Mesa, Ruben A.

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 Introduction: The impact of genomic alterations, such as mutations in ASXL1, on the risk of disease progression and leukemic transformation in patients with myelofibrosis (MF) is well established. Further, emerging data suggests that the number and type of mutations may impact response to therapies such as ruxolitinib or imetelstat. Allogeneic hematopoietic stem cell transplant (allo-HSCT) remains the only potentially curative treatment for MF patients. However, the impact of somatic mutations on overall survival (OS) and relapse-free survival (RFS) is poorly understood. Using next-generation sequencing of pre-transplant blood and bone marrow samples from a well clinically-annotated cohort of MF patients who underwent allo-HSCT, we sought to determine the impact of mutational burden on outcomes. Methods: A multicenter retrospective analysis of a cohort of 84 patients was carried out. This included 52 patients treated on the MPD-RC 101 prospective study (NCT00572897), 18 patients treated at Prince Margaret Hospital, and 14 patients treated at Memorial Sloan Kettering Cancer Center. Patient and transplant characteristics are displayed in Table 1. DNA was extracted from pre-transplant bone marrow aspirate samples or peripheral blood samples. High-throughput sequencing of a panel of genes was performed. Average coverage of 829x (standard deviation of ±130) was obtained. Mutect was utilized to call single point variants (comparing our samples to a pool of normal samples) and PINDEL was used to call short insertions and deletions. We excluded all mutations present in at least one database of known non-somatic variants (DBSNP and 1000 genomes) and absent from COSMIC. Univariate Cox regression and Kaplan-Meier graphics were used to investigate the association of patient, transplant, and disease characteristics with OS and RFS. Results: JAK2V617F was the most frequent mutation detected in 41(48.8%) patients (Table 2). Eighteen patients (21.4%) had triple negative disease (negative for JAK2, MPL, and CALR mutations). Univariate analysis included the following: patient characteristics (age, gender), transplant characteristics (related vs. unrelated donor, matched vs. mismatched donor and myeloablative vs. reduced intensity conditioning) and disease characteristics (DIPSS and presence of mutations). Decreased OS was associated with unrelated donor status (HR 2.09, 95% CI: 1.03-4.23, p=0.04), reduced intensity conditioning (HR 4.21, 95% CI: 1.01-17.59, p=0.049), triple negative disease (HR 2.09, 95% CI: 1.02-4.30, p=0.04), and presence of U2AF1 (HR 2.53, 95% CI: 1.10-5.81, p=0.03) or SUZ12 mutations (HR 3.92, 95% CI: 1.19-12.21, p=0.02). Decreased RFS was associated with unrelated donor status (HR 2.27, 95% CI: 1.16-4.45, p=0.02), and the presence of SUZ12 mutation (HR 6.97, 95% CI: 2.37-20.49, p<0.001). A descriptive decrease in RFS in patients with U2AF1 (HR 2.15, 95% CI: 0.94-4.88, p=0.07) was observed but did not reach statistical significance. Importantly, mutations previously reported to be associated with reduced OS and RFS in the non-transplant setting, such as ASXL1, EZH2, IDH1/2, and SRSF2, were not associated with poorer outcomes in this analysis in transplanted patients. In an exploratory multivariate analysis including donor type (related vs. unrelated) and presence of U2AF1 and SUZ12 mutations, there was a significantly reduced OS and RFS in patients who harbor these mutations regardless of donor type (OS: HR 5.30, 95% CI: 2.08-13.47, p<0.001; RFS: HR 5.49, 95% CI: 2.27-13.30, p<0.001). In patients without the above mutations, having an unrelated donor was associated with worse OS (HR 2.55, 95% CI: 1.09-5.96, p=0.03) and RFS (HR 2.61, 95% CI: 1.17-5.83, p=0.02, Figure 1). Conclusions: Our analysis demonstrates that mutations previously associated with poor prognosis in MF, such as ASXL1, do not appear to confer a worsened prognosis in patients undergoing allo-HSCT, suggesting transplant may be able to overcome the impact of these mutations. However, mutations in SUZ12 and U2AF1 are associated with reduced OS in univariate and multivariate analysis (together with donor type). Further studies with larger cohorts of patients are indicated to validate these findings, and to elucidate the impact of these mutations on disease biology. Disclosures Rampal: Incye and CTI: Consultancy. Mascarenhas:Janssen: Research Funding; CTi Biopharma: Research Funding; Promedior: Research Funding; Merk: Research Funding; Incyte: Research Funding. Mesa:Galena: Consultancy; Gilead: Research Funding; Promedior: Research Funding; Incyte: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding; Ariad: Consultancy; Novartis: Consultancy. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding.

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 : 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 Introduction: Polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are chronic, Philadelphia-negative myeloproliferative neoplasms (MPNs) that are characterized by deregulated myeloid lineage cell production, leading to a high symptom burden, including abdominal pain/discomfort from splenomegaly, fatigue, depressive symptoms, sleep disturbance, sexual problems, and pruritis, among other symptoms. Yoga interventions have been demonstrated to be efficacious for improving symptom burden in other cancer populations. Additionally weight has been shown to moderate symptom burden response in cancer patients. In MPN patients, it is unknown if weight influences symptom burden response. Therefore, the purpose of this analysis was to examine the differences at baseline and post-intervention in symptom burden between overweight and normal weight MPN patients participating in an online yoga intervention. Methods: MPN patients were asked to participate in 60 minutes of online-streamed yoga weekly for 12 weeks. Participants were asked to complete online self-report surveys administered via Qualtrics at baseline (week 0), mid-point (week 7), post-intervention (week 12), and follow-up (week 16). Survey measures included demographics, total symptom burden and fatigue (MPN Symptom Assessment Form [MPN SAF]) as well as NIH PROMIS measures of pain, anxiety, depression, sleep, and sexual function. BMI status was determined through self-report height and weight obtained in the baseline survey. For statistical analyses, BMI was dichotomized into an overweight (OW) category (BMI ≥25 kg/m2) and a normal weight (NW) category (BMI <25 kg/m2). Results: A total of 38 MPN patients completed the 12-week intervention. The majority of participants were diagnosed with either PV (n=16) or ET (n=16), with MF being less common (n=6). Median age was 56 years (range 29-72) with most participants being female (n=34). A minority were OW (n=12). At baseline, total symptom score (TSS) was descriptively higher in OW vs NW participants (mean 42.8 [SD 16.2] vs 32.7 [SD 10.9], p=0.06) with no other differences observed for PROMIS outcomes. OW participants had significantly improved TSS (p=0.002), anxiety (p=0.002), sleep (p=0.02), and vaginal discomfort (p=0.04) at the end of the intervention (week 12, Table 1). Improvements in NW participants did not reach statistical significance for any scales except sleep at week 12 (p<0.001). From baseline to follow-up (week 16), NW participants had significant improvements in TSS (p=0.003), depression (p=0.003), and sleep (p=0.007). OW participants maintained significant improvements in only sleep at week 16 (p=0.005). Conclusion: In MPN patients participating in a 12-week, online streamed yoga intervention, some differences in response to the intervention were observed between OW and NW participants. However, statistical power for definitive analysis of weight as a moderator for improvement in symptom burden was limited due to a small sample size. Considering the lack of interventions in MPN patients and the potential role that weight has on outcomes in other cancer populations, a randomized controlled trial investigating the effects of online yoga in a larger sample of MPN patients is warranted along with further investigation of effectiveness of the intervention within groups of participants by weight. Disclosures Gowin: Incyte: Membership on an entity's Board of Directors or advisory committees. Mesa:Promedior: Research Funding; Incyte: Research Funding; Ariad: Consultancy; CTI Biopharma: Research Funding; Novartis: Consultancy; Gilead: Research Funding; Galena: Consultancy; Celgene: Research Funding.

Abstract Introduction: Polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are Philadelphia-negative myeloproliferative neoplasms (MPNs) leading to risk of vascular events, splenomegaly and cytopenias in advanced disease as well as disease-originating symptoms, including (but not limited to) fatigue, depressive symptoms, insomnia, inactivity, sexual problems, and pruritis. Current therapy with JAK inhibition has improved MPN symptom burden, yet even in responders, unmet needs remain for alleviating fatigue, mood related symptoms, and insomnia. Yoga used as non-pharmacologic therapy has been shown to be efficacious for improving anxiety, depression, sleep quality, and fatigue in other cancer populations, including hematological malignancies. Due to a lack of this type of research in MPN patients, we undertook the first yoga study in this population as a feasibility trial (i.e., acceptability, demand, practicality) of home-based, online-streamed yoga for improving MPN patient symptom burden. Methods: MPN patients were recruited nationally using social media. Participants were asked to complete 60 minutes of online-streamed yoga weekly for 12 weeks. The yoga video selection included MPN-specific videos as well as others chosen specifically with potential splenomegaly in mind. Additionally, participants were asked to complete online self-report surveys administered via Qualtrics. Survey measures included demographics, total symptom burden and fatigue (MPN Symptom Assessment Form [MPN SAF]) as well as NIH PROMIS measures of pain, anxiety, depression, sleep, and sexual function. Surveys were administered at baseline (week 0), mid-point (week 7), post-intervention (week 12), and follow-up (week 16). Weekly yoga minutes were collected through online self-report. Results:Patients: Two hundred and forty-four MPN patients completed the eligibility survey, 134 were eligible, 55 completed the informed consent, and 38 MPN patients completed the 12-week intervention. The majority of participants were diagnosed with either PV (n=16) or ET (n=16), with MF being less common (n=6). Additionally, the majority of participants were female (n=34), Caucasian (n=37), married (n=30) of a normal BMI category (n=26), and had attained a Bachelor's degree or higher (n=25). Median age of those participating was 56 years (range 29-72). Yoga Participation & Safety:Approximately 37% (n=14) of study participants averaged ≥60 min/week of yoga. Yoga participation averaged 50.8±36.2 min/week. Additionally, 75% of participants felt safe from injury while participating in online yoga. Only one adverse event was reported (irritated enlarged spleen). Feasibility:Overall, 68% of participants were either satisfied or very satisfied with online yoga and 75% felt that is was helpful for coping with MPN-related symptoms (i.e., acceptability, practicality). However, only 43% of participants reported that they were likely or very likely to continue their online yoga practice (i.e., demand). Impact of Yoga Intervention: From baseline (week 0) to post-intervention (week 12, n=30), there were significant improvements in total symptom burden (effect size [ES] in standard deviation units=-0.36, p=0.004), anxiety (ES=-0.67, p=0.002), depression (ES=-0.41, p=0.049), sleep (ES=-0.58, p<0.001), and fatigue (ES=-0.33, p=0.04). These improvements remained significant at follow-up (week 16, n=28) for all outcome measures with a trend for maintained fatigue improvement (ES=-0.34, p=0.06). There were no significant differences in outcomes between those that averaged <60 min/week of yoga compared to those that averaged ≥60 min/week of yoga. Conclusions: A 12-week, home-based, online-streamed yoga intervention is feasible (i.e., accepted, practical) for MPN patients. Although the sample size was small and there was no control group, the results suggest that online yoga may be effective for improving MPN symptom burden, with statistically significant improvements observed in total symptom burden, fatigue, anxiety, depression, and sleep. A randomized, controlled trial is warranted to evaluate home-based, online-streamed yoga on MPN patient outcomes. If effective, yoga may represent a unique non-pharmacologic complement to standard therapies in a population with a heterogeneous symptom profile and significant symptom burden. Disclosures Gowin: Incyte: Membership on an entity's Board of Directors or advisory committees. Mesa:Ariad: Consultancy; Galena: Consultancy; Incyte: Research Funding; Gilead: Research Funding; Novartis: Consultancy; Promedior: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding.

Abstract Background: Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET), are chronic MPNs associated with a broad array of symptoms that may negatively impact patients’ quality of life (QoL). To enhance patient care, it is important to have a current and clear understanding of how MPNs affect the overall health and daily lives of patients. The MPN LANDMARK SURVEY was developed to examine patients’ perceptions of these MPNs related to disease burden, QoL, productivity, and activities of daily living (ADLs). Methods: Eligible patients diagnosed with an MPN were recruited to participate in an online survey conducted from May–July 2014in the US. Patients were asked about the overall burden of disease and impact of symptoms on their QoL, productivity, and ADLs. Descriptive analyses were conducted to assess these outcomes and examined by calculated (not reported) prognostic risk score (MF - DIPSS: Passamonti, Blood 2010; PV: Tefferi, Leuk 2013; ET - IPSET: Passamonti, Blood 2012) and symptom severity quartiles, which were determined using the MPN Symptom Assessment Form (MPN-SAF) total symptom scores. Results: 813 patients (MF=207; PV=380; ET=226) responded to the survey. A majority of patients were female (MF, 54%; PV, 62%; ET, 72%), approximately half were aged 60–74 years (MF, 55%; PV, 51%; ET, 46%), and most were covered by health insurance (>98%). Nearly half (48%) were diagnosed within the last 5 years and average time to diagnosis from first symptoms was >2 years. A high proportion of patients had intermediate to high prognostic risk scores (MF, 94%; PV, 87%; ET, 44%). The majority of patients reported feeling anxious or worried about their MPN (MF, 91%; PV, 78%; ET, 74%). Among all groups, fatigue was the most severe symptom reported (mean MPN-SAF score=6.0–6.4 on a scale of 0–10). A subset of patients in each group described their symptoms as very severe (severity score ≥7 on a scale of 0–10; MF: fatigue [59%], problems with sexual desire [49%], inactivity [46%]; PV: inactivity [48%], fatigue [49%], problems with sexual desire [49%]; and ET: problems with sexual desire [49%], fatigue [50%], headaches [40%]). The majority of patients reported that MPN-related symptoms reduced their QoL (MF, 81%; PV, 66%; ET, 57%); this was reported in all risk groups but more frequently by patients with a high risk score vs a low risk score in MF and ET (MF, 89% vs 69%; PV, 63% vs 65%; ET, 71% vs 59%). A more substantial QoL impact was reported by patients in high vs low symptom quartiles (MF, 95% vs 51%; PV, 94% vs 33%; ET, 93% vs 15%). Similarly, MPNs also had a marked negative impact on reduced work hours, sick days, voluntary job termination, receipt of medical disability, early retirement, and ADLs (Table 1). For example, among patients employed, approximately one fourth reported missing ≥1 day of work (MF, 29%; PV, 19%; ET, 23%) in the last 30 days before the survey. Even patients with low prognostic risk scores often reported missing ≥1 day of work (MF, 33%; PV, 23%; ET, 22%) or cancelling ≥1 day of planned activities (MF, 46%; PV, 35%; ET, 34%). Patients in the high vs low symptom quartiles were more likely to call in sick to work (MF, 48% vs 0%; PV, 52% vs 4%; ET, 38% vs 0%) or cancel ≥1 day of planned activities (MF, 77% vs 5%; PV, 56% vs 7%; ET, 67% vs 3%). Conclusion: The findings from this large, first-of-its-kind survey demonstrate a marked burden of disease across all 3 MPNs that is not limited to symptoms but extends to QoL, productivity, and ADLs. Although high prognostic risk scores have long been associated with a significant burden of disease, in this study, patients with a low risk score also reported significant burden. The symptom burden reported is consistent with previous studies, thus validating the present dataset. MPN treatment considerations should include reducing the symptom burden and improving QoL and productivity to enhance the overall health and lives of MPN patients. Disclosures 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. Miller:Incyte Corporation: Honoraria, Research Funding. Thyne:Incyte Corporation: Speakers Bureau. Mangan:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Goldberger:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Fazal:Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau. Ma:Incyte Corporation: Consultancy. Wilson:Incyte Corporation: Honoraria. Dubinski:Incyte Corporation: Employment, Equity Ownership. Boyle:ICF International: Employment, Equity Ownership. Mascarenhas:Incyte Corporation: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Research Funding.

Abstract Background: We sought to retrospectively analyze the clinical differences, at diagnosis and throughout the disease course, between patients with primary myeloifbrosis whom undergo blastic transformation (PMF-BP) and those whom expire from PMF complications without undergoing transformation. Methods: An international collaborative database of patients with PMF which progressed to PMF BP, and a control group of individuals with PMF who expired secondary to PMF was created. Data regarding clinical course, bone marrow, karyotypic, quantitative JAK2V617F analysis (when able), laboratory values, and therapy at the diagnosis of PMF, PMF BP and up to 4 return visits (R1-4) in between these milestones was abstracted. Results: COMPARISON AT DIAGNOSIS OF PMF: 136 cases of PMF who eventually underwent PMF-BP were included, with a control group of 42 PMF patients, were analyzed. Both groups of patients had similar demographic (median age at diagnosis 59 years (range 23–83)/ 59.1 (15–93); and disease parameters (median hemoglobin 10 g/dL (range 2–15.7) /9.8 (4.9–14.6); median platelet count 181 x 109/L (range 7–1400)/168 (16–1916)), and Lille PMF prognostic scores (p = n.s.) for PMF-BP vs. PMF control group respectively. Additionally, blasts (peripheral blood /marrow) were a median of 0% (range 0–18%)/ 2% (range 0–16%) for the study group versus 0.25% (range 0–5%)/ 3% (range 0–4%) (p = n.s. for both) for the control group, respectively. Both groups had similar rates of requiring therapy (86%; 93%) and survival from diagnosis (median 34 months (range 2–441); 29 months (1–236)) (p = n.s.). However, lactate dehydrogenase (LDH) (although high in both groups) was higher at diagnosis (median 802 IU/L (range 83–10353) vs. 416 IU/L (124–2197)) (p=0.04), as well as an abnormal marrow karyotype (85% vs. 25%; p<0.001) amongst the PMF BP group. SUBSEQUENT CLINICAL COURSE: Analyzing the clinical evolution between groups demonstrated persistently higher LDH and worsening thrombocytopenia in the PMF-BP cohort (see figure). Decreasing Platelets Approaching PMF BP Decreasing Platelets Approaching PMF BP Peripheral blood blasts increased in both groups, but values above 10% were unique to the PMF BP group. Additionally marrow karyotype displayed clonal evolution developed in 56% of the PMF-BP patients as opposed to 14% of controls (p<0.001). Initial and serial quantitative JAK2V617F mutation analysis (available from 20 /19 patients from the PMF-BP and control group at diagnosis, with 11 / 12 serial samples) showed no difference between the groups, nor a pattern of mutation burden elevation with transformation to leukemia in the study group. Conclusions: Increasing LDH, peripheral blood blast percentages >10%, and clonal evolution are features commonly seen in PMF patients whom evolve to blast phase and may be a harbinger of movement towards PMF BP.