Geyer, Holly L.

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) is a myeloproliferative neoplasm that is characterized by significant scar tissue and fibrosis in the bone marrow, enlarged spleen and/or liver from extramedullary hematopoiesis, and may include significant constitutional symptoms such as bone pain, night sweats, pruritis, and cachexia. The only curative therapy is allogeneic stem cell transplant. Although the symptom burden has been explored in the literature, the impact of hematopoietic stem cell transplant (HCST) on QoL in patients with MF has not been evaluated. We sought to longitudinally describe QoL in patients undergoing HCST for MF. Methods: We prospectively followed patients undergoing HSCT for MF. We assessed symptoms, functioning, and QoL using the FACT-BMT and MPN-SAF total symptom score (TSS) pre-transplant and at day 30, day 100 and one year post-transplant. Scores at the post-transplant time points were compared with baseline scores by paired t-tests. Pearson correlations between FACT-BMT and MPN-SAF TSS questionnaires were also computed. Results: 16 patients were enrolled [median age 64.0 (49-69) years; 13 (81%) male; 13 (81%) Caucasian], two did not have day 30 data as they died prior to then or did not go to transplant. Fourteen patients had day 30 information, 11 had day 100 information, and only 4 had one year information. Of the 14 who had day 30 information, 6 patients died within the first year, two from treatment related mortality and four from relapse. One patient had intermediate-1 risk, the remainder of the patients were intermediate-2 or high risk. All patients had RIC conditioning. Mean MPN-SAF TSS score was 28.1 (SD=14.2) and FACT-BMT total score was 99.8 (SD=17.4) at baseline. FACT-BMT and MPN-SAF TSS at baseline were inversely correlated; lower symptom score was associated with higher QoL (r=-0.62; p=0.01). FACT-BMT at day 30 was lower (mean change: -12.5, SD=16.7; p=0.03). Two MF-specific symptoms showed improvement that reached statistical significance compared to baseline: night sweats mean improvement day 30, 2.5 (SD=3.1; p=0.01) and mean improvement day 100, 1.7 (SD=2.6; p=0.05, Figure 1); headache mean improvement day 100, 1.5 (SD=1.9) p=0.02. In general, scores showed a worsening at day 30, improvement at day 100 and stability at one year. The MPN-SAF TSS worsened at day 30 (6 points) and improved by day 100 (4.5 points). Changes that showed improvement at day 100 include Brief Fatigue Inventory (BFI) with a mean improvement of 1.2 points and concentration (1 point). Of the four surveys that were collected at one year, a modest decline was noted in BFI (1.5 points), inactivity (1.5 points) and cough (3 points). However improvements were noted in night sweats (2.25 points), abdominal discomfort (1 point), insomnia (1.75 points), bone pain (1 point). Discussion: This is the first study to evaluate serially the QoL and symptom burden of patients who underwent a transplant for MF. A decline in QoL in the first 30 days was observed, with modest improvement at day 100. Few surveys have been completed at 1 year to date in this ongoing study. Collection of surveys past one year may be more informative regarding long-term impact of transplant on quality of life. Figure 1 Figure 1. Disclosures Mesa: Gilead: Research Funding; Novartis: Consultancy; Ariad: Consultancy; CTI Biopharma: Research Funding; Galena: Consultancy; Celgene: Research Funding; Promedior: Research Funding; Incyte: Research Funding.

Abstract Background We have previously reported on the high prevalence and severity of challenges with intimacy and sexuality amongst a large international cohort of MPN patients (Emanuel JCO 2012). We sought to further analyze the relationships between issues of intimacy (sexual desire and function), their relationships to MPN disease features, individual MPN symptom prevalence and severity, language, and overall quality of life. Methods Data was collected among an international cohort of patients with MPNs. Subjects completed the BFI, MPN-SAF, and EORTC QLQ-C30 instruments. Surveyed symptoms on the MPN-SAF 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. Specifically, the MPN-SAF sexuality item asked about “problems with sexual desire or function”. Total symptom score (TSS) was computed based on 10 symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. Pairwise associations between the MPN-SAF sexuality item and continuous and categorical covariates were investigated using Pearson correlations and analysis of variance/t-tests, respectively. Multivariate regression models were used to investigate impact of groups of covariates on the sexuality item with the final multivariate model selected using forward regression. Results Demographics A total of 1908 MPN patients (essential thrombocythemia=799, polycythemia vera=671, myelofibrosis=432, missing=6) completed the sexuality item. Participants were of typical age (median=60, range 15-94) and gender (female=53%). Overall, 1218 subjects described sexuality related complaints (score >0) with an overall mean symptom score of 3.5 (median=2.0, SD=3.7, range 0-10); 725/1908 (38%) patients had severe sexuality related complaints (score >4). Univariate Analysis Among the QLQ-C30 functioning scales, all domains had similar statistically significant correlations (r=-.26 to -.32, all p<0.001). Among QLQ-C30 symptom scales, all QLQ-C30 symptoms displayed correlations ranging between .08 and .29 (all p<0.001). Among MPN-SAF items, the MPN-SAF sexuality item correlated most significantly with the TSS (r=.41, p<0.001), along with MPN-SAF symptoms (r=.16 to .39; all p<0.001). MPN-SAF sexuality measure significantly differed by anemia (means: absent 3.3, present 4.5; p<0.001), leukopenia (means: absent 3.4, present 4.4; p=0.01), thrombocytopenia (means: absent 3.3, present 4.5; p<0.001), red cell transfusion (means: no 3.5, yes 5.0; p<0.001), MPN subtype (ET mean 3.1, PV mean=3.6, MF mean=4.4; p<0.001) and language (means ranged from 2.4 [Swedish] to 4.6 [Chinese]; p<0.001). MPN-SAF sexuality did not significantly differ by age, gender, prior thrombosis or prior hemorrhage. Multivariate Analysis In a multivariate model of MPN-SAF sexuality containing all QLQ-C30 functioning scales, physical (p=0.001), emotional (p=0.01), cognitive (p=0.005) and social (p=0.002) functioning were all statistically significant. Numerous symptoms were also significant in a multivariate model of MPN-SAF sexuality containing all other MPN-SAF symptoms (all p<0.05; abdominal pain, inactivity, dizziness/vertigo/lightheadedness, insomnia, depression/sad mood, cough, night sweats and overall QOL). The final multivariate model based on forward regression starting with all demographics, clinical variables, and patient-reported QLQ-C30 scales and MPN-SAF items found age, language, QLQ-C30 role functioning and MPN-SAF items (insomnia, depression/sad mood, night sweats and QOL) to be significant (p<0.05). Conclusions Sexuality related complaints have been linked to both physiologic and psychologic origins and are highly prevalent within the MPN population. The results of this study congruently identified close associations between sexuality and function within emotional, cognitive and social domains. Additionally, the correlations of sexuality issues with MPN symptoms and disease features further suggest this item is a key correlate of overall functionality and quality of life. Future investigations into the causative factors and biological correlates of this complaint may assist in addressing this ongoing challenge. Disclosures: Etienne: novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Roy:Novartis, BMS: Honoraria. Harrison:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria; Shire: Speakers Bureau; S Bio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Birgegard:Vifor Pharma: Honoraria. Mesa:Eli Lilly and Co: Research Funding; Genetech: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Sanofi: Research Funding; NS pharma: Research Funding; Celgene: Research Funding.

Abstract Introduction Myelofibrosis (MF) and Post PV/ET MF represents a group of debilitating hematological disorders in which quality of life (QOL) is severely compromised in most patients as a result of persistent constitutional symptoms, progressive cytopenias, and splenomegaly. Conventional therapeutic modalities have largely focused on symptoms palliation rather than cure. Allogeneic stem cell transplantion (ASCT) remains the only potential curative option for intermediate and high risk disease. Till now, outcome data for MF have historically focused on survival benefit. Until now, few studies have evaluated the QOL, financial burden, and symptom response in MF patients undergoing treatment including ASCT. The development of the Myeloproliferative Symptom Assessment Form Total Symptom (MPN-SAF TSS) score in 2012 allows us to objectively quantify with a standardized tool these crucial aspects of patients care. The Myeloproliferative Neoplasm Quality of Life (MPN-QOL) Study Group aims to objectively quantify symptomatic response to standard available treatments by utilizing the MPN-SAF TSS. We introduce two MPN-QOL prospective trials currently in active enrollment: The MPN Experimental Assessment of Symptoms by Utilizing Repetitive Evaluation (MEASURE) Trial and the Symptoms Yielded in Myelofibrosis Patients after Transplant as Objectified by MPN-SAF TSS (SYMPTOMS) Trial. Our intention with these studies is to quantify the QOL and symptom burden of PMF and post PV/ET MF patients undergoing treatment including ASCT. Methods The MEASURES trial is a prospective questionnaire based study evaluating the responsiveness of the MPN-SAF TSS in detecting symptomatic changes in target symptoms for an anticipated 180 ET, PV and MF (including primary MF, post-ET and post PV MF) patients receiving non-experimental medical therapy (aspirin, hydroxyurea, anagrelide, interferon, busulfan, melphalan, cladribine, thalidomide, lenalidomide, prednisone, danazol, ruxolitinib) and/or phlebotomy. Patients complete the MPN-SAF for seven consecutive days at the time of enrollment and repeat the survey for an additional seven consecutive days between 90 days and six months. Patients also complete the MDASI, EORTC and Global Impression of Change Items on the first day of the second assessment. Physicians acquire demographic, laboratory, physical examination and radiographic data, along with serial response assessments. In parallel, the SYMPTOMS trial is prospective questionnaire based study evaluating the QOL of patients undergoing ASCT utilizing MPN-SAF TSS, the FACT-BMT, Global Impression of Change, and a financial questionnaire. Patients will be evaluated at various time points pre-transplant, day 30, day 100 and 1 year post-transplant. Participants (N=110) will be prospectively enrolled from Mayo Clinic Arizona (MCA) with other centers to soon join. To date we have enrolled 5 patients from MCA on the SYMPTOMS trial and 32 patients on the MEASURES trial. Results Both trials began open enrollment in the summer of 2012 and remain in recruitment phase. Our updated preliminary data will be presented at the ASH 2013 meeting Conclusion Myeloproliferative Neoplasms have been associated with debilitating symptom profile that can significantly impair the QOL. We recognize the burden of this disease and treatment and have therefore initiated two ongoing parallel prospective trials with goals to quantify the QOL and symptom burden of MPN patients. By quantifying degree of burden and impairment in QOL in a standardized format in MPN patients undergoing a range of treatments, we will in the future be better able to inform our patients of the likely benefits and toxicities of the available treatment options. Disclosures: Birgegard: Vifor Pharma: Honoraria.

Abstract Background We have previously reported on the high prevalence and severity of insomnia amongst a large international cohort of MPN patients (Emanuel JCO 2012). We sought to further analyze the relationships between insomnia and the MPN disease features (in particular splenomegaly, status of blood counts), individual MPN symptom prevalence and severity, language, and overall quality of life. Methods Data was collected among an international cohort of patients with MPNs. Subjects completed the BFI, MPN-SAF, and EORTC QLQ-C30 instruments. Surveyed symptoms on the MPN-SAF 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. Specifically, the MPN-SAF insomnia item asked about “difficulty sleeping”. Total symptom score (TSS) was computed based on 10 symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. Pairwise associations between the MPN-SAF insomnia item and continuous and categorical covariates were investigated using Pearson correlations and analysis of variance/t-tests, respectively. Multivariate regression models were used to investigate impact of groups of covariates on the insomnia item with the final multivariate model selected using forward regression. Results Demographics A total of 1992 MPN patients (essential thrombocythemia=834, polycythemia vera=703, myelofibrosis=449, unknown=6) completed the insomnia item. Participants were of typical age (median=61, range-15-94) and gender (female=54%). Overall, 1307 subjects endorsed the MPN insomnia item (score >0) with an overall mean symptom score of 3.0 (median=2.0, SD=3.1. range=0-10); 603/1992 (30%) of patients had severe insomnia related complaints (score >4). Univariate Analysis Among QLQ-C30 functioning scales, emotional functioning most highly correlated with the MPN-SAF insomnia item (r=-.47, p<0.001) with all other domains also having statistically significant but slightly weaker correlation (all p<0.001). Among QLQ-C30 symptom scales, insomnia (r=.79, p<0.001) and fatigue (r=.45, p<0.001) most highly correlated with the MPN-SAF insomnia item with all other QLQ-C30 symptoms having correlations between .13 and .37 (all p<.001). Among MPN-SAF items, the MPN-SAF insomnia item correlated with all MPN-SAF items (all p<0.001) including the TSS (r=0.55, p<0.001) and most highly with depression (r=.52, p<0.001), concentration problems (r=.43, p<0.001), overall QOL (r=.41, p<0.001), night sweats (r=.41, p<0.001), and extremity tingling (r=.40, p<0.001). MPN-SAF insomnia significantly differed by gender (means: M 2.4, F 3.4; p<0.001), language (means ranged from 2.6 [Italian] to 3.6 [German]; p=0.01), anemia (means: absent 2.8, present 3.5; p<0.001), prior hemorrhage (means: no 2.9, yes 3.7; p=0.01), and requiring red blood cell transfusion (means: no 2.9, yes 3.6; p=0.03), with a trend for a difference by MPN type (ET mean=2.7, PV mean=3.0, MF mean=3.2; p=0.06). Multivariate Analysis In a multivariate model of MPN-SAF insomnia containing all QLQ-C30 functioning scales, physical, emotional, and cognitive functioning along with global health status/QOL were all significant (all p<0.001). Numerous symptoms were also significant in a multivariate model of MPN-SAF insomnia containing all other MPN-SAF symptoms (all p<0.05: headaches, extremity tingling, depression, sexual problems, night sweats, pruritus, fever, and QOL). The final multivariate model based on forward regression starting with all demographics, clinical variables, and patient-reported QLQ-C30 scales and MPN-SAF items found age, gender, QLQ-C30 emotional functioning and MPN-SAF items to be significant. Conclusions Insomnia is highly prevalent and severe in MPN patients and closely correlates with most other MPN-related symptoms and functional domains bearing a multi-faceted impact on overall quality of life. Correlations between insomnia and emotional, cognitive, and physical complaints including depression/sad mood, concentration problems, night sweats, and numbness/tingling in the extremities suggest that the cause of MPN-related sleep complaints is likely complex. Future studies should evaluate the impact of interventions on MPN associated insomnia as well as its biological underpinnings. Disclosures: Etienne: novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Roy:Novartis, BMS: Honoraria. Harrison:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria; Shire: Speakers Bureau; S Bio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Birgegard:Vifor Pharma: Honoraria.

Abstract Background Inflammatory deregulation may be a major factor in cancer related symptoms (Dantzer Nature Rev Clin Oncol 2012). Improved symptoms in myelofibrosis (MF) patients treated with single arm ruxolitinib (JAK1/JAK2 inhibitor) studies has been correlated with normalization of selected cytokines increased pre-therapy (c-reactive protein, IL-1ra, MIP-1b, TNF-a, and IL-6; Verstovsek NEJM 2010). We sought to assess the impact of JAK1/JAK2 inhibitor therapy on cytokine levels and the relationship between cytokine levels and symptoms prior to and during JAK1/JAK2 inhibitor therapy in the phase III placebo controlled COMFORT-I trial (Verstovsek NEJM 2012). Methods Cytokine levels (89 cytokines measured at baseline and at weeks 4 and 24) and MF symptoms (assessed by MFSAF 2.0 – Mesa JCO 2013) were collected during the blinded phase of COMFORT-I. Patients were randomized to ruxolitinib vs. placebo. Plasma was used for the measurement of cytokines using Rules-Based Medicine, Inc. (Austin, TX) Human MAP panel. Associations between the MFSAF total symptom score (TSS) and log2-transformed cytokine data were investigated at baseline using Spearman correlations and linear regression. Mixed models were used to assess cytokine and TSS changes over time within each arm and overall. Logistic regression was used to assess the relationship between baseline cytokines and TSS response (>/=50% reduction from baseline) at week 24, and between week 4 cytokine changes and TSS response (>/=50% reduction from baseline) at week 24 within each arm and overall. Mixed and logistic regression models combining data across arms also included terms for visit, arm, and visit-by-arm interaction. All models also included age, gender, and body mass index (BMI). Given the large number of cytokines being investigated, p<0.001 was considered statistically significant. Cytokine values below the limit of detection were set at the lowest limit of detection and 25 cytokines were excluded from statistical analysis due to having more than 30% of data missing or below the limit of detection. Results Patients: 309 subjects were randomized in COMFORT-I with median age 68 (range 40-91), 46% female, 50% primary myelofibrosis, and 61% high risk. All 309 subjects had cytokines measured at one or more of the three visits included in this analysis, with 308 having cytokine values paired with a TSS score at the same visit. Cytokines at Baseline: At baseline, the highest Spearman correlations with symptomatic burden (as assessed by the TSS) were observed for APOA1 (rho=-.21) and FERRITIN (rho=-.20), followed by INTLK5, MIP1A, MMP3, INTLK2, MGB, INTLK1A, and INTLK7 with correlations between -.15 and -.17 (all p<0.01). After adjusting for age, sex, and BMI, VCAM1 and APOA1 were significantly associated with TSS at baseline. Cytokine and Symptom changes during trial: Changing levels of 5 cytokines were significantly associated with change of TSS over time beyond the change due to visit, arm, visit-by-arm interaction, age, sex and BMI including VCAM1, LEPTIN, TIMP1, B2MICG, and TNFRII. Within the placebo arm, only 5 cytokines significantly changed over time compared to 46 cytokines in the ruxolitinib arm (visit-by-arm interaction was significant for 43 in the overall models). VCAM1, B2MICG, and TNFRII were among the 5 cytokines which changed in the placebo arm, and VCAM1, LEPTIN, TIMP1, B2MICG, and TNFRII were among the 46 cytokines which changed in the ruxolitinib arm. No baseline cytokines and no changes in cytokines at week 4 univariately predicted week 24 TSS response within either arm at the p<0.001 level. Conclusions In the first serial assessment of MF symptoms and plasma cytokine levels in the conduct of a placebo controlled trial we found 5 cytokines in which improved levels correlated with decreased MF symptom burden in ruxolitinib treated patients. Development of a multivariate model for predicting symptom response, correlations with splenic response and impact on survival benefit of therapy is ongoing. Disclosures: No relevant conflicts of interest to declare.

Abstract Background We have previously reported on the significant, but heterogeneous baseline MPN symptom burden among an international sample of MPN patients (including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF)) utilizing the MPN Symptom Assessment Form (MPN-SAF) and the derivative Total Symptom Score (MPN-SAF TSS). Recent clinical trials have sought to determine optimal MPN symptom response criteria, such as absolute 10 point improvement in MPN SAF TSS for ET/PV (ELN Criteria, Barosi et. al. Blood 2013) and 50% reduction in MPN-SAF TSS for MF (IWG-MRT, Tefferi et. al. Blood 2013). We sought to determine the role of improvement in MPN-SAF TSS quartiles as potential thresholds to assess symptomatic response to therapy. Methods Utilizing prospectively gathered MPN-SAF TSS (Emanuel et. al. JCO 2012) in patients we assessed potential thresholds of response by evaluating quartile thresholds for severity of symptom burden. The MPN-SAF TSS was scored as the average of 10 symptoms (individual symptoms scores of 0-10, with a total score of 0 (best) to 100 (worst)). MPN-SAF TSS quartiles were identified by the percentage of scores between 0-24% (quartile 1 (Q1)), 25-49% (quartile 2 (Q2)), 50-74% (quartile 3 (Q3)), 75-100% (quartile 4 (Q4)). Results MPN-SAF TSS Quartiles: MPN-SAF TSS quartiles were identified among 1858 MPN patients (ET N=775, PV N=654, and MF N=423). Overall MPN-SAF TSS scores of 0 - 7 were designated as Q1, 8 - 17 as Q2, 18 - 31 as Q3, and ≥ 32 was as Q4. MPN-SAF TSS scores were significantly different between clusters (p<0.001). Associations Between Quartiles and Demographic/ Disease Factors: As quartiles increased, the proportion of PV and ET patients diminished and MF increased (Table 1, p<0.001). Cytopenias and transfusion dependence increased in prevalence in the higher quartiles (p<0.001). A history of prior thrombosis was also significantly more prevalent in the quartiles with highest symptom burden (p<0.001). The prevalence of women was significantly higher among the more symptomatic quartiles females 48.9% Q1, 49.4% Q2, 58.4% Q3, and 60.1% Q4; p<0.001). Associations Between Individual Symptoms and MPN-SAF TSS Quartiles: All individual symptoms measured in the MPN-SAF TSS were significantly worse in quartiles as they increased (p<0.0001). Evaluation of Prognostic Scoring and MPN-SAF TSS Quartiles: Comparison of each patients individual risk score (IPSET, PV, DIPSS for MF) and worsening symptom quartile showed the highest correlation with MF patients (DIPSS) (Table 1). However, ET and PV risk scores were not surrogates for symptom burden by quartile. Conclusions Distribution of MPN patient symptomatic burden by MPN-SAF TSS quartiles provides an easy-to-calculate method to cluster and analyze MPN patients of similar burden. Although MF patients are most prevalent in the most severe quartile of MPN symptomatology it is notable that Q4 has many patients with PV and ET. Future prospective efforts are ongoing to assess the potential of using changes in quartile (i.e. improving from Q3 to Q1) as potential symptomatic response thresholds. Disclosures: Etienne: novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Roy:Novartis, BMS: Honoraria. Harrison:Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees; S Bio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Shire: Speakers Bureau; Celgene: Honoraria; YM Bioscience: 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, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vannucchi:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Birgegard:Vifor Pharma: Honoraria.

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.

Abstract Abstract 5061 Background: Ruxolitinib was approved for commercial use for the therapy of intermediate- and high-risk myelofibrosis (MF) in the USA in November 2011. We sought to assess the initial clinical experience on the use of ruxolitinib outside of the clinical trial setting at our high volume MPN program. Methods: Twenty-eight patients with intermediate- or high-risk myelofibrosis (including PMF, post-PV and post-ET myelofibrosis) prescribed ruxolitinib at our center within the first seven months after FDA approval were included in this analysis. Baseline disease information, treatment history, dynamics of ruxolitinib dosing, impact on cytopenias, splenic response, and symptoms were assessed. Results: A total of 28 patients with post-ET MF (n=7), post-PV MF (n=6) and primary MF (n=15) began ruxolitinib between November, 2011 and May, 2012. Twenty-seven patients had been treated with previous therapies. The JAK2V617F mutation was present in 79% of patients. The mean number of weeks from diagnosis of MF to treatment with ruxolitinib was 218 (8–929). The average spleen size at the start of therapy was 11. 5cm (0–36) below the left costal margin. DIPSS Plus scores classified patients as Intermediate-1 (53%), Intermediate-2 (29%) and High risk (18%). Symptoms at the start of therapy included fatigue (78%), early satiety (25%), night-sweats (68%), abdominal pain (61%), pruritis (32%), weight-loss (57%), bone pain (21%), and fevers (11%). The average hemoglobin concentration, WBC count and platelet counts were 10. 9 g/dL (7. 6–13. 8), 13. 5 × 10(9)/L (3. 1–53. 8) and 295 × 10(9)/L (32–844) respectively. The median duration to follow-up was 72 days (4–144 days). The majority of patients began therapy at 20 mg BID (68%). Most patients seen in follow-up experienced reduction in splenic size (64%), 36% of which had complete resolution of palpable splenomegaly within a mean follow-up of 78 days (10–142). Significant improvements were noted in symptoms including fatigue (68%), early satiety (71%), night sweats (47%), abdominal pain (71%), pruritis (55%), weight loss (69%), bone pain (33%) and fevers (33%). Dosage reductions were required for four patients with anemia (n=3) and thrombocytopenia (n=1). Two patients required the addition of anagrelide/hydroxyurea for platelet counts >1, 000 × 10(9)/L. Excluding patients with preexisting thrombocytosis >600 × 10(9)/L, the percentage reduction of platelets from baseline by weeks 4, 9 and 15 were 34%, 13%, and 12% respectively. Eight patients required red blood cell transfusions for anemia, three of which who had begun therapy with hemoglobin concentrations under 9 g/dL. Excluding the 8 transfusion-dependent patients, the percentage reduction in hemoglobin concentration from baseline by weeks 4, 9, and 15 was 7%, 6%, and 14% respectively. Non-hematological toxicities requiring dosage adjustments included hyperkalemia (n=1) and fatigue/dizziness/headaches (n=1). Five patients underwent dose increases for lack splenic (n=3) and symptomatic (n=2) response. Six patients discontinued the drug for disease progression requiring stem cell transplant (n=2), lack of constitutional symptom improvement (n=1), diarrhea (n=1), thrombocytopenia (n=1) and anemia (n=2). Five patients had platelet counts below 100 × 10(9)/L (19–94 × 10(9)/L) and began therapy at reduced starting doses. All patients seen in follow-up reported significant improvements in symptoms and splenomegly was reduced >50% in two patients seen in follow-up within 4 weeks of initiating therapy. Two patients underwent dose increases after 5 months of therapy to enhance response. No bleeding events were reported. By week 15, no decrease was noted in platelet levels from baseline in the 3 patients seen in follow-up. Two patients required danzol (n=1) or platelet transfusions (n=1) for thrombocytopenia. Conclusion: Randomized controlled trials have proven ruxolitinib's efficacy in reducing constitutional symptoms, cytopenias and splenomegaly in myelofibrosis patients. This study represents a confirmation of the efficacy this drug provides in reducing splenomegaly and symptoms observed in clinical trials when utilized in a standard practice setting. Toxicities are minimal and have been generally well controlled with dose reductions, even in patients with baseline thrombocytopenia. In conclusion, ruoxlitinib appears to be an efficacious and well-tolerated therapy with limited adverse effects. Disclosures: Mesa: Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.