Citations

Abstract Abstract 2852 Background: The 18-item Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF, Scherber et al Blood 2011) given in conjunction with the 9-item Brief Fatigue Inventory (BFI, Mendoza et al Cancer 1999) is a patient-completed questionnaire for assessing symptoms in persons with MPNs. The MPN-SAF has been translated and validated in 9 languages to date. The Total Symptom Score (TSS) is computed from 10 of the most pertinent MPN-SAF items to assess symptom burden in MPN patients and to evaluate response to therapy. Psychometric properties of the TSS have been previously reported (Emanuel et al Blood 2012). The purpose of this analysis is to compare MPN-SAF symptoms and psychometric properties of the TSS across 9 languages in an international sample. Methods: Data were collected in an international cohort of subjects with MPNs. Surveyed symptoms included fatigue, early satiety, abdominal pain and discomfort, inactivity, headaches, concentration, dizziness, extremity tingling, insomnia, sexual problems, mood changes, cough, night sweats, pruritus, bone pain and fever on a 0 (absent) to 10 (worst imaginable) scale. TSS was computed using the published scoring algorithm on a 0 (all symptoms absent) to 100 (all symptoms worst imaginable) scale. Demographic and disease-related data including disease type, gender, and age had to be present to be included in analysis. Demographics were compared across languages groups using ANOVA and chi-squared tests. Symptoms and TSS were compared across language groups using a general linear model adjusting for disease type, age, and gender with post-hoc Tukey pairwise comparisons. Internal consistency and factor structure of the TSS were investigated overall and within language groups using Cronbach's alpha and principal-axis factoring analysis. Results: Subject Demographics and Disease Type: 1,851 subjects with polycythemia vera (PV N=655), essential thrombocythemia (ET N=769) and myelofibrosis (MF N=427; 286 primary MF, 61 PV-MF, 80 ET-MF) were prospectively enrolled and administered the MPN-SAF and BFI in 1 of 9 languages: English [UK] 55, English [US] 102, Italian 186, Swedish 114, German 112, French 457, Spanish 192, Dutch 236, and Chinese 397. Age (median 61, range, 15–94) and gender (55% F) were typical. Disease type and age varied across language groups (both p <0.001). MPN-SAF Symptoms and TSS: Symptom frequencies ranged from 19% (fever) to 88% (fatigue) overall with mean severities ranging from 0.4 (SD=1.3, fever) to 4.3 (SD=2.3, fatigue). Fatigue had the highest mean severity among all symptoms within each language group. Overall, mean TSS was 21.5 (SD=16.7) with the Swedish (mean=18.1, SD=15.2) and Dutch (mean=27.6, SD=17.1) cohorts reporting the lowest and highest unadjusted TSS means, respectively. When comparing symptom items across languages (adjusting for disease type, age, and gender), concentration and sexual problems had the most statistically significant pairwise differences (11 and 10, respectively, out of a possible 36) followed by dizziness and overall quality of life (9 each, out of a possible 36). No statistically significant pairwise differences were observed for abdominal discomfort, headache, extremity tingling, or insomnia. For the TSS, the Dutch cohort appeared to statistically significantly differ (all p <0.05) with all other languages except the English cohorts. All other TSS pairwise comparisons were not statistically significant. TSS Internal Consistency and Factor Structure: The TSS had excellent internal consistency overall (Cronbach's alpha 0.83) as well as within language groups (Cronbach's alpha 0.81–0.86). Overall factor analysis identified a single underlying construct among the 10 TSS items. Factor loadings ranged from 0.41 for fever to 0.73 for inactivity. A single factor solution was appropriate for each language group with factor loadings ranging from 0.18 to 0.85. Conclusion: This analysis suggests that the available translations of the MPN-SAF are generally acceptable for use in a broad context. The TSS demonstrated acceptable internal consistency and similar factor structure across all language groups. Most symptom and TSS comparisons between languages were not statistically significant, but for the few which differed, further studies are needed to evaluate whether these variances are due to disease-related factors or due to linguistic or cultural influences present in the cohorts. Disclosures: Kiladjian: Novartis: Honoraria, Research Funding; Celgene: Research Funding; Shire: Honoraria. Griesshammer:Shire: Honoraria. Roy:Novartis, BMS: Speakers Bureau. Harrison:Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding. Passamonti:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.

Abstract Abstract 1726 Background: We previously reported that symptom burden among persons with ET and PV can be severe and adversely affect QOL. The presence of severe symptoms is linked to poor prognosis. There is considerable inter-subject heterogeneity regarding which symptoms are present in which subjects. No studies have empirically evaluated whether disease characteristics can be grouped in related symptom clusters. Using our previously validated 18 item Myeloproliferative Neoplasm Assessment Form (MPN-SAF) (Blood 2011;118:401–408) given in conjunction with the 9 item Brief Fatigue Inventory (BFI) (Cancer 1999;85:1186–1196), we sought to evaluate symptom burden by means of cluster analysis. Methods: Data was collected from an international cohort of subjects with MPNs including demographics, disease features and the completed BFI and MPN-SAF instruments. Surveyed symptoms included fatigue, early satiety, abdominal pain and discomfort, inactivity, headaches, concentration, dizziness, extremity tingling, insomnia, sexual difficulties, mood changes, cough, night sweats, pruritus, bone pain and fever on a 0 (absent) to 10 (worst-imaginable) scale. Development of symptom clusters was based on consideration of r-squared in hierarchical clustering using Ward linkage. Final cluster assignment was based on the nonhierarchical k-means method. Comparisons between symptom clusters were based on ANOVA and chi-squared tests. Results: Subject Demographic and Disease Characteristics: Data from 1,141 subjects with PV (N=519) and ET (N=622) was prospectively collected (Chinese 236, French 305, German 45, Italian 114, Dutch 191, English 56, Spanish 109, Swedish 85. Age (mean 59, range, 26–87) and gender (54% F) were typical. Five clusters were selected (Figure 1). Frequencies of prior bleeding, spleen size, anemia, presence of any lab abnormality, language, gender, and MPN type varied significantly between clusters (P<0.05). Cluster 1: The “Reduced Symptom” Profile (n=421 (37%; 60% ET, 40% PV) The largest cluster, subjects had increased complaints of sexual difficulties and fatigue. There was a slightly higher proportion of subjects with ET (60%) versus PV. There were fewer lab abnormalities (28% prevalence) and less prior bleeding (3%) compared to other clusters. Spleen size was smallest of the cluster (1 cm below costal margin). Cluster 2: The “Fatigue-dominant” Group (n=286 (25%; 56% ET, 44% PV)). Subjects in this cluster were predominantly female and had relatively few laboratory abnormalities (19%) than other cohorts. They are characterized by high severity of fatigue compared to end-organ symptoms. Symptom profiles emphasize fatigue, QOL and insomnia with some end-organ complaints. The cohor 63% of the cohort. Cluster 3: The “End-Organ Complaints” Group (n=210 (18%; 49% ET, 51% PV)). Male predominant (56%), subjects had mainly macro-vascular symptom complaints including sexual difficulties, insomnia, and overall QOL, with few microvascular related symptoms (low itching/night sweats). Cluster 4: “Cognitive Complaints” Cluster (n=110 (10%; 53% ET, 47% PV)). The smallest cluster and female predominant (64%), main complaints include fatigue, insomnia, loss of concentration, numbness, and sad mood. Cluster 5: The “Highly Symptomatic” Cluster (n=114 (10%; 44% ET, 56% PV)). Subjects had many cognitive complaints and symptoms correlated with severe micro-vascular abnormalities (pruritus) and or splenomegaly. This cluster had the largest spleen sizes (mean 3 cm), the highest prevalence of prior thrombosis (29%), and highest frequency of lab abnormalities (43%). Cognitive and end-organ complaints were rated as most severe. Conclusion: This analysis offers new means of evaluating persons with PV and ET utilizing symptom clusters. Laboratory and physical abnormalities differed significantly between symptom clusters indicating that our groupings likely result from biological alterations present in specific disease phenotypes. Future studies should investigate correlations between clusters and prognosis and genotype. Disclosures: Kiladjian: Celgene: Research Funding; Novartis: Honoraria, Research Funding; Shire: Honoraria. Roy:Novartis, BMS: Speakers Bureau. Harrison:Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Passamonti:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.

Abstract BACKGROUND: The presence of constitutional symptoms has been associated with increased mortality risk in myelofibrosis (MF) (Blood 2010;115(9):1703-8). New therapies exist which alleviate the severe symptom burden profile observed in MF patients but are only approved for use in those with intermediate-2 or high risk disease (N Engl J Med 2012;366:787-798). However, it has been proposed that there are patients who may benefit from symptom based treatment regardless of prognostic score (Am Soc Hematol Educ Program 2014;2014:277-286). We have recently characterized symptom score cutoffs at which patients would statistically benefit from treatment based on symptom scores alone (Scherber et. al. EHA 2016: a2250). These treatment thresholds included aMyeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS or MPN-10) total score of greater than or equal to 20, a worst individual item score of greater than 5, or a combined criteria of those with both an MPN-10 total score of greater than or equal to 20 and a worst individual item score greater than 5. This abstract represents an additional analysis of our MF cohort to better characterize the profile of patients who meet criteria for symptom-based therapy. METHODS: Patient demographics, symptom burden via the MPN-10 score (JCO 2012;30(33)4098-103), and disease traits were collected from MF patients and their physicians at a single time point during therapy. Previously we identified MPN-10 cutoffs via AkaikeÕs Information Criterion (AIC) analysis (Ecology 2014;95: 631-6), which represented the optimal model among all models specified for the data at hand to determine which patients would most benefit from symptom-directed therapy. RESULTS: Demographics. 695 MF patients without previousruxolitinib therapy were included in this analysis. Overall, of 455 patients (65.4%) fit a cutoff of having a single worst symptom item of greater than 5/10. 401 patients (57.7%) had a MPN-10 score of equal to or greater than 20. A total of 381 (54.8%) patients fit both of these criteria. A distribution of worse MPN-10 individual scores is shown in Table 1. Mean TSS score was 26.4 (SD=17.7). Symptom Criteria Associations. Demographics and disease traits: Neither mean age or age greater than 60 was significantly associated with meeting any of the symptom score cutoff criteria. Females were significantly more likely to meet any of the symptom score cutoffs (for all criteria, p=0.0003 or less). Patients with splenomegaly, particularly spleen size of greater than 15cm below the LCM, were significantly more likely than those with a normal sized spleen to meet any of the three criteria (spleen enlargement of any size p=0.014 or less; spleen greater than 15cm p=0.0114 or less). Patients who met any of the three symptom criteria tended to have a longer MPN duration, although this trend did not meet significance. A prior history of thrombosis was not associated with achieving any cutoff criterions. Symptom burden: Individuals who met the any symptom criteria were significantly more likely to have higher DIPSS prognostic risk score (for all p=0.0002 or less). Laboratory values: For those meeting criteria for a worst symptom greater than 5, mean WBC was 11.7 vs 9.1 x 109/L (p=0.025) and platelet count was 238.7 versus 329.1 (p=0.023). For those meeting criteria for a TSS greater than or equal to 20, mean WBC was 11.8 vs 9.5 x 109/L (p=0.04). For individuals meeting both criteria, mean WBC was 11.9 vs 9.5 x 109/L (p=0.034). The presence of peripheral blasts were significantly more common in patients with an individual worst symptom score greater than 5 (p=0.0364). Hemoglobin level was not significantly associated with symptom criteria for any cutoffs. CONCLUSION: Our analysis indicates that patients who would be treated based on symptom criteria are similar to patients who would be treated based on high risk features such as high DIPSS prognostic score, concerning blood count abnormalities (i.e., leukocytosis, thrombocytopenia, presence of peripheral blasts), and splenomegaly (particularly massive splenomegaly). Thrombosis history and age were not associated with criterion cutoff assignment, and it is notable that elderly age nor history of thrombosis alone would likely alter treatment choice other than anticoagulation. This data supports that JAK2 inhibitor treatment be strongly considered in patients meeting symptom based criteria. Disclosures Dueck: Bayer: Honoraria. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zweegman:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Schouten:Sanofi: Consultancy; Novartis: Consultancy. Etienne:ARIAD: Speakers Bureau; Pfizer: Speakers Bureau; novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau. Harrison:Shire: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Radia:Novartis: Honoraria; Pfizer: Honoraria. Cervantes:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mesa:Promedior: Research Funding; Celgene: Research Funding; CTI: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy.

Abstract Background: Chronic lymphocytic leukemia (CLL) patients exhibit variable times from diagnosis to the need to initiate therapy. Previous studies have demonstrated that the rates of CLL cell proliferation (birth) and elimination (death plus recirculation to solid tissues) could be estimated using the incorporation of deuterium (2H), taken in the form of heavy water (2H2O), into the DNA of dividing cells. In a cross-sectional study of patients with early and late stage CLL, birth rates above 0.35% per day were associated with more aggressive disease. The NIH-sponsored CLL Research Consortium (CRC) conducted a prospective study on patients with early stage disease to assess the relationship between CLL-cell birth rate and the length of time to initiation of initial therapy. Methods: Eligible patients had untreated early stage (Rai 0, 1 or 2) disease, and were no more than 3 years from diagnosis. Additional clinical parameters included age at diagnosis, gender, mutational status of the immunoglobulin heavy chain variable region (IGHV), 70-kD zeta-associated protein (ZAP-70) (binary split at 20%) and CD38 (binary split at 30%) expression, and FISH cytogenetics by the Dohner hierarchy. Heavy water was administered daily for 6 weeks, and peripheral blood was obtained for kinetic measurements at the end of weeks 3, 6, 9, 12, and 16. CLL birth rates for blood samples were measured at the same facility (KineMed, Inc, Emeryville, CA) by quantifying deuterium incorporation into the deoxyribose moiety of DNA of tumor cells, using isotope ratio mass spectrometry (IRMS). Subjects were followed for time to administration of therapy; subjects still without treatment at time of analysis were censored, as were subjects who exited the study to receive treatment outside of the established criteria. To assess the impact of birth rate and other factors on time to first therapy, Kaplan-Meier curves were compared using the logrank test for univariable analyses; stepwise Cox proportional hazards regression models were used to build multivariable models. Results: Between July 2005 and February 2009, 119 subjects were enrolled through the CRC. 107 subjects were eligible. For 10 eligible patients, exit from the study prior to completion of protocol-mandated heavy water consumption (n=5) or technical issues (n=5) made it impossible to obtain estimates of birth rate. The 97 eligible subjects for whom birth rates were available form the basis of this report. 60% of subjects were male; median age 57 years (range 40-85). Median birth rate was 0.32%/day (range 0.07-1.31%/day). 43 subjects (44%) had birth rates higher than the previously reported threshold of 0.35%/day. With a median follow up of 4 years, 33 eligible subjects (34%) required treatment. IGHV status (31 subjects unmutated), elevated ZAP-70 (31 subjects), elevated CD38 (21 subjects), and hierarchical categorization of FISH anomalies (4 del(17p), 5 del(11q), 8 tri(12), 50 del(13q)) were examined for association with differential time to first therapy in univariable analyses. All were associated with earlier need for therapy (p <0.001) except for genomic aberrations defined by FISH (p = 0.96). Birth rate > 0.35%/day was also significantly associated with shorter time to first therapy (p < 0.001). In multivariable modeling, only birth rate and IGHV status met the criteria for inclusion (Wald p-value < 0.05). Hazard ratios were 3.51 (p = 0.002) for birth rate above 0.35%/day and 5.0 for unmutated IGHV status (p < 0.001). The association between elevated birth rate and shorter time to first treatment was observed within subjects with both unmutated and mutated IGHV (see Figure 1). Conclusion: An increased birth rate of CLL cells early in the disease course is a strong predictor of an earlier need for treatment in univariable analysis, as are unmutated IGHV, elevated ZAP-70 expression and elevated CD38 expression. However, only unmutated IGHV and an increased birth rate contribute significantly to the multivariable model. This adds a direct measure of B-cell kinetics to the array of biomarkers available to subjects with CLL. Figure 1 Time to treatment by birth rate and IGHV status Figure 1. Time to treatment by birth rate and IGHV status Disclosures Murphy: KineMed, Inc: Equity Ownership. Emson:KineMed, Inc.: Employment, Equity Ownership. Li:KineMed, Inc.: Employment, Equity Ownership. McConnel:KineMed, Inc.: Equity Ownership. Turner:KineMed, Inc.: Employment, Equity Ownership. Busch:KineMed, Inc.: Equity Ownership. Hellerstein:KineMed Inc: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Chiorazzi:KineMed, Inc.: Stock options Other.

Abstract Abstract 1736 Background: Histone deacetylase inhibition (HDACi) has shown a potent inhibitory activity on the autonomous proliferation of hematopoietic cells of PV and ET patients carrying the JAK2V617F mutation (Leukemia. 2008;22(4):740–7). Hematological responses have been recorded during treatment with the HDACi givinostat in patients with PV and myelofibrosis (Blood. 2011; 118:a1748). Additionally, combinational use of givinostat and hydroxyurea (HU) have shown encouraging clinical response in PV (Br J Haematol. 2010;150:446–55). Recent laboratory studies of vorinstat-treated JAK2V617F knock-in mice have observed normalization of peripheral blood counts, markedly reduced splenomegaly and decreased mutant allele burden (Blood 2012; 119, 3779–89). Despite this evidence of hematologic response, to date no studies have evaluated specific changes in symptom burden among PV and ET patients treated with HDACi. METHODS ET and PV patients from the UK were enrolled in a non-randomized, open-label phase II multicenter study of the HDACi vorinostat (Haematologica 2011;96(s2):a1023). Patients were asked to complete the 18 item Myeloproliferative Neoplasm Assessment Form (MPN-SAF) (Blood 2011;118:401–408), 9 item Brief Fatigue Inventory (BFI) (Cancer 1999;85:1186–1196) and 30 item EORTC QLQ-C30 (J Natl Cancer Inst 1993; 85(5):365-76) at enrollment, week 12, week 24, and week 36. From weeks 1 through 24, participants were given 400mg of vorinostat daily and were observed from weeks 24 to 36. RESULTS Participant Demographics and Mutational Status: 15 PV and 10 ET patients were enrolled in the study. Median age of participants was 65 and 48% of participants were female. JAK2 mutations were present in 5/10 (50%) of ET and 14/15 (93%) of PV patients. Change in Symptom Severity with Vorinostat: Although most symptom severity changes did not reach statistical significance likely due to the small sample size, individual symptoms of headache (mean 1.6 baseline to 0.5 wk 36, mean maximum improvement 0.5 from baseline), dizziness (mean 1.6 baseline to 0.9 wk 36, mean maximum improvement 0.6 from baseline), sad mood (mean 2.6 baseline to 1.9 wk 36, mean max improvement 0.2 from baseline), and bone pain (mean 2.7 baseline to 0.8 wk 36, mean max improvement 0.7 from baseline) indicated consistent reductions in severity. Change in Symptom Incidence with Vorinostat: Non-sustained reductions in symptom incidence were seen with initiation of therapy for items of dizziness (50% baseline, 43% wk12, 55% wk 24, and 38% wk 36), numbness (65% baseline, 38% wk 12, 36% wk 24, 63% wk 36), sad mood (55% baseline, 47% wk 12, 40% wk 24, 50% wk 36), and itching (65% baseline, 50% wk 12, 40% wk 24, 75% wk 36). Change in MPN-SAF TSS Score with Vorinostat: Overall, MPN-SAF TSS did not vary significantly for the cohort over the course of the study (score change −.4 week 12, −0.5 week 24, −1.2 week 36, Figure 1). However, 9/17 participants who had a TSS of at least 6 at baseline had an overall improvement of at least 6 points (a moderate improvement) on at least one assessment after baseline. Of these, 5 of those 9 participants had an improvement of at least 10 points, which constitutes a large improvement in symptom burden based on a distributional definition of clinical significance using the standard deviation from a previous cohort. CONCLUSION This study represents the first analysis of symptom burden among PV and ET patients receiving vorinostat to date. In addition to previously identified changes in clinical and hematologic response, reductions in symptom burden including QOL and fatigue were observed in patients receiving vorinostat therapy which was most noticeable in patients with high baseline burden. The toxicity profile of vorinostat also suggests that better results might have observed if individualized assessment of clinicohematological responses including an integrated a marker for response into daily clinical practice and tailoring pharmacotherapy based on side effect profile (Leukemia. 2012;26(5):1148–9). Although further investigation among larger cohorts is needed, preliminary data is encouraging for successful therapeutic use of vorinostat in a clinical setting and with possible combinational therapy to reduce symptom burden among PV and ET patients. Disclosures: Harrison: Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.

Abstract Background: The Philadelphia chromosome negative chronic myeloproliferativeneoplasms (MPNs) including essential thrombocythemia (ET), polycythemia vera(PV), and myelofibrosis (MF) are a group of diseases of myeloid clonal lineage with significant symptom burden. MPN patients have also been found to have a high likelihood of mood disturbance related to their MPN, including symptoms of depression and anxiety (BMC Cancer. 201616:167). To date, the relationship between disease factors and depressive symptoms among MPN patients has not been well characterized. Methods: We have previously published the results of a 70-item internet-based survey which evaluated fatigue-relieving strategies among MPN patients (Cancer. 2016 Feb 1;122(3):477-85). Surveyed data included mental health questionnaires including a measure of symptoms of depression, the PHQ-2, (Ann Fam Med. 2010. 8(4): 348-353), a measure of positive and negative moods the POMS-short form (J Nerv Ment Dis. 1979;167(10):612-4) and a measure of symptoms of depression and anxiety, the MHI-5 (J Consult Clin Psychol. 1983. 51;730-742). This abstract is a secondary analysis of data collected among this cohort. Data: Demographics A total of 1788 individuals diagnosed with an MPN participated in the survey. 1389 patients answered questions regarding mood and psychological comorbidities. Many MPN patients reportedthat they had been seen by a health provider for care or diagnosis of depression (32%), anxiety (29.5%), stress (26.2%), or grief(15.0%). Overall, 24.0% of ET, 22.2% of PV, and 22.9% of MF patients endorsed symptoms of depression based on their score of greater than or equal to 3 on the PHQ-2. Demographic and Psychosocial Correlates Younger patients were significantly more likely to have PHQ-2 score of equal to or greater than three (57.0 years vs 59.5 years, p=0.0006). Gender, race, and country of origin did not significantly correlate with screening positive for symptoms of depression. Higher BMI was associated with a higher likelihood of screening positive for symptoms of depression (BMI 26.2 vs 24.6, p=0.005). Not surprisingly, having received treatment for mood problems in the last 6 months (p<0.0001) along with medications for mood disorders (p=0.03) were significantly associated with increased symptoms of depression. Specifically, the use of psychostimulants (p<0.0001), antidepressants (p<0.0001), anti-anxiety medications (p=0.0005) and prescription pain medications (p<0.001), were significantly associated with elevated PHQ-2 score. Individuals with lower educational attainment were more likely to endorse depressive symptoms (p=0.0001) as well as those who were unable to work from home due to a medical disability (p<0.0001). Tobacco use was significantly associated with depressive symptoms (p=0.0002). Symptom and Mental Health Correlates Increased MPN-SAF TSS (MPN-10) score and all individual symptom items in the MPN-SAF were significantly associated with symptoms of depression (p<0.0001, Table 1). Increased POMS-B Subscales scores and total score along with lower MHI score was associated with positive depression screening. When asking patients what interventions they had tried to reduce fatigue, those who endorsed volunteer activities (18% vs 25.4%, p= 0.0062) and exercise (19.7% vs 32.2, p<0.0001) were significantly less likely to screen positive for symptoms of depression. Prognostic Risk Scoring Correlates For MF, PV and ET prognostic risk scoring did not significantly correlate with PHQ score (for all, P>0.005). Conclusions Depression and mood disorders among individuals with malignancy represent a particular challenge for health care providers, particularly in MPN patients who have been found to have a higher risk of depression than the general population. In our cohort, prognostic risk did not correlate with risk of depression. Based on these findings, it is critical that physicians who see MPN patients should closely monitor these patients for signs of depression and provide appropriate treatment when needed. Continued investigation into treatment of mood disorders among MPN patients is warranted, as patients may benefit from both symptom-directed therapies as well as traditional therapies. Encouragement of volunteering and exercise activities should be considered for thesepatientsas participation may be associated with improved mood status. Disclosures Harrison: Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau. Mesa:Galena: Consultancy; Incyte: Research Funding; Gilead: Research Funding; Novartis: Consultancy; CTI: Research Funding; Promedior: Research Funding; Ariad: Consultancy; Celgene: Research Funding.

Abstract BACKGROUND: Symptom burden in essential thrombocythemia (ET) and polycythemia vera (PV) is severe even among individuals with low risk disease (Blood 2012. 12;123(24):3803-10). New therapies exist which alleviate the severe symptom burden and reduce splenomegaly in ET and PV patients (N Engl J Med 2015; 372:426-435). This analysis is the first to date to evaluate thresholds at which symptom-based treatment can be considered for ET and PV patients who are intolerant or resistant to hydroxyurea (HU). METHODS: Patient demographics, symptom burden, and disease traits were collected from ET and PV patients at a single time point during therapy. The MPN-10 total symptom score (TSS, JCO 2012;30(33)4098-103) was utilized to assess symptom burden. Symptom criteria models were determined as previously described among a population of MF patients (Scherber et. al. EHA 2016: a2250). Cutoffs were then evaluated in a cohort of ET and PV patients to assess for utility as a symptom model among this population. RESULTS: Demographics and symptom burden: 838 PV and 867 ET patients with previous hydroxyurea therapy were included in this analysis. Patients were of mean age (54.9 years ET, 64.0 years PV) and gender (69.2% female ET, 55.7% female). Mean disease duration was 6.0 years for ET and 7.3 years for PV.Among ET and PV patients, 15.0% and 24.2% had prior thrombosis respectively. In evaluating prognostic risk, ET patients tended to be low (45.5%) or intermediate risk (42.9%) with only a minority of patient meeting criteria forhigh risk disease (11.6%). Laboratory findings: ET patients had a mean platelet value of 598.7x 109/L(SD=283.4). Among PV patients, mean hematocrit was 45.8% (SD=8.1) and 42.6% of patients had a hematocrit of greater than 45%. White blood cell count was normal between the two groups (ET mean 8.3 x 109/L, PV mean 9.0 x 109/L). Symptoms: Mean worst symptom severity was 6.4 out of 10 (SD=2.7). Among ET patients, worst symptom was most frequently fatigue (32.7%, mean 5.0/10, SD=3.1, overall prevalence 88%) followed by night sweats (13.6%, mean 2.0/10, SD=3.0, overall prevalence 53%) and concentration difficulties (8.6%, mean 3.1/10, SD=3.0, overall prevalence 68%). For PV, worst individual symptom items were most frequently fatigue (29.2%, mean 5.2/10, SD=3.0, overall prevalence 91%), pruritus (14.1%, mean 3.2/10, SD=3.2, overall prevalence 69%), and night sweats (12.8%, mean 2.5/10, SD=3.0, overall prevalence 57%). Cutoff Scoring: 47.0% of ET patients fit criteria for TSSgreater than to equal to 20; 59.0%% had a single itemgreater than 5; and 45.7% had both a TSS greater than or equal to 20 and a single item greater than 5. Among PV participants, 54.5% had aTSS greater than to equal to 20; 66.1% had a single itemgreater than 5; and 51.5% had both a TSS greater than or equal to 20 and a single item greater than 5. Each scoring method was significantly associated with individual item scores (Table 1). Prognostic scoring was not significantly associated with any of the symptom cutoffs evaluated. Correlations: Among ET patients, a prior history of thrombosis was significantly associated with having a worst symptom item greater than 5 (p=0.043). ET patients with lower hemoglobin were significantly more likely to meet criteria for a MPN-10 score greater than or equal to 20 or to meet combined criteria for a MPN-10 greater than or equal to 20 and single worst item greater than 5 (for both p=0.01 or less). For PV, lower hematocrit levels were significantly associated with having an individual worst symptom score of greater than 5 (44.9% versus 46.7%, p=0.0376). CONCLUSION: Assessment of ET and PV symptoms, now measurable through standardized and practical instruments such as the MPN-10, is an integral part of determining therapeutic impact of newer therapies in both clinical practice and trial settings. In our modeling, patients with severe symptom burden profiles are well represented by utilizing cutoff criteria including aworst individual symptom item of greater than 5 out of 10, an MPN-10 score of greater than or equal to 20, or combined criteria of both cutoffs. These cutoffs can be considered when determiningwhich HU intolerant or resistant patients would most benefit fromsymptom orientedtreatment. Disclosures Kiladjian: AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding. Schouten:Novartis: Consultancy; Sanofi: Consultancy. Etienne:BMS: Speakers Bureau; ARIAD: Speakers Bureau; Pfizer: Speakers Bureau; novartis: Consultancy, Speakers Bureau. Harrison:Incyte Corporation: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Radia:Pfizer: Honoraria; Novartis: Honoraria. Cervantes:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mesa:Promedior: Research Funding; Celgene: Research Funding; CTI: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy.

Abstract MAJIC is a phase II trial of Ruxolitinib (RUX) vs Best Available Therapy (BAT) in essential thrombocythemia (ET) patients with resistance/intolerance to Hydroxycarbamide (HC) per European LeukemiaNet (ELN) criteria. Primary outcome was rate of complete hematological response (CHR) within 1 year (ELN criteria); secondary outcomes included partial HR, safety, thrombosis, hemorrhage, progression free survival (including transformation), molecular response (MR), symptom & quality of life (QOL) assessment. We present new data concerning molecular, symptom & clinical responses. Patients were stratified by JAK2V617F status, patient-reported symptoms & QOL determined using EQ5D, MDASI & MPN Symptom Assessment Form (MPN10), & compared using linear mixed models of post-baseline scores through month 12 adjusting for baseline; response was defined as ≥50% reduction in MPN10 total symptom score (TSS). JAK2/CALR/MPL allele burdens were assessed at baseline & 4 monthly. 110 patients were eligible for the modified ITT analysis, 58 (52%) & 52 (48%) in RUX & BAT arms respectively, comprising 44 males, 66 females, mean age 64.2ys, & resistant (24.5%), intolerant (51.8%) or both (22.7%) to HC. CHR was achieved in 27 (46.6%) of RUX patients vs 23 (44.2%) BAT patients (χ2 test p= 0.81). PHR occurred in 26 (44.8%) & 27 (51.9%) of RUX & BAT treated respectively. Grade 3 or 4 anemia occurred in 19% & 0% for RUX arm vs 0% (both grades) for BAT arm, grade 3 or 4 thrombocytopenia in 5.2% & 1.7% of RUX vs 0% (both grades) of BAT patients respectively. Grade 3 or 4 infections occurred in 10.3% of RUX patients vs 3.6% BAT arm. 9 RUX treated patients had 10 thrombotic events & 1 RUX patient a hemorrhage; vs 5 thrombotic & 5 hemorrhagic events in BAT patients (adjusted following central review). Transformations to post-ET MF occurred in 8 RUX vs 3 BAT treated patients, 1 RUX patient developed AML. 2 non-treatment related deaths occurred in each arm. Mean MPN-10 TSS & individual symptoms of early satiety & itching during the first 12 months were all significantly lower for RUX vs BAT (all p<0.05). Patients who achieved CHR had significantly better TSS, fatigue, inactivity, concentration problems, & MDASI symptom interference (all p<0.05) at baseline vs those without; however, scores during treatment did not appear to differ between CHR & non CHR groups after adjusting for these baseline differences. Allele burden during study & MRs (per ELN-IWG criteria Barosi Blood 2013) are shown in Table 1. Assays for JAK2 V617F were performed independently in 3 centres using qPCR (Guy's), TSCA NGS (Oxford) & amplicon-based NGS (Salisbury) & revealed Mean (range): JAK2 (Guy's): 33.2 (0.1-94.6), N=52; JAK2 (Oxford): 38.0 (0.5-92.2), N=52; JAK2 (Sal): 38.3 (0-90.0), N=50 (limited to JAK2 positive only). With Interclass Correlation Coefficient as follows ICC (Guy's v Oxford): 0.92 (95% CI 0.86-0.95) ICC (Guy's v Sal): 0.92 (95% CI 0.86-0.95) ICC (Oxford v Sal): 0.997 (95% CI 0.994-0.998). Notably MRs (n=5) only occurred with RUX treatment. There was no pattern of MR or progression with C/PHR or transformation, but 1 patient who transformed to PET MF had a complete MR. In a separate analysis baseline symptoms & QOL were not associated with JAK2, CALR, nor MPL status. Within RUX, baseline symptoms & QOL did not predict MR; however, fatigue, early satiety & abdominal discomfort (all p<0.05, Table 1) were significantly lower among those with MR vs not during treatment with a descriptively higher symptom response rate (2/4 [50%] vs 9/30 [30%]). Three non pre-specified multivariate analyses were performed to assess baseline factors influencing CHR (modelled for: treatment received, HC resistance or intolerance, white cell count, platelets, Hb & JAK2/CALR status); occurrence of ≥ grade 3 anemia or thrombocytopenia (modelled for: Hb (≥ 100g/dl) JAK2/CALR status); & transformation to PET-MF (modelled for: treatment, Hb ≤100g/dl). Only baseline Hb ≤100g/dl was significant for grade 3+ anemia (OR [95% CI]=0.17 [0.04, 0.72]), & PET-MF only occurred in patients with baseline WBC <10x109/L. This updated analysis shows that HC resistant/intolerant ET is clinically & molecularly diverse. We confirm that these patients are at high risk of thrombosis & transformation as suggested in prior retrospective studies. Molecular responses were limited to RUX & for the first time we demonstrate such responses may correlate with symptom improvement but not always with progression events. Disclosures Harrison: Shire: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Mead:Novartis: Honoraria, Research Funding, Speakers Bureau. Aliman:Novartis: Other: Institutional funding and grant for international conference. . Chen:Novartis: Other: Advisory Board. Coppell:Novartis: Other: Travel, accommodation and conference attendance. Knapper:ONO pharmaceuticals: Research Funding; Novartis: Honoraria, Other: Travel and expenses for international conferences. Ali:Novartis: Honoraria, Other: Conference sponsorship, advisory board meetings. Hamblin:Novartis: Other: Advisory Board. Dueck:Bayer: Honoraria. Cross:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Mesa:Celgene: Research Funding; Promedior: Research Funding; CTI: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. McMullin:Novartis: Honoraria, Speakers Bureau.

Abstract Background : Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by erythrocytosis, and in many cases leukocytosis and thrombocytosis. PV is driven by activating mutations in the JAK/STAT pathway, primarily JAK2V617F. For high-risk patients, a commonly used first-line therapy is hydroxyurea (HU); however, a subgroup of patients become intolerant of or resistant to HU. The phase 3 RESPONSE trial compared ruxolitinib (RUX) and best available therapy (BAT) in patients with PV who were intolerant of or resistant to HU (modified European LeukemiaNet criteria). Patients randomized in the BAT arm were permitted to cross over to receive RUX from Week 32 of the study. The results of the primary analysis comparing RUX to BAT prior to crossover have been reported, in which RUX was superior to BAT in achieving hematocrit control, reductions in spleen volume, and improvements in PV-related symptoms. This current analysis was conducted to evaluate the efficacy of RUX treatment in patients who crossed over from BAT relative to their original BAT treatment and relative to those originally randomized to RUX. Methods : Enrollment criteria included PV diagnosis, age ≥18 years, resistance to or intolerance of HU, splenomegaly, and phlebotomy requirement to control hematocrit. Patients were randomized 1:1 to receive open-label RUX 10 mg BID or BAT administered based on investigator judgment. BAT may have included HU, interferon/pegylated interferon, pipobroman, anagrelide, immunomodulators (eg, lenalidomide or thalidomide), or no medication. The protocol allowed for dose modifications (RUX, 5-mg BID increments [25 mg BID max]; BAT was adjusted per investigator judgment). Patients in the BAT group could cross over to RUX from Week 32 if they had not met the primary endpoint, or after Week 32 due to protocol-defined disease progression. The primary study endpoint was a composite of hematocrit control and a ≥35% reduction in spleen size at Week 32. Hematocrit was assessed at screening, every 2 weeks from Day 1 to Week 12, followed by every 4 weeks until Week 32, and 2, 4, 6, 8, 16, 24, and 32 weeks following crossover. Spleen volume was assessed by magnetic resonance imaging at screening and study Weeks 16, 32, 48, 64, 80 and every 32 weeks thereafter. The number of phlebotomy procedures was evaluated over time in each group. Results : A total of 110 patients were randomized to RUX and 112 to BAT; study discontinuation by Week 32 (before crossover was permitted) was 11% in both groups. However, most patients in the BAT arm crossed over to receive RUX treatment immediately after the Week 32 visit (84% between Weeks 32 and 48); only 3% of patients remained in the BAT arm compared with 85% in the RUX arm at the time of the data analysis (median 81-week follow-up). With up to 32 weeks on BAT therapy, 25% of patients in this group did not require a phlebotomy; in contrast, with up to 32 weeks on RUX, 79% of patients after crossover and 74% of patients initially randomized to RUX did not require phlebotomy. The number of phlebotomy procedures adjusted for 100 patient-years during BAT therapy was 196.8 vs 38.5 after crossover to RUX and 34.1 on randomized RUX treatment. Reduction in spleen volume from baseline at any visit occurred in 49% of patients receiving BAT, vs 73% of patients after crossover to RUX and 88% of patients initially randomized to RUX. The proportion of patients achieving at least a 35% reduction in spleen volume (best percentage change) was 1.8% during BAT treatment vs 38.5% after crossover to RUX and 60.0% during randomized RUX treatment. Conclusion : Treatment with RUX after crossover from BAT resulted in improved clinical outcomes compared with original BAT treatment. These findings support the primary RESPONSE results and further validate the efficacy of RUX in this patient population. Disclosures Kiladjian: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Masszi:Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Durrant:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa:Incyte Corporation: Research Funding; CTI: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Eli Lilly: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Sanofi: Research Funding; Celgene: Research Funding. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Li:Novartis Pharmaceuticals : Employment, Equity Ownership. Habr:Novartis Pharmaceuticals: Employment, Equity Ownership. Verstovsek:Incyte Corporation: Research Funding.

Abstract BACKGROUND: The study of rare diseases is limited by the uncommon nature of the conditions as well as the widely dispersed patient populations. Current rare disease registries such as the National Organization of Rare Diseases utilize centralized platforms for data collection; however because of their broad nature, these do not always capture unique, disease specific elements. Hairy Cell Leukemia (HCL) is a rare leukemia globally with approximately 900 new cases diagnosed in the US each year. The HCL Foundation undertook creation of a Patient Data Registry that collects data from multiple HCL Centers of Excellence (COE) around the globe to better understand the complications, treatment outcomes, disease subtypes, comorbid conditions, epidemiology, and quality of life of patients with HCL. METHODS: Investigators at The Ohio State University Department of Biomedical Informatics and Division of Hematology in collaboration with the HCL Foundation developed a Patient Data Registry (PDR) for the longitudinal capture of high quality research data. This system differs from other registries in that it uses a federated( rather than centralized) architecture, wherein data is queried and integrated in an on-demand manner from local registry databases at each participating site. Further, the data collected for use in the registry combines both automated exports from existing electronic health records (EHRs) as well as additional data entered via a set of web-based forms. All manually entered data comes from source documents, and data provenance spanning electronic and manually entered data is maintained via multiple technical measures. Patients may be enrolled at HCL COE, or, if they do not have access to a COE they may enroll via a web-based portal (www.hairycellleukemia.org). At this time due to regulatory requirements the web-based portal is available to US patients only. All data are de-identified (see Figure 1: De-Identification Workflow) which reduces regulatory burden and increases opportunities for data access and re-use. End users have access to data via a project-specific query portal. RESULTS: The Patient Data Registry has been deployed at The Ohio State University, Royal Marsden Hospital, and MD Anderson Cancer Center, and is undergoing deployment at the University of Rochester. Up to 25 international HCL COE may participate. In addition, US patients are actively entering the registry via the web-based portal. To date, 227 patients have been consented to the registry with 119 of these being via the web-based entry point. CONCLUSION: We created an international and web-based patient data registry which will enable researchers to study outcomes in HCL in ways not previously possible given the rarity of the disease. This work was made possible by research funding from the Hairy Cell Leukemia Foundation. Figure De-Identification Workflow Figure. De-Identification Workflow Disclosures Andritsos: Hairy Cell Leukemia Foundation: Research Funding. Anghelina:Hairy Cell Leukemia Foundation: Research Funding. Lele:Hairy Cell Leukemia Foundation: Research Funding. Burger:Pharmacyclics: Research Funding. Delgado:Gilead: Consultancy, Honoraria; Novartis/GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Infinity: Research Funding. Jones:AbbVie: 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; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lozanski:Beckman Coulter: Research Funding; Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding. Montserrat:Morphosys: Other: Expert Testimony; Vivia Biotech: Equity Ownership; Gilead: Consultancy, Other: Expert Testimony; Pharmacyclics: Consultancy; Janssen: Honoraria, Other: travel, accommodations, expenses. Parikh:Pharmacyclics: Honoraria, Research Funding. Park:Genentech/Roche: Research Funding; Amgen: Consultancy; Juno Therapeutics: Consultancy, Research Funding. Robak:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Tam:janssen: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Heckler:Hairy Cell Leukemia Foundation: Research Funding. Payne:Hairy Cell Leukemia Foundation: Research Funding.