Citations

Abstract Introduction Individuals with the Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) have previously been shown to experience symptoms in excess to age and comorbidity matched peers. Although numerous assessments of symptom burden and quality of life have been utilized among MPN populations, including the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Patient Reported Outcomes Measurement Information System (PROMIS¨) fatigue scale, and Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-10), there are currently no validated assessments of overall health. Developed by the EuroQol Group to assess heath status, the EQ-5D is an internationally validated self-assessment which may be useful in the assessment of health state among MPN patients (Annals of Medicine, 2001. 33:337-43). Methods The EQ-5D evaluates five dimensions of mobility, self-care, usual activities, pain/discomfort and anxiety/depression, on a scale from no problems to extreme problems and assesses patient reported health state via a numerical visual analogue scale (VAS) ranging from 0 to 100. The health state score is a composite score of these items ranging from 0 to 1.0, with higher scores indicating an improved health state. EQ-5D survey participants were essential thrombocythemia (ET) and polycythemia (PV) patients participating in the MAJIC United Kingdom (UK) trial. The MAJIC trial is a randomized, phase II study of best available therapy versus JAK inhibition in individuals with PV or ET who have been resistant or intolerant of cytoreduction with hydroxyurea /hydroxycarbamide. This study was one of the first Trials Acceleration Programme (TAP) trials and is funded by Leukaemia Lymphoma Research, with drug supplied by Novartis. Only baseline EQ-5D assessments taken at study enrollment were included in this analysis. Comparative analysis was preformed using the MPN-10 (J Clin Oncol.2012. 30:4098-103). Results: Participant Demographics: Sixty six patients with ET and 55 patients with PV completed the EQ-5D questionnaire. Median respondent age was 65 years old and half of respondents were female (54%). Average MPN duration was 10 years for ET and 9.2 years for PV. EQ-5D Scoring: Severe to extreme difficulties in the items of mobility, self-care, usual activities, pain/discomfort and anxiety/depression were common (Table 1).Patients with PV tended to have higher proportion of patients with severe to extreme difficulties in individual disease dimensions, higher VAS score, and worsened health state compared to their essential thrombocythemia counterparts, although these effects were not significant. Average VAS health score was 70.4 (+21.2) for ET and 66.5 (+19.6). When evaluating the health state composite score, the mean ET score was 0.74 (+0.32) and mean PV score was 0.66 (+0.28). EQ-5D Validation: The EQ-5D had excellent internal consistency (CronbachÕs alpha=0.87) and strong internal correlation. When evaluating external validity, strong correlations existed between the EQ-5D and the MPN-SAF TSS scales for dimensions of mobility, usual activities, pain and overall health state (many items with r >0.5 and p<0.001). Conclusions: The EQ-5D is a valid and accurate instrument for the brief assessment of health state among MPN patients. This instrument demonstrates excellent clinical utility in a large clinical study cohort and can be used in both clinical practice and trial settings. When comparing EQ-5D health state scores, ET and PV patients had worsened health than the general UK population age 60 to 69 (0.774; Med Decis Making. 2011.31(6)800-4), but similar health to individuals with other malignancies including breast cancer (0.760), prostate cancer (0.743), and lung cancer (0.689). Disclosures Mesa: NS Pharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Incyte Corporation: Research Funding; Pfizer: Research Funding; Promedior: Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Pfizer: Research Funding. Harrison:CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Shire: Speakers Bureau; Gilead: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

Background: Serum folate (SF), vitamin B12 (B12), and iron deficiencies (def) are common causes of nutritional anemias. These deficiencies are usually multifactorial, with nutritional and non-nutritional factors playing a role. SF, B12, and iron levels are usually ordered in the setting of anemia, and malnutrition with or without neurologic symptoms. Since folic acid fortification, the prevalence of SF def in the United States (US) is <1% in the general population. B12 def and iron def range between 6-12%, and 1-11% respectively depending on the population studied. The prevalence of nutritional anemias secondary to SF, B12, and/or iron def by racial groups in the US is poorly studied, and most data available focuses on non-Hispanic whites (NHW). We aimed to determine the prevalence of anemia secondary to nutritional deficiencies by racial groups in the US. Methods: We performed a retrospective analysis of patients with SF, B12 and iron levels at Mayo Clinic Arizona between 01/2010 and 10/2018. Race was classified according to the NIH criteria. Normal laboratory values were determined according to our lab reference and the US National Health and Nutrition Examination Survey (NHANES) III. SF levels (mcg/Lt) were defined as deficient <4, normal ≥4.0, and excess ≥20. B12 levels (ng/L) as deficient <150, borderline 150-400, normal >400-900, and excess ≥900. Iron def was determined by ferritin levels (mcg/L) as low <24, normal 24-336, elevated ≥336 for men, low <11, normal 11-307, elevated ≥307 for women. Demographics and clinical variables were compared between groups by chi-square test for frequency data or Kruskal Wallis rank-sum test for continuous variables. Multivariable logistic regression was used for a sample-level analysis adjusting for age and gender and using NHW as a reference group. Results: A total of 79,926 SF, 107,731 B12, and 39,827 ferritin samples from 67,683 patients were analyzed. Demographics and sample analysis are presented in Table 1. In the sample-level analysis, 23,008 (25%) had anemia with higher prevalence in the American Indian/Alaskan Native (AI/AN) 49% and African Americans (AA) 43% (p<0.001). The prevalence of SF def was 446/79,926 (0.6%), B12 def 1,548/107,731 (1.4%), and iron def 5,212/39,827 (13.1%). 23 had concomitant SF and B12 deficiency, 25 SF and iron def, and 144 B12 and iron def. The SF def prevalence by racial groups was: AI/AN 11 (1.9%), AA 19 (1.1%), NHW 378 (0.6%), Hispanic 28 (0.5%), Asian 4 (0.2%). The B12 def prevalence by racial groups was: Asian 89 (3.4%), NHW 1,274 (1.4%), Hispanic 87 (1.3%), AA 30 (1.3%), AI/AN 10 (1.3%). Iron def prevalence by racial groups: AI/AN 71 (20.5%), Asian 198 (17.6%), AA 180 (16.9%), Hispanic 432 (15.6%), NHW 4,161 (12.4%). In the multivariate sample-level analysis, the presence of anemia was higher in the AI/AN (OR: 4.51, 95%CI: 3.70-5.49, p<0.0001), AA (OR 3.34, 95%CI: 2.99-3.74, p<0.0001), Asian (OR 1.52, 95%CI: 1.35-1.73, p<0.0001) and Hispanic racial group (OR 1.41, 95%CI: 1.30-1.52, p<0.0001). SF def was more common in the AI/AN (OR: 2.94, 95%CI: 1.60-5.39, p<0.001) and AA (OR 1.71, 95%CI: 1.08-1.53, p=0.02). B12 def was more common in the Asian racial group (OR: 2.535, 95%CI: 20.03-3.16, p<0.0001). Iron def was more common in the AI/AN (OR: 1.62, 95%CI: 1.21-2.17, p<0.001), Asian (OR 1.31, 95%CI: 1.0-1.57, p=0.003), and AA racial group (OR 1.26, 95%CI: 1.05-1.52, p=0.001). Conclusions: In our cohort, we show that despite the low prevalence of nutritional anemias in the US, racial disparities exist. Major differences were observed in the prevalence of anemia, SF def and iron def especially among AI/AN and AA. These differences may be linked to medical causes, nutritional practices and other social determinants of health. More research regarding the causes of these disparities and its clinical implications on a population level are needed. Targeted strategies to improve folate, B12 and iron intake in at higher risk populations could decrease adverse outcomes and decrease healthcare disparities caused by nutritional anemias. T able 1. Sample-level comparison by race Disclosures No relevant conflicts of interest to declare.

The TP53 pathway has been shown to be dysregulated in myeloproliferative neoplasms (MPN) through several different mechanisms, including TP53 mutations, TP53 deletions and Murine Double Minute 2 (MDM2) overexpression. Downregulation of the TP53 pathway likely plays a role in MPN progression as evidenced by the association of TP53 loss of heterozygosity with transformation to acute leukemia and the presence of inactivating mutations of TP53 found in a proportion of MPN-blast phase (MPN-BP) cases (Kubesova et al, Leukemia. 2018;32(2):450-61). Furthermore, MDM2 inhibition induces TP53 pathway upregulation and consequent targeting of hematopoietic stem and progenitor cells in polycythemia vera (PV) and myelofibrosis (MF). The MDM2 inhibitor, idasanutlin, has shown activity in a Phase I trial of high-risk PV patients (Mascarenhas et al. Blood. 2019 Jun 5). An additional regulator of TP53 is protein phosphatase, Mg2+/Mn2+ dependent 1D (PPM1D) which by dephosphorylating TP53 and stabilizing MDM2 regulates the DNA damage response pathway and apoptosis. Somatic activating mutations of PPM1D are present in both solid and hematologic malignancies and are specifically associated with therapy-related myeloid disorders (Hsu et al. Cell Stem Cell. 2018 Nov 1;23(5):700-13). Grinfeld et al. (N Engl J Med. 2018 Oct 11;379(15):1416-30) recently reported that in their genomic analysis of 2035 MPN patients, PPM1D was the eighth most common mutated gene in MPNs at 1.9% frequency. To determine whether there was an association of PPM1D mutations with MPNs we analyzed the genomic data of patients who participated in several clinical trials executed by the Myeloproliferative Neoplasm Research Consortium (MPN-RC). Of 89 MPN-BP patients, 5 patients harbored a PPM1D mutation with a median variant allele frequency (VAF) of 17%. In comparison, 4 out of 135 high risk PV and ET patients harbored a PPM1D mutation with a median VAF of 24%. All mutations were truncating which is consistent with previous reports of PPMID mutations in malignancies. The PPM1D gene is located on the long arm of chromosome 17 (17q23.2) and we hypothesized that cytogenetic aberrations involving this gene locus might also contribute to abnormalities of PPM1D function. Through analysis of our cytogenetic database, 16/1,124 (1.4%) MPN patients were found to have cytogenomic abnormalities involving the region containing the PPM1D gene. Eight of these patients had karyotypic abnormalities, including 3 pts with isochromosome 17q resulting in a gain of 17q and a loss of 17p, including the TP53 gene. The other 4 patients had structural variations of 17q which might lead to aberrant expression of PPM1D. One patient by FISH analysis had gain of 17q. Ten patients had cytogenomic aberrations of 17q detected through analysis of array comparative genomic hybridization and single nucleotide polymorphism (aCGH+SNP), 2 of which had concurrent karyotypic abnormalities of 17q. All patients had a gain or copy neutral loss of heterozygosity (cnLOH) of the 17q22-24.2 region. CnLOH of this region could lead to aberrant overexpression of the PPM1D gene. One of the 8 patients with cnLOH of 17q harbored a PPM1D mutation. Of the 16 patients with 17q cytogenomic abnormalities, 7 (44%) had MPN-BP and 7 (44%) patients had ET or ET that progressed to myelofibrosis (MF) or MPN-BP indicating an association of these abnormalities with advanced disease. By quantitative real time-PCR we determined the PPM1D transcript levels in mononuclear cells from 31 MPN patients without known PPM1D mutations (7 polycythemia vera (PV), 6 ET, 14 MF, 4 MPN-BP) and compared the transcript levels to mononuclear cells from healthy control patients. Forty-two percent (13/31) patients had overexpression of PPM1D (>1.5 fold increase range). Fold increase ranged from 1.5-8 and overexpression was present in the following diagnoses: 4/7 PV, 1/6 ET, 8/14 MF and 0/4 MPN-BP. We have provided evidence that a number of abnormalities of PPM1D including activating mutations, cytogenetic aberrations and transcript overexpression are present in a significant proportion of MPN patients. These abnormalities in PPM1D can be additional events that lead to the downregulation of TP53 and contribute to MPN disease progression. We propose that inhibitors of PPM1D may be used in combination with other drugs that upregulate TP53 to treat MPN patients. Disclosures Rampal: Constellation, Incyte, and Stemline Therapeutics: Research Funding; Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy. Mascarenhas:CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche: Consultancy, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Promedior: Research Funding; Merus: Research Funding. Hoffman:Merus: Research Funding.

Background Interferons are recognized as active agents in the treatment of patients with high risk essential thrombocythemia (ET) or polycythemia vera (PV), both in the upfront setting as well as beyond. Several trials have shown high rates of hematologic and molecular responses with the use of interferons, however, data on direct comparison of interferon activity in patients with early disease in comparison to patients refractory or resistant to prior therapies, such as hydroxyurea (HU) are lacking. We conducted a controlled analysis of the activity of pegylated interferon alfa-2a (PEG) in two prospective parallel clinical trials conducted in these two unique patient populations. Methods The MPD-RC 111 (NCT01259817) was an international, multicenter, phase 2 open-label clinical trial that evaluated PEG therapy in patients with high risk PV and high-risk ET who were either refractory or intolerant (R/I) to HU by modified ELN criteria. The MPD-RC 112 trial (NCT01258856) enrolled patients with high risk ET/PV who were treatment-naïve (TN) (HU <3 months) and randomized them (1:1) to PEG or HU. All patients randomized to PEG were included in this analysis. Both protocols were conducted concurrently at the MPD-RC member institutions and utilized a similar primary endpoint of overall response rate (complete and partial response rates) by ELN Criteria at 12 months confirmed by the same blinded central review committee. Both studies utilized the same PEG starting dose of 45 mcg weekly and was titrated for response to a maximum of 180 mcg weekly. Secondary endpoints included safety information, impact on disease biomarkers, bone marrow (BM) response, and quality of life data. Results Patients ET: 39 TN and 65 R/I ET patients were available for this analysis. Median disease duration was 2.9 months in TN and 37.3 months in R/I patients. Baseline characteristics and demographics were similar in the two cohorts except lower baseline hemoglobin level in RI patients. (Table1A) PV: 43 TN and 50 R/I PV patients were included. Median disease duration was 2.5 months in TN and 54.8 months in R/I patients. Baseline characteristics only differed by lower frequency of phlebotomy rate in R/I patients. (Table1B) Baseline symptoms scores and quality of life were similar in TN and RI groups (Table 2) Response ET: CR/PR/ORR at 12 months were observed in 43.1%/26.2%/69.2% in R/I ET patients and in 43.6%/25.6%/69.2% in TN ET patients (p=0.99 for ORR). (Table 3, Figure 1) PV: CR/PR/ORR at 12 months were observed in 22%/38%/60% in R/I PV patients, and in 27.9%/58.1%/86% in TN PV patients (p=0.005 for ORR). (Table 3, Figure 1) Safety PEG was equally well tolerated throughout both treatment groups with treatment discontinuation due to adverse events occurring in 14.6% in TN patients and 13.9% in R/I patients. The mean (SD) dose of PEG was 102.7 (52.3) mcg in R/I ET patients and 128.7mcg (46.4) in R/I PV patients. For TN patients, mean dose was 85.7mcg (59.7) in ET and 93.5 mcg (44.0) in PV. Adverse events were consistent with historic reports of PEG use and the distribution of events was similar in R/I and TN patients. (Table 4) Conclusion This intention to treat response analysis included TN and R/I ET and PV patients with balanced baseline characteristics who received prospective therapy with PEG. Patients with ET had a higher overall response rate at 12 months that was equivalent in patients who were treatment-naïve and in patients who were intolerant or refractory to HU. By contrast, patients with PV who were treatment-naïve had a higher ORR than patients those intolerant or refractory to HU. We conclude that treatment with PEG is an effective therapeutic option both treatment naïve PV and ET as well as those previously treated with HU, however PEG as a second line agent is especially effective in ET patients. Disclosures Yacoub: Hylapharm: Equity Ownership; Agios: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Ardelyx: Equity Ownership; Cara: Equity Ownership; Dynavax: Equity Ownership. Mascarenhas:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche: Consultancy, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merus: Research Funding. Mesa:AbbVie: Research Funding; Samus: Research Funding; Incyte: Research Funding; Sierra Onc: Consultancy; Genotech: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; CTI Biopharma: Research Funding; La Jolla Pharma: Consultancy. Rampal:Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy; Constellation, Incyte, and Stemline Therapeutics: Research Funding. Silver:PharmEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. McMullin:Daiko Sanyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Italopharma: Membership on an entity's Board of Directors or advisory committees. Ewing:Novartis: Honoraria, Other: Meeting attendance sponsorship ; Bristol Myers-Squibb: Other: Meeting attendance sponsorship . O'Connell:Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Mead:Bristol Myers-Squibb: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; CTI: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Pfizer: Consultancy. De Stefano:Alexion: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Baer:Astellas: Research Funding; Al Therapeutics: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Forma: Research Funding; Kite: Research Funding; Takeda: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kremyanskaya:La Jolla: Consultancy; Incyte, Celgene, Constellation, Protagonist.: Research Funding. Hexner:novartis: Research Funding. Rambaldi:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Omeros: 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, Other: travel support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, travel support. Ritchie:Genentech: Other: Advisory board; Tolero: Other: Advisory board; agios: Other: Advisory board; Pfizer: Other: Advisory board, travel support; Celgene: Other: Advisory board; Jazz Pharmaceuticals: Research Funding; Celgene, Novartis: Other: travel support; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; Celgene, Incyte, Novartis, Pfizer: Consultancy. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Celgene: Consultancy. Harrison:Promedior: Honoraria; Incyte: Speakers Bureau; Sierra Oncology: Honoraria; Celgene: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; CTI: Speakers Bureau; AOP: Honoraria; Shire: Speakers Bureau; Roche: Honoraria; Gilead: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Hoffman:Merus: Research Funding. OffLabel Disclosure: Pegylated Interferon Alfa-2a for in Patients with Polycythemia Vera or Essential Thrombocythemia

Background: Pegylated Interferon-alpha (PEG-IFNa) improves hematologic parameters and reduces mutant allele fraction in patients with myeloproliferative neoplasms (MPNs); however, widespread clinical use is limited by frequent discontinuation due to side effects. Identifying biomarkers of response to PEG-IFNa therapy might identify patient subsets most likely to derive benefit from this therapy. Serum pro-inflammatory cytokine levels are increased in MPN patients and associated with adverse clinical outcomes. The effect of PEG-IFNa therapy on cytokine levels in MPN patients and correlation with clinical response has not been elucidated. We hypothesized that identification of cytokine signatures could predict for clinical/molecular response to PEG-IFNa in MPNs. Methods: Pre- and post-treatment serum samples were collected from available patients enrolled on the Myeloproliferative Disorders Research Consortium (MPD-RC) 111/112 trials-multicenter studies assessing efficacy of PEG-IFNa in patients with high-risk polycythemia vera/essential thrombocythemia either up front or in the setting of hydroxyurea failure/intolerance. Serum was prepared using the Millipore MAP Human 41-Cytokine Magnet Bead System (Millipore; Cat:HCYTOMAG-60K) and run on the Luminex FLEXMAP 3D platform. Data was analyzed using Luminex xPonent 4.3 software. Correlative mutational data on 156 genes implicated in myeloid malignancies was also available for all patients. Age-matched serum from healthy individuals (N=6) was obtained from AllCellsTM for use as wild-type (WT) controls. Baseline cytokine samples were compared between groups of interest by use of Wilcoxon rank-sum test. Change from baseline in cytokines for each group were compared to the null hypothesis of zero change. P values <0.05 were considered statistically significant. Results: Pre- and post-treatment serum samples were available on 29 MPN patients from the MPN-RC 111/112 cohorts. 21 patients were classified as complete responders (CRs) vs. 8 non-responders (NRs) using European LeukemiaNet criteria. Baseline cytokine levels were generally increased in both CRs and NRs compared to WT, including significant increases in Eotaxin (p=0.023), IL3 (p=0.048), IP10 (p=0.04), and TNFa (p=0.006) (Table 1), as well as a non-significant trend increase in IL8 (p=0.076). Notably, other cytokines were decreased at baseline in comparison to WT, including EGF (p<0.001), as well as MDC (p=0.040) and PDGFaabb (p=0.02), in line with previous studies. Compared to CRs, NRs displayed significantly lower levels of GRO (p=0.020), MDC (p=0.003), and PDGFaabb (p=0.026) at baseline along with elevated levels of IP10 (p=0.028) suggesting pre-treatment levels of these cytokines might predict response to therapy. Comparison of pre- and post- treatment samples revealed a general increase in median cytokine levels in CRs, with significant changes in GM-CSF (p=0.012), IP10 (p<0.001), MCP1 (p=0.015) and IFNa itself (p=0.010). Notably, median cytokine levels in NRs post-treatment, including IFNa, were relatively unchanged from baseline despite on-going PEG-IFNa therapy. Additional pre-treatment serum samples, as well as correlative analysis of cytokine changes with JAK-STAT driver mutant allele fraction and mutational profiling are underway and will be presented at the meeting. Conclusions: Preliminary findings suggest individual cytokines are affected by PEG-IFNa in MPNs. Furthermore, baseline levels of GRO, MDC, PDGFaabb, and IP10 correlate with response to PEG-IFNa. These data may identify MPN patients most likely to respond to PEG-IFNa therapy and those for whom this therapy may be most appropriate. Further analysis with a larger cohort of treatment-naïve patients is underway to validate these findings and identify additional molecular and cytokine signatures of response to PEG-IFNa therapy. Disclosures Yacoub: Agios: Speakers Bureau; Hylapharm: Equity Ownership; Dynavax: Equity Ownership; Cara: Equity Ownership; Ardelyx: Equity Ownership; Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Mascarenhas:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merus: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees. Levine:Lilly: Honoraria; Qiagen: Membership on an entity's Board of Directors or advisory committees; Imago Biosciences: Membership on an entity's Board of Directors or advisory committees; Loxo: Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Research Funding; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Research Funding; Gilead: Consultancy; Amgen: Honoraria; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Novartis: Consultancy. Hoffman:Merus: Research Funding. Rampal:Constellation, Incyte, and Stemline Therapeutics: Research Funding; Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy.

Abstract Objective Breast implant augmentation is the most common cosmetic surgical procedure performed in the United States. The purpose of this study was to determine if patients with breast augmentation surgery are aware of the effect of breast implants on the mammographic detection of cancer. Methods An institutional review board exempt patient awareness survey was distributed at a single breast imaging facility to women undergoing screening mammography. Comparative statistical analyses were performed between patients with and without breast implants. Results The respondents were divided into three groups: no prior breast surgery (74%; 524/711), breast surgery with implants (21%; 152/711), and breast surgery without implants (5%; 35/711). Patients with breast implants were more aware that implants decrease the amount of breast tissue seen on a mammogram (75%; 105/141) and that implants result in the need for more mammogram views (70%; 103/147), as compared with patients with no surgery (46%; 221/484 and 31%; 147/478, respectively) (P &lt; 0.001). More women with breast implants reported learning from breast imaging staff rather than from their surgeon that implants decrease the amount of breast tissue seen on a mammogram (46%; 49/106 vs. 38%; 40/106). Of 137 respondents, 35% (n = 48) reported that the effect of implants on their mammogram was discussed preoperatively. Of those who did not recall a preoperative discussion, 42% (16/38) indicated this knowledge would have factored into their decision to get breast implants. Conclusion This study highlights an opportunity for providers to engage in more education and shared decision-making with patients considering breast augmentation surgery to ensure preoperative counseling includes discussion of the effect of implants on mammography.

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. Treatments include pharmacologic approaches, phlebotomy, and bone marrow transplant. Outcome studies have historically focused on hematologic improvement and survival benefit. Few prospective studies have evaluated patient-reported symptoms and quality of life outcomes after standard therapy. The Myeloproliferative Neoplasm Quality of Life (MPN-QOL) Study Group aims to objectively quantify symptomatic response to standard treatments. Here we provide updated results for the prospective MPN Experimental Assessment of Symptoms by Utilizing Repetitive Evaluation (MEASURE) trial. Methods: The MEASURE trial is a prospective international cohort study evaluating responsiveness of the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS or MPN-10) in an anticipated 480 ET, PV, and MF patients receiving non-experimental medical therapy and/or phlebotomy. Patients complete the MPN-SAF TSS (JCO 2012) for seven consecutive days at enrollment then again for seven days between 90 days and six months later. Patients also complete the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) and M.D. Anderson Symptom Inventory (MDASI) instruments at enrollment and on the first day of the second assessment. Physicians report demographic, laboratory, and clinical data. Results: Demographics To date, 340 patients have enrolled and 270 have completed both study visits. Participants include ET (60%), PV (29%), and MF (12%; including 68% primary MF, 12% post-ET, 20% post-PV) patients. Enrolled patients are 51% male. The most common therapies received prior to enrollment were aspirin (34%), phlebotomy (15%), hydroxyurea (14%), and warfarin/clopidogrel/anticoagulation (6%). The most common current MPN therapies were hydroxyurea (67%), aspirin (24%), phlebotomy (9%), and ruxolitinib (8%). Information on mutational analysis was also collected; 77% of patients have a known JAK2 V617F mutation, 3% have an MPL W515 mutation. Symptom Measures On the MPN-SAF TSS, the majority of individual symptoms assessed did not change significantly between the two assessment time points while on standard therapy. Notable exceptions were a significant decrease in weight loss (mean 2.0 vs. 1.7 on a 0=absent to 10=worst imaginable scale, p=0.005) and a significant worsening in quality of life (mean 3.6 vs. 3.8 on a 0=as good as it can be to 10=as bad as it can be scale, p=0.04). No changes were seen in other symptoms including early satiety, abdominal discomfort, night sweats, fatigue, inactivity, poor concentration, bone pain, itching, or fever. Similarly, the cumulative MPN-SAF TSS score remained stable at a mean of 24.4 over the treatment period. These findings were congruent with those observed using the EORTC QLQ-C30 instrument, with no significant changes seen in emotional, physical, role, cognitive, or social functioning. Finally, the MDASI also revealed a lack of change in either symptom severity (mean 2.7) or symptom distress (mean 3.0) scores, which remained stable over the study period. Discussion: Myeloproliferative neoplasms are associated with burdensome symptoms that significantly compromise quality of life. To date, no studies have quantified symptomatic response to standard-of-care treatments. Overall, results from the MEASURE study suggest that standard treatments have limited systematic impact on patient symptomatology over time, with no improvements in overall quality of life. However, we note the relatively low proportion of patients in this cohort treated with ruxolitinib, which has been shown previously to improve symptom burden, and this may have impacted the symptom responses seen in the group as whole; detailed responses by treatment and MPN subtype will be presented. Figure. Figure. Disclosures Dueck: Pfizer: Honoraria; Bayer: Employment; Phytogine: Employment. Ross:BMS: Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Research Funding. Tam:Janssen: Honoraria, Research Funding; Gilead: Honoraria; AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Travel funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria; Beigene: Honoraria, Other: Travel funding; Pharmacyclics: Honoraria; Gilead: Honoraria; Roche: Honoraria; Beigene: Honoraria, Other: Travel funding. Radia:Novartis: Speakers Bureau; Blueprint: Consultancy. Mesa:UT Health San Antonio - Mays Cancer Center: Employment; Celgene: Research Funding; NS Pharma: Research Funding; Pfizer: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Promedior: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy.

Abstract Background: Myelofibrosis (MF) is a clonal bone marrow disorder characterized by a constitutional symptoms, splenomegaly, anemia, elevated WBC and bone marrow fibrosis. Ruxolitinib is a JAK2 inhibitor approved for patients with Intermediate-2 (INT-2) or high risk disease based on dynamic international prognostic scoring system (DIPSS)), however, there are limited options for patients with early disease. Interferon alpha (IFNa) is a cytokine therapy that has been used in treatment of chronic myelogenous leukemia and polycythemia vera (PV). In these diseases, there can be a reduction in the clonal burden in addition to a hematologic response. Therefore, we sought to use this therapy in patients with MF. Methods: Patients who had MF were enrolled on an IRB approved clinical protocol in a single arm, single institution study. Patients were stratified to either an early disease arm (characterized by intermediate 1 (INT-1) risk or advanced disease (Int-2 or high risk disease based on DIPSS). Patients were started on Ropeginterferon alfa 2b (P1101) at 50 ug every two weeks, and the dose was titrated up to either 300 ug every other week, or unacceptable toxicity. Patients were monitored for response based on international working group criteria. Results: Demographics: Eight patients with MF have been enrolled on the study to date (Early: 2, Int/High: 6). Median age was 69.5 (45 - 88), five patients were female. Five patients had primary MF (PMF) and 3 had post-essential thrombocythemia or post PV MF. Three patients had previous treatment for their disease. Four patients continue to receive active treatment (2 early disease, and 2 advanced disease), and for those who remain on treatment, they range from 7 - 29 cycles. Efficacy: Three patients experienced a clinical improvement (1 based on MPN-SAF total symptom score, and 2 based on reduction of spleen size). Both early stage patients have had a CI based on spleen responses as their best response and currently remain on treatment. The remaining 2 who are on therapy had stable disease. Those who remain on therapy have been receiving treatment for 7-29 cycles with continued response. Toxicity: A grade 3 adverse event (AE) potentially attributable to the treatment occurred in 4 patients (50%), 3 (37.5%) patients had anemia, and 2 (25.0%) patients had lymphopenia. Only one patient discontinued therapy due to AEs (dizziness, atrial fibrillation). Reasons for stopping include disease progression (1), toxicity (1) and lack of benefit (2). The median number of cycles for those who ended treatment was 8 (4-10). No deaths have occurred. Discussion: P1101 appears to be a well-tolerated therapy that has shown a durable clinical improvement in 37.5% in a small study. These results, along with historic data suggesting possible reduction in clonal burden, suggest that ongoing studies are warranted to further understand the clinical benefit of P1101 in MF. Disclosures Palmer: Novartis: Research Funding. Zimmerman:PharmaEssentia: Employment. Zagrijtschuk:PharmaEssentia: Employment. Mesa:Gilead: Research Funding; CTI: Research Funding; Celgene: Research Funding; Ariad: Consultancy; Promedior: Research Funding; Incyte: Research Funding; Galena: Consultancy; Novartis: Consultancy.

Abstract Introduction Patients with myeloproliferative neoplasms (MPN) typically experience debilitating symptom profiles and profound quality of life (QoL) decrements. Characterizing symptom burden in MPN clinical trials is vital to inform efficacy analyses. Previous studies have shown clinicians and researchers depend on patient-reported outcomes (PROs) to glean disease-related symptoms and signs of QoL decline. The current literature also shows that integrating PROs into the routine care of patients with cancer is associated with increased survival compared with usual care. However, the extent to which PROs are employed in MPN clinical trials is undescribed. ClincalTrials.gov is a registry of clinical trials mandated by the US Congress and implemented in 2000 by the National Institutes of Health. This study used data from ClinicalTrials.gov to evaluate the characteristics of MPN clinical trials over time and their use of PROs as primary and secondary outcomes. Methods The statistical software R and the rclinicaltrials package were used to download data from ClinicalTrials.gov. Trial data were included in this study if the following criteria were met: (1) the words essential thrombocythemia, polycythemia vera, myelofibrosis, or myeloproliferativeneoplasm (MPN) were used in the registered primary disease condition or official trial title; (2) the trial start date was between January 1, 2000 - July 1, 2018; (3) primary/secondary outcome data were available. Trial outcome data were then parsed for PRO text phrases including MPN-Symptom Assessment Form, quality of life, questionnaire, patient-reportedoutcome, and more specific PRO items (e.g., bone pain, concentration problems, and depression). Descriptive statistics and regression analysis were used to assess rates of primary/secondary outcomes over time. Results Clinical trial characteristics There were 535 trials satisfying the inclusion criteria. Since 2000, the number of registered MPN-related clinical trials ranged from 11 to 36 trials per year with 28 trials registered annually on average (Figure 1). Of the 535 trials, 470 (88%) were interventional and 65 (12%) observational. Trials often employed multiple intervention types including: drug (77%); procedure (28%); biological (19%); radiation (13%); genetic (3%); behavioral (2%); device (2%); dietary supplement (1%); other (24%) [percentages do not sum to 100% as categories are not mutually exclusive]. Eligibility criteria varied widely, though most used 18 years old as the minimum age requirement (71%; 379/535) and nearly all included both genders (>99%; 533/535). PRO outcomes over time Of the 535 MPN trials, the number of primary outcomes within MPN trials did not change over time (p=.50) with an average of 1.6 per trial. Around 8% of MPN clinical trials had PRO-related primary outcomes; this rate also did not change over time (Figure 1: solid red line; p=.97). However, the total number of secondary outcomes per trial has increased since 2000 (p<.001). From 2000-2005, 2006-2011, and 2012-2018 there was an average of 2.8, 3.3, and 5.2 secondary outcomes per trial, respectively. Also, the proportion of MPN clinical trials with PRO-related secondary outcomes has increased steadily over time (Figure 1: dashed blue line; p<.001). On average, from 2000-2005, 2006-2011, and 2012-2018 the proportion of MPN clinical trials with PRO-related secondary outcomes increased from 8% to 23%, to 33%. Conclusion Analysis of ClinicalTrials.gov data suggest that patient-reported outcomes are being implemented into MPN clinical trials at increasing rates. While this suggests that MPN trials are becoming more patient-centered, PROs are included more often as secondary endpoints than primary endpoints. This analysis also suggests an increase in the number of secondary endpoints in recent years in MPN clinical trials, consistent with observed trends of growing complexity and increasing amount of data captured in clinical trials in general. Disclosures Mesa: Ariad: Consultancy; Galena: Consultancy; Gilead: Research Funding; Promedior: Research Funding; Incyte: Research Funding; Novartis: Consultancy; CTI: Research Funding; Celgene: Research Funding. Scherber:Orphan Pharmaceuticals: Honoraria; Incyte: Consultancy. Dueck:Bayer: Employment; Phytogine: Employment; Pfizer: Honoraria.

Abstract Background: Polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF) are chronic myeloproliferative neoplasms (MPNs) characterized by clonal cell proliferation, splenomegaly, and significant symptom burden. Integrative medicine interventions may offer unique symptom management strategies. (Gowin, et al., EHA 2017). Here we describe integrative interventions utilized and association with symptom burden, quality of life, depression, and fatigue adjusted for lifestyle confounders. Methods:Patients were recruited via social media. Consent and online self-report surveys were completed capturing patient demographics, disease-specific data, integrative medicine utilization, symptom burden via MPN-Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), depression screening via Patient Health Questionnaire (PHQ)-2, fatigue via Brief Fatigue Inventory (BFI), and overall quality of life (QoL). MPN-SAF TSS, QoL, BFI, and PHQ2 were compared by participation in the most frequently utilized interventions (Yes vs No). Intervention comparisons were adjusted for alcohol consumption, smoking status, BMI, current dietary modification, and MPN type using multiple linear and logistic regression. Results: Patients: A total of1087 patient surveys were consented. Of these, 858 had 10 or more responses. See Table 1 for patient characteristics. Integrative Medicine Therapies Descriptive Analysis: Integrative medicine therapies most frequently utilized by patients included aerobic activity (51.5%), massage (28.4%), yoga (25.6%), nutrition (25.2%), strength training (23.8%), acupuncture (19.3%), meditation (19%), breathing exercises (18.4%), chiropractic (16.2%), support groups (14.5%), mindfulness based stress reduction (13.6%), walking meditation (12.0%), pet therapy (9.4%), aromatherapy (8.6%), music therapy (8.0%), progressive muscle relaxation (7.0%), guided imagery (6.4%), homeopathy (6.3%), manual therapy (osteopathy/cranial sacral) (6.2%), reiki (5.8%), therapeutic touch (5.7%), Tai Chi (5.2%), art therapy (4.9%), traditional Chinese medicine (4.3%), Qigong (3.5%), cooking classes (3.0%), laughter therapy (2.9%), Ayurveda (2.4%), biofeedback (2.2%), dance therapy (2.1%), hypnosis (2.0%), resilience training (0.9%), IV vitamin therapy (0.8%), and narrative medicine (storytelling) (0.3%).Diet modification was reported in 47.7% of patients, including Mediterranean diet (19.0%), paleo/high protein/low carbohydrate (8.9%), vegetarian (8.6), plant based (5.2%), gluten free (5.2%), low FODMAP (1.8%), vegan (1.2%), and raw (0.6%) diets. Only 24% of patients reported receiving nutrition advice from their healthcare practitioner (HCP). Supplement utilization by MPN type was 162 patients (48.4%)in ET, 80 patients (42.8%) in MF, and 142 patients (45.2%) in PV. Overall, 20.6% patients reported not disclosing their natural product usage to their HCP. The most frequently utilized supplements included vitamin D, multivitamin, magnesium, omega 3, and calcium. Adjusted symptom association with integrative therapy intervention: MPN symptom burden: Aerobic activity (P=<.001)and strength training (P=.01) was associated with lower mean symptom burden. Use of massage (P=<001) and support groups (P=<.001) was associated with higher levels of symptom burden. QOL:Higher quality of life was reported in those receiving massage (P=.04)and support groups (P=.002). Lower quality of life was noted in those using aerobic activity (P=<.001)and strength training (P=.001). Depression (PHQ-2):Lower depression screening score was noted in those participating in aerobic activity (P=.006), yoga (P=.03), and strength training (P=.02). Fatigue (BFI):Lower fatigue was noted in those participating in aerobic activity (P=<.001) and strength training (P=.03). Higher fatigue was noted in those participating in massage (P=<.001) and breathing techniques (P=.02). See Table 2. Conclusion: In a geographically diverse MPN patient population, and when adjusting for healthy lifestyle practices overall, patterns of lower symptom burden, fatigue, depression, and higher QoL were revealed with integrative medicine utilization. Although limited by gender discrepancy and patient reported data, this study may offer a foundation to structure future integrative medicine trials to complement standard therapies in MPN patients. Disclosures Gowin: Incyte: Consultancy, Other: Scientific Advisory Board, Speakers Bureau. Mesa:UT Health San Antonio - Mays Cancer Center: Employment; Promedior: Research Funding; NS Pharma: Research Funding; CTI Biopharma: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy; Pfizer: Research Funding; Celgene: Research Funding.