Scherber, Robyn M.

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: 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: Myeloproliferative neoplasms (MPN) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are clonal hemopathies characterized by burdensome symptom profiles and impaired quality of life. Few studies have evaluated patient-reported outcomes during treatment with non-experimental pharmacological regimens. Aims: The Myeloproliferative Neoplasm Quality of Life (MPN-QOL) Study Group aims to objectively quantify MPN symptom severity, frequency and quality of life at baseline and throughout treatment with non-experimental therapies utilizing the Myeloproliferative Neoplasm Symptom Assessment Form - Total Symptom Score (MPN-SAF TSS; JCO 2012). In this abstract, we provide updated results for the prospective international cohort trial currently in active enrollment: the MPN Experimental Assessment of Symptoms by Utilizing Repetitive Evaluation (MEASURE) trial. Methods: This study aims to recruit 180 international ET, PV, and MF (including primary MF and post-ET or post-PV MF) patients receiving non-experimental medical therapy and/or phlebotomy. Patients complete the MPN-SAF for seven consecutive days at enrollment and repeat the survey for an additional seven consecutive days between 90 days and six months. Patients also complete the European Organisation for Research and Treatment of Cancer (EORTC) and M.D. Anderson Symptom Inventory (MDASI) instruments at enrollment and on the first day of the second assessment. At visits, physicians acquired demographic, laboratory, physical examination, and radiographic data. Descriptive statistics were used to summarize data. Results: Clinical Data The MEASURE trial opened for enrollment in 2012 and remains in recruitment phase with 15 participating international sites. To date, 39 patients have been enrolled and 25 have completed both study visits. Participants include ET (28%), PV (24%), and MF (48%; 50% primary MF, 8% post-ET, 42% post-PV) patients. The majority of patients are male (64%) and of expected age (mean 69.3, range 39-89) for the disorders. Seventeen percent had prior thrombosis, 9% required red blood cell transfusion, and none reported prior splenectomy or hemorrhage. Mean hematologic measures included hemoglobin 13.2 g/dL, WBC count 11.4 x109/L, ANC 8.5 x109/L, and platelets 514 x109/L. Therapies received prior to enrollment included aspirin (n=16), hydroxyurea (n=11), phlebotomy (n=8), warfarin/clopidogrel/anticoagulation (n=8), erythropoietin (n=2), and interferon (n=1). The most common current MPN therapies were hydroxyurea (n=9), aspirin (n=9), interferon (n=4), and phlebotomy (n=2). Symptom Assessment In comparing MPN-SAF TSS mean symptom scores, all symptoms except bony pain improved between the first and second visits, including fatigue, early satiety, abdominal discomfort, inactivity, concentration, night sweats, itching, fever, weight loss, and overall quality of life (Figure1). Total MPN-SAF TSS scores improved from a mean of 32.3 to 25.9. On the EORTC, mean scores for physical, role, emotional, and social functioning improved from the first to the second visit (Figure 2). Cognitive functioning showed a slight decline. Global health status measure improved from 60.2 to 72.9. On the MDASI, symptom severity scores decreased from 3.6 to 2.8 from the first to second visit (Figure 3). Symptom distress measure decreased from 4.1 to 3.0. Discussion: Interim results from the MEASURE trial demonstrate that standard, non-experimental treatment regimens offer improvement in quality of life-related symptoms on multiple patient-reported survey instruments including the MPN-SAF TSS, EORTC QLQ-C30, and MDASI. Updated data including symptom correlations and mutational analysis to be presented at the 2016 ASH conference. Disclosures Ross: Novartis Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria. Radia:Novartis: Honoraria; Pfizer: Honoraria. McMullin:Novartis: Honoraria, Speakers Bureau. Cargo:Novartis: Honoraria; Celgene: Honoraria, Research Funding. Sekhar:Novartis: Research Funding. Mesa:Gilead: Research Funding; CTI Biopharma: Research Funding; Galena: Consultancy; Ariad: Consultancy; Incyte: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Promedior: Research Funding.

Abstract Background Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) represent three of the most common Philadelphia chromosome negative myeloproliferative neoplasms (MPN). Individuals with these disorders suffer from excessive debilitating fatigue compared to age-matched controls. Although cytokine deregulation and impaired hematopoiesis contributes to the intrinsic causes of MPN-related fatigue, there may be contributory effects of underlying mood. To date few studies have prospectively evaluated the role of mood disorders on fatigue among this population. Methods A 70-item internet-based survey was developed by MPN investigators and patient/advocates and hosted by the Mayo Clinic Survey Research Center. The survey was promoted online via multiple MPN-related webpages including the MPN Forum, MPN Net, MPN Research Foundation, and MPN Voice during February/March of 2014. Surveyed data included disease demographics such as splenomegaly, thrombosis, hemorrhage transfusions, medications, and phlebotomies. The MPN-SAF (including the MPN 10), and Brief Fatigue Inventory were used to assess disease burden (Blood. 2011 14;118(2):401-8). Mental health was assessed using the Profile of Mood States (POMS-short form (J Nerv Ment Dis. 1979;167(10):612-4)), Patient Health Questionaire (PHQ-2 (Ann Fam Med. 2010. 8(4): 348–353)) and Mental Health Inventory (MHI-5 (J Consult Clin Psychol. 1983. 51;730-742)). Results Demographics: Overall 1788 MPN patients participated in the survey. Of these, 1676 consented to participate and provided additional data (answered at least 10 questions). Of these, 555 (33%) patients had ET, 651 (39.0%) have PV, and 417 (25.0%) have MF. Respondents were 68% female with a mean age of 59. Overall brief fatigue inventory score had a mean of 4.4 (range 0-10). MPN-10 score average was 28.4 (range 0-83). Psychological Comorbidities: Mental health assessments were obtained among participants. Mean PHQ-2 score was 1.6 (SD = 1.6, range 0-6.0). Twenty three percent of respondents scored greater than or equal to three on the PHQ-2 indicating a high probability of depression (mean = 1.6 (SD = 1.6, range 0-6)). Additionally, average MHI-5 score was 21.8 (SD = 4.9), with scores less than 60 likely representing a mental disorder with minimal misclassification rate (BMC Psychiatry. 2008. 19;8:10). Mean POMS-B score was 76.9 (SD=19.9, mean subscale scores: tension-anxiety 15.1, vigor-activity 6.0, fatigue-inertia 10.0, depression-dejection 15.5, confusion-bewilderment 14.3, anger-hostility 15.7). Patients frequently endorsed having being seen for or diagnosed with depression (32.0%), anxiety (29.5%), stress (26.2%), and grief (15.0%). Of participants, 22.2% had received active treatment of a mood disorder in the past 6 months. When queried on treatments of mood disorders, respondents often had received medication treatments (81.4%), counseling/therapy (40.3%), and group therapy (6.0%). Correlations: Many significant correlations were observed between MPN-SAF items and PHQ, MHI-5, and POMS-B (Table 1). When evaluating likelihood of depressive symptoms (as assessed by a PHQ), survey items including older age (p= 0.0006) and lower educational attainment (p=0.0001) were noted to have significant association with depressive symptoms . Higher BFI, MPN-10, and individual MPN-SAF scores were significantly associated with a higher likelihood of depressive symptoms (p<0.0001). Conclusions Overall many MPN patients reported having had coexisting mood disorders. The frequency of mood disturbance is likely greater than that in the general population (e.g., 11% of individuals in the primary care population have PHQ-2 greater than or equal to 3 (Ann Fam Med. 2010; 8(4): 348–353) and average control population POMS-B total mood disturbance score = 34.1 (BioPsychoSocial Medicine 2011, 5:6)). The causality of relationship between mood disorders and MPN-related fatigue severity is not entirely clear, fatigue could contribute to depressive symptoms, depression could cause fatigue, or it can be bidirectional. Thus mood disorders may represent a primary or secondary process in the disease course. Evaluation of MPN-related fatigue should be multifactorial, and should take into consideration underlying mood disorders as part of a comprehensive assessment and subsequent treatment regimen. Disclosures Harrison: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Gilead: Honoraria; SBio: Consultancy; Shire: Speakers Bureau. Mesa:Incyte: Research Funding; Novartis: Consultancy; Gilead: Research Funding; Genentech: Research Funding; Promedior: Research Funding; Ns Pharma: Research Funding; Celgene: Research Funding; Lilly: Research Funding; Cti: Research Funding.

Abstract Background: Philadelphia chromosome negative myeloproliferative neoplasms (MPN) include myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). Pertinent to these disorders is the high persistence, prevalence, and severity of fatigue. Overall, excessive fatigue compared to age and gender matched controls occurs in greater than 95% of MPN patients (Blood. 2011;118(2):401-8). Physiologic etiologies of fatigue in these patients include cytokine dysregulation and impaired hematopoiesis, however to date no one has investigated the impact that cofounding medical illnesses have on MPN fatigue burden. Methods: A 70-item internet-based survey was developed by a team of MPN investigators, patient advocates from MPN Forum, and hosted by the Mayo Clinic Survey Research Center. The survey was promoted online via multiple MPN-related webpages including the MPN Forum, MPN Net, MPN Research Foundation, and MPN Voice during late February to March of 2014. Surveyed data included disease demographics such as splenomegaly, thrombosis, hemorrhage transfusions, medications, and phlebotomies. The MPN-SAF (including the MPN 10) was utilized including the 10-item brief fatigue inventory was used to assess disease burden (Blood. 2011 Jul 14;118(2):401-8). Comorbid conditions were assessed, including hypothyroidism, anemias, sleep disturbances, obesity, and heart and lung disorders. Data: Demographics. Overall 1788 MPN patients participated in the survey. Of these, 1676 consented to participate and provided additional data (i.e., completed at least 10 questions). Of these, 555 (33%) patients had ET, 651 (39.0%) had PV, and 417 (25.0%) had MF. Among MF patients, 44.1% had primary MF, 29.7% had post-PV MF, and 26.2% had post-ET MF. Respondents were 68% female with a mean age of 59. Overall brief fatigue inventory score had a mean of 4.4 (range 0-10). MPN-10 score average was 28.4 (range 0-83). Medical Comorbidities. Overall, many patients endorsed having comorbid medical diseases that could contribute to overall fatigue (Table1). Overall 20.2% of patients endorsed having low thyroid function, with 10% indicating they obtained this diagnosis in the last six months. Twenty three percent endorsed having a new sleep disturbance in the last six months. On average, patients tended to have an average to above average BMI (mean =26.3, median = 25.0). However, many patients also experienced a high rate of unintended weight loss (11.8% with >11lb weight loss in the last 6 months). Cytopenias were also frequently encountered, with 14.7% of participants having required previous transfusions. Among these, 46% required transfusions in the last 6 months. Thrombosis (18.3%), hemorrhage (14.7%), and anemia (48.0%) were relatively common. In the last six months, 11.1% of patients required iron supplementation and 2.2% required erythropoietin injections. Many patients also endorsed the use of medications that could contribute to overall fatigue. Correlations. Items significantly correlated with worsened fatigue score (BFI greater than or equal to four) included female gender (<0.001), age (p=0.0047), lower education level (<0.001) and lower BMI (<0.001). Current use of alcohol and tobacco was also significantly associated with greater burden of fatigue (<0.001 and 0.0025, respectively). Items not significantly associated with fatigue included DIPSS (MF only), IPSET (ET only) or PV risk scoring. Conclusions Overall patients with MPN experience an exclusive pattern of disabling fatigue. Many fatigue-related medications and medical comorbidities may contribute to the debilitating fatigue seen among MPN patients, although no specific comorbidities could account for the high prevalence of fatigue. Rates of comorbid disease burden varied widely compared to the general population. For some diseases including diabetes, rates among MPN populations were less than the general population (National Diabetes Statistics Report, 2014), however the rates of other comorbidities, such as hypothyroidism, were higher (J Clin Endocrinol Metab 2002;87:489–99). Similar to our previous studies, females tended to suffer from a higher mean fatigue burden than males (Geyer ASH 2014). Clinical and research-related determination of fatigue should take into account cofounding comorbid medical conditions that can contribute to overall fatigue burden. Disclosures Harrison: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Shire: Speakers Bureau; CTI: Consultancy; YM Bioscience: Consultancy; Gilead: Consultancy; SBio: Consultancy. Mesa:Incyte: Research Funding; Novartis: Consultancy; Gilead: Research Funding; Genentech: Research Funding; Promedior: Research Funding; Ns Pharma: Research Funding; Celgene: Research Funding; Lilly: Research Funding; Cti: Research Funding.

Abstract Background Polycythemia vera (PV) is a clonal myeloproliferative disorder characterized by erythrocytosis, splenomegaly and a frequently burdensome symptom profile. Despite current guidelines of aspirin, phlebotomy, and selective cytoreduction, many patients have inadequately controlled PV-related symptoms and/or disease features. We performed a comparison of PV symptom burden/disease feature phenotypes to understand unmet needs in current medical management. Methods Data was collected prospectively amongst an international cohort of PV patients including symptom burden, demographics, and disease features. Subgroups were identified who had previously failed hydroxyurea (PV-HU), required ongoing phlebotomy (PV-P), had palpable splenomegaly (PV-S), or had all 3 features (PV-HUPS). Control groups were derived from the remaining PV patients lacking the specified subgroup trait; patients in whom the trait status was unknown were excluded from each respective control group. All participants completed the MPN specific symptom burden questionnaire (MPN-SAF TSS (MPN-10 – Table 1)) and had no prior history of splenectomy. Surveyed symptoms on the MPN-10 included the patient's perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. PV risk scores were calculated using the 2013 criteria (Leukemia 2013). Comparison of symptoms between groups employed t-tests. Results Patient Demographics and Disease Features Between Phenotypic Groups A total of 1334 PV patients completed the MPN-10, and were assigned to categories of PV-HU (499 [37%]), PV-P (646 [48%]), PV-S (369, [28%]), and PV-HUPS (148 [12%]). The demographics between these groups were similar (comparable age (median range 60-63), PV risk scores (mean risk range: Low 16.4-23.7%; Intermediate 31.4%-36.6%; High 42.8%-47%). Mean hemoglobin was similar among PV subgroups (range 14.4-14.9); PV-HUPS had a higher mean WBC count (20.3 g/dL vs. 8.8-11.8 g/dL) and platelet count (703.5 x 10(9)/L vs. 327.5-462.8 x 10(9)/L), and disease duration (11.5 years vs. 6.4-8.8 years). Prior thrombosis was most common in PV-S patients (28.5% vs. 21.8-25.2%) and prior hemorrhage was most common in PV-HUPS patients (23.8% vs. 13.7-15.8%). Symptom Burden The MPN-10 scores of each problematic PV phenotype (HU, P, S, HUPS) were compared to the remainder of the PV cohort lacking the trait (PV-control; Table 1). Both individual symptom scores and TSS were highest for PV-HUPS patients (mean TSS 32.5 vs. 27.7-29.2). All problematic PV subgroups demonstrated significant differences for individual symptoms and TSS compared to PV-control. Comparing "problematic" subgroup responses, PV-HU patients described more inactivity whereas PV-S patients described more early satiety and pruritus. No statistical differences were noted in PV-HU, PV-P and PV-HUPS patient responses to MPN-10 items of "fever" and "weight loss". Discussion PV patients who have either failed HU, are undergoing phlebotomy and/or have splenomegaly exhibit moderate to severe symptomatology and demonstrate unmet medical need for management. As evidenced in this study, considerable overlap in symptomatology exists in PV-HU, PV-P, PV-S and PV-HUPS. Current randomized trials of JAK inhibitors have demonstrated benefits in a PV-HUPS phenotype. This data suggests that PV patients with any evidence of inadequate control (PV-HU, P, or S) have similarly unmet needs and may be candidates for clinical trials, intensification of medical therapy or perhaps JAK inhibitor therapy. Disclosures Kiladjian: Shire Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding. Besses:Shire Pharmaceuticals: honoraria for educational lectures Other. Birgegard:Shire Pharmaceuticals: Consultancy, Honoraria, Research Funding. Etienne:Novartis, BMS, Pfizer, Ariad: Honoraria. Roy:Merck: Peg-Interferon provided for academic clinical trial in CML Other. te Boekhorst:Novartis: Consultancy. Griesshammer:Novartis: Honoraria; Shire: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Roche: Honoraria. Mesa:Incyte Corporation, CTI, NPS Pharma, Inc., Gilead Science Inc., Celgene: Research Funding.