included in the current study. Protocol eligibility criteria included absolute neutrophil count of × 109/L, platelet count of 50 × 109/L and hemoglobin level of < 10 g/dL. Patients with prior thalidomide or lenalidomide therapy were excluded from study participation. Response was assessed by the International Working Group for Myelofibrosis Research and Treatment criteria (IWG-MRT) (Blood. 2006). Pomalidomide was administered daily and continued indefinitely in responding patients. Prednisone was given for the first 3 months only, in a tapering dose schedule, starting at 30 mg/day. RESULTS: A total of 84 patients were enrolled from April 2007 through May 2008 and received treatment with pomalidomide alone 2 mg/day (n=22), pomalidomide 2 mg/day + prednisone (n=19), pomalidomide 0.5 mg/day + prednisone (n=22) or prednisone alone (n=21). Short-term toxicity details have previously been published (Tefferi et al. JCO 2009) and were remarkable for the lack of neuropathy and low prevalence of grade 3 or 4 myelosuppression (5–16%). Based on an intent-to-treat analysis, 16 (25%) of the 63 patients receiving pomalidomide alone or with a 3-month course of prednisone responded at a median of 1.8 months (range 0.9–6.9) from treatment initiation; all responses represented improvement in anemia with little or no effect on splenomegaly. Specifically, 12 of the 16 treatment responders became transfusion independent and the remaining 4 had a hemoglobin increase of > 2 g/dL (median best hemoglobin response = 11.9 g/dL; range 8.5–15.9). Responding patients usually displayed increases in platelet count but there was no consistent change in serum lactate dehydrogenase level. As of August 2009, ten (63%) of the 16 treatment responders were still in anemia remission and receiving pomalidomide therapy; median time on treatment was 19 months (range, 14–26) and median response duration was 17 months (range, 13-24). No new side effects emerged during this period. Six patients discontinued treatment because of either loss of response (n=5) or progressive splenomegaly/leukocytosis (n=1); 3 patients with continued anemia remission have had substantial increases in their spleen size, which qualifies as spleen progression per IWG-MRT. Among 9 patients with available cytogenetic information, all 3 with unfavorable karyotype relapsed while none of the 6 with favorable karyotype did. A small number of patients (n=7) had follow-up bone marrow examination at 1 to 2 years, at the discretion of their treating physician; none of these patients displayed any change in bone marrow fibrosis or JAK2V617F mutational status. Suppression of a monosomy 7 clone was documented in two patients. In one, the percentage of abnormal metaphases decreased from 90% to 15% after 11 months of treatment with pomalidomide but increased back to 100% four months later, when the patient relapsed while still on treatment. In the second patient, the percentage of abnormal metaphases was 65% at baseline, remained at 75% after 10 months of pomalidomide therapy, but decreased to 7% after one month of treatment discontinuation for relapse; a repeat examination in this patient after another 3 months (still off therapy) showed monosomy 7 and new additional abnormalities (including 4q21q25 deletion) in 65% of metaphases evaluated. CONCLUSION: Longer-term follow-up of pomalidomide-treated patients with myelofibrosis confirm the drug's favorable side effect profile. Also, the majority of treatment responders maintain their remission, which is exclusively anemia remission, for at least one year and several remain in remission after 2 years of therapy. The drug has limited effect on splenomegaly and progressive splenomegaly might occur in some patients despite continued remission in anemia. The presence of unfavorable cytogenetic abnormalities predicts relapse. Disclosures: Gale: Celgene: Employment.