Ross, David M

Abstract Introduction: Therapy related myeloid neoplasm (t-MN) is a rare but devastating complication of cytotoxic therapy used for management of unrelated malignancy or autoimmune diseases. Therapeutic options for t-MN are limited and although hypomethylating agents (HMA) are frequently used, the benefit of it in t-MN is unclear. There are no prospective trials of HMA in t-MN and published experience is based on retrospective analysis of small number of cases (n=42 to 54). The aim of this study was to assess the efficacy of HMA therapy in t-MN patients and evaluate predictors for it. Methods: t-MN patients managed with first line HMA therapy were analyzed. This study was approved by the participating institutional review board. Criteria for inclusion were a pathologically confirmed diagnosis of t-MN based on WHO 2016 criteria, age >18 years, and ≥1 cycle of decitabine or azacitidine. Patient characteristics were summarized by frequency (percentage). Overall survival was calculated from the time of starting azacitidine to last follow up or death date using Kaplan-Meier analysis. Multivariable analysis was performed using Cox proportional hazard model. Statistical analysis was performed using R program and significance was defined as P<0.05. Results: Of the 554 t-MN patients analyzed, 184 (33%) patients were treated with HMA as the first line therapy and were included in the study. Median age at t-MN diagnosis was 70 (IQR 64-75) years and 112 (60%) patients were male. At the time of diagnosis, 84% (n=154) and 16% (n=30) patients were classified as t-MDS and t-AML and 47% (87/184) and 46% (49/107) of the evaluable patients had complex karyotype and TP53 somatic mutations (TP53 Mut) respectively. Azacitidine (n=145, 79%) was most frequently used HMA followed by decitabine (n=39, 21%). Median survival of the whole cohort since t-MN diagnosis was 13.2 months. At the time of analysis further treatment details were available for 78 patients and outcome of these patients were compared with primary MDS (p-MDS) and oligoblastic AML managed at the same institute. Completion of six-cycles of HMA (50% vs. 62%; P=0.07) and overall response rate (47 vs. 50%, P=0.22) was not significantly different between t-MN and p-MDS. However, median OS of t-MN was significantly poor compared to p-MDS (10 vs. 20 months, P=0.0004; Figure 1A). In t-MN patients treated with HMA as the first-line agent, median OS was significantly shorter in t-AML compared to t-MDS (7 vs.10 months, P=0.04; Figure 1B). Median OS was significantly shorter in patients with TP53 Mut and complex karyotype (Figure 1C-D). In Cox proportional hazard analysis, t-AML and complex karyotype were independently associated with poor outcome. Conclusion: This study demonstrates significantly poor outcome of t-MN patients treated with HMA therapy as first line. The outcome is particularly poor in t-AML and patients with complex karyotype and TP53 Mut. Hence there is urgent need for clinical trials of novel therapies for t-MN. Figure 1 Figure 1. Disclosures Sharplin: Kite Gilead: Honoraria; Novartis: Other: Travel Support. Ross: Keros Therapeutics: Consultancy, Honoraria; Bristol Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

e19040 Background: Clinical trials investigating JAK1/JAK2 inhibitors for myelofibrosis (MF) subjects have measured symptom improvement as a minimum 50% reduction in total symptom score (TSS) at the end of a 24-week treatment period. This landmark analysis is based on post-baseline score changes from Weeks 21 (W21) to 24 and requires vastly different absolute TSS improvements for patients with very high or low baseline (BL) TSS to reach responder status. A phase 3 clinical study, SIMPLIFY-1, randomized 432 intermediate and high risk JAK inhibitor (JAKi) naive MF patients 1:1 to momelotinib (MMB) or ruxolitinib (RUX). Non-inferiority on the MPN-SAF TSS response rate endpoint at W24 was not met (MMB: 28% vs RUX: 42%); however, improvement in each of the 7 TSS items was similar for MMB vs RUX. To understand the discrepancy, we applied item analysis and mixed effect models for repeated measures (MMRM) to SIMPLIFY-1. Methods: Analyses were conducted in the intention-to-treat (ITT) population and in a symptomatic subset (selected as subjects with BL TSS ≥ 10). The distributions of TSS items were examined at BL and shift in scores at W24 (health state shifts) were assessed. GEE models were used to estimate item-level odds ratios using multiple predictive imputations for missing data. MMRM compared mean change in TSS from BL to W24 using data from all visits. The meaningful change threshold (MCT) was determined using Patient Global Impression of Change. Results: BL scores across items were heterogenous in the MMB and RUX groups; the proportion of subjects with no or mild symptoms (0–3 on a 0-10 point scale) ranged from 44% (tiredness) to 81% (itching). Distributions of BL scores were different across arms with 6 out of 7 items in the MMB arm reporting more severe or very severe symptoms (scores of 7-10) at BL. Despite the imbalance in BL scores, item-level health state shifts showed similar improvements for MMB and RUX. Categorical responder analysis showed no significant differences on any items. Odds ratios for each between-group comparison ranged from 0.74 to 1.20. MMRM mean TSS change at W24 was 6.35 (MMB) vs 7.87 (RUX) in the ITT and 8.80 (MMB) vs 10.46 (RUX) in the symptomatic subset. Mean TSS were near the within-subject MCT of 8 points in the ITT and exceeded the MCT in the symptomatic subset. The between-group difference was 1.52 (95% CI: (0.196, 2.847)) in the ITT and 1.67 (95% CI: -0.134, 3.468) in the symptomatic subset. Conclusions: Comparable item health state shifts at W24 and similar improvements in mean TSS as shown by MMRM, with a minimal between-group difference of 1.52 on the 70 point scale in context of an 8-point MCT suggest MMB provides clinically relevant and comparable symptom improvements to RUX; these analyses require further validation in independent data sets. Imbalance in BL symptom scores in MMB subjects may have contributed to the inability to demonstrate non-inferiority in TSS response rate at W24. Clinical trial information: NCT01969838.

Background Activating mutations in JAK2 are the molecular hallmark of PV. However, achieving molecular remission is not a validated endpoint in PV, as its correlation with patient-relevant endpoints, such as thrombotic events or disease progression, is not well established. The expression of MDM2, a negative regulator of wild-type p53, is significantly higher in CD34+ cells from patients with PV vs those from healthy controls. Therefore, MDM2 antagonists such as idasanutlin (idasa) may have selective and potentially disease-modifying effects in PV. This exploratory analysis reports baseline mutational profiling and serial measurements of JAK2 V617F variant allele frequency (VAF) from patients treated with idasa in the Phase II NP39761 study (NCT03287245). Methods Patients with PV, as defined by the 2016 World Health Organization criteria, were eligible for inclusion if their disease was HU resistant/intolerant according to European LeukemiaNet criteria and they were phlebotomy dependent (≥ 1 phlebotomy in the 16-wk period prior to screening). Prior PV therapy with ruxolitinib and/or interferon was allowed. Idasa was given orally once daily on days 1-5 of 28-day cycles for up to 24 mo. The starting dose was 150 mg, but dose increase (to 200 mg) or decrease (to 100 mg) was allowed per protocol-defined criteria. The primary efficacy endpoints were hematocrit control (HTC), defined as maintaining acceptable hematocrit levels with ≤ 1 phlebotomy between cycle 1, day 1 (C1D1) and wk 8 and no phlebotomy after wk 8, and complete hematologic remission (CHR), defined as HTC together with platelets < 400 × 109/L and white blood cell count < 109/L on the day of response assessment (or most recent test). JAK2 V617F VAF was analyzed at screening and at C3D28, C5D28 and wk 32. The JAK2 V617F VAF was determined using quantitative polymerase chain reaction. Baseline blood samples were sequenced using the Foundation Medicine FoundationOne Heme next-generation sequencing panel, which interrogates > 400 DNA-sequenced genes, to explore the genetic landscape of PV beyond JAK2 V617F. Results All 27 patients enrolled in the study harbored JAK2 V617F. Baseline and ≥ 1 later JAK2 VAF measurements were available in 23 patients, allowing for analysis. The median age was 56 y (range, 34-74), and 7 patients (26%) had been previously treated with ruxolitinib. Median treatment duration was 257 days (range, 5-677), and the median number of treatment cycles was 8 (range, 1-22). JAK2 V617F VAFs at baseline were highly variable, ranging from 7% to 96% (median, 66%). A reduction in JAK2 V617F VAF was observed as early as after 3 cycles (median reduction, 39%; n = 19) and was sustained in patients receiving treatment, with a median reduction of 58% at C5D28 (n = 17) and of 76% at wk 32 (n = 13). The median reductions in JAK2 V617F VAF were significantly higher for patients with CHR and HTC than in nonresponders on C3D28 (CHR, P < 0.01; HTC, P = 0.04) and C5D28 (CHR, P < 0.01; HTC, P = 0.03), with a similar trend also at wk 32 (CHR, P = 0.06; HTC, P = 0.19) (Figures). Baseline targeted sequencing (n = 16) identified several additional subclonal mutations. However, no TP53 mutations were detected. Variants in TET2 and ASXL1 were detected in 37% (6 of 16) and 20% (3 of 16) of patients, with VAFs of 2%-51% and 38%-50%, respectively. Notably, 68% of the patients had variants detected in 1 to 3 DNA repair genes, including ATM (VAF, 47%-52%), ATR (VAF, 49%), BRCA2 (VAF, 47%-51%), PARP1 (VAF, 52%), PARP3 (VAF, 48%), FANCM (VAF, 47%-50%), BLM (VAF, 48%) and MSH3 (VAF, 49%). In the absence of sequencing of patient-matched non-hematologic tissue and the VAFs being ≈50%, it is possible some of these variants are germline. Whether such variants predispose to PV is unknown. Conclusions Idasa has relevant clinical activity in patients with PV who are resistant to or intolerant of HU and showed rapid JAK2 V617F VAF reduction in a subset of patients as early as after 3 treatment cycles. The median JAK2 VAF reduction was significantly greater in patients who achieved CHR and HTC after 3 and 5 cycles of idasa treatment, suggesting that early molecular response was associated with higher likelihood of clinical response. Baseline mutations were seen in several genes commonly mutated in PV. A high frequency of variants in DNA repair genes has not previously been reported in PV and may contribute to genomic instability in this disease. Figure Disclosures Passamonti: Roche: Other: Support of parent study and funding of editorial support; BMS: Speakers Bureau; Novartis: Speakers Bureau. El-Galaly:F. Hoffmann-La Roche: Current Employment, Other: Support of parent study and funding of editorial support. Gerds:Celgene: Consultancy, Research Funding; Gilead Sciences: Research Funding; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; AstraZeneca/MedImmune: Consultancy; Roche/Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; Pfizer: Research Funding; Apexx Oncology: Consultancy; Sierra Oncology: Research Funding. Gupta:Incyte: Honoraria, Research Funding; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy. Higgins:Roche: Current Employment, Current equity holder in publicly-traded company, Other: Support of parent study and funding of editorial support. Huw:Roche: Current Employment, Other: Support of parent study and funding of editorial support. Maffioli:Roche: Other: Support of parent study and funding of editorial support. Mesa:Sierra Oncology: Consultancy; Incyte: Research Funding; Samus Therapeutics: Research Funding; Promedior: Research Funding; Genentech: Research Funding; Novartis: Consultancy; CTI BioPharma: Research Funding; LaJolla Pharmaceutical Company: Consultancy; AbbVie: Research Funding; Bristol Myers Squibb: Research Funding. Rambaldi:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yacoub:Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support; Ardelyx: Current equity holder in publicly-traded company. Mascarenhas:Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution).

Background PV is a clonal myeloid neoplasm characterized by activating mutations in JAK2 and increased red blood cell production. Reduction of thrombosis risk through lowering of hematocrit (Hct) and thus blood viscosity is critical, but management of constitutional symptoms is also important. HU is an effective and well-tolerated first-line treatment (tx) for PV, but pts who develop resistance to or intolerance of HU have limited tx options. A Phase I study of idasanutlin, an MDM2 antagonist leading to increased p53 activity, showed encouraging efficacy and potential disease-modifying effects via rapid reduction in JAK2 V617F variant allele frequency in 11 pts with PV. These results prompted the larger, international Phase II study of idasanutlin in HU-resistant/intolerant PV (NCT03287245); data from the initial phase of the study are reported here. Methods Pts meeting the 2016 WHO criteria for PV were eligible for inclusion if they had HU-resistant/intolerant disease according to the European LeukemiaNet (ELN) criteria and were phlebotomy dependent (≥ 1 phlebotomy in the 16-wk period prior to screening). Prior PV tx with ruxolitinib (rux) or interferon was allowed. Idasanutlin was given orally once daily on days 1-5 of 28-day cycles for up to 24 mo. The starting dose was 150 mg; increase to 200 mg was allowed for non-responders at cycle 3, day 28, and reduction to 100 mg was permitted for toxicity and for pts treated beyond cycle 12. Antiemetic prophylaxis was mandatory in cycle 1 throughout the study and later became mandatory in all cycles. The primary endpoint (wk 32) was the composite response of Hct control (HTC) and spleen volume reduction > 35% by CT/MRI in pts with splenomegaly (> 450 cm3) and HTC alone in pts without splenomegaly. Key secondary endpoints included safety, complete hematologic response (CHR; defined as HTC and normalization of platelets/leukocytes) and ELN response. Results A total of 27 pts were included in this study and received tx with idasanutlin. Median age was 56 years (range, 34-74) and 16 pts (59.3%) were male (Table 1). All pts had JAK2 V617F mutation; 7 had previous exposure to rux. Median tx duration was 257 days (range, 5-677); the median number of treatment cycles was 8 (range, 1-23). Dose modifications occurred in 17 pts (63.0%; Table 2). A total of 3 serious AEs occurred: atrial flutter, atrial fibrillation and nausea/vomiting (n = 1 each). The serious cardiac AEs occurred in pts with pre-existing hypertension and a past incident of heart failure not symptomatic upon enrollment, respectively. No deaths, transformation to acute myeloid leukemia, progression to myelofibrosis or thrombotic events occurred during the study. AEs occurring in ≥ 15% of pts are listed in Table 3; gastrointestinal toxicity and fatigue were the most common events. The population for primary endpoint evaluation consisted of pts with response assessed at wk 32 (n = 16). One of 13 pts with baseline splenomegaly achieved a composite response (7.7%; Table 4). Nine of 16 pts (56.3%) among all evaluable pts achieved HTC: 6 of 11 rux-naive pts (54.5%) and 3 of 5 rux-exposed pts (60.0%). Eight of 13 pts (61.5%) among all pts had HTC duration ≥ 12 wk beyond wk 32: 5 of 9 rux-naive pts (55.6%) and 3 of 4 rux-exposed pts (75.0%). At wk 32, 8 of 16 pts (50.0%) achieved a CHR, with 6 of 13 (46.2%) having a CHR duration ≥ 12 wk beyond wk 32. Overall response rates per modified ELN response criteria in pts with baseline splenomegaly, pts without baseline splenomegaly and in all pts were 69.2% (9 of 13), 66.7% (2 of 3) and 68.8% (11 of 16), respectively; 9 of 15 pts (60%) among all pts had a response duration ≥ 12 wk beyond wk 32. Median (range) laboratory value changes at wk 32 were: platelets, −253 × 109/L (−2083 to +175) and leukocytes, −4.8 × 109/L (−25.3 to +3.4). At wk 32, 6 of 14 pts (42.9%) had a ≥ 50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score. Conclusions Idasanutlin showed relevant clinical activity in pts with HU-resistant/intolerant PV and also in a subset of pts with prior rux tx. However, the low-grade gastrointestinal toxicity profile of idasanutlin was not effectively mitigated with antiemetic prophylaxis and led to frequent discontinuations. These results iterate the importance of tolerability of novel therapies administered over the long term for pts with PV. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Higgins:Roche: Current Employment, Current equity holder in publicly-traded company, Other: Support of parent study and funding of editorial support. Anders:Roche: Current Employment, Other: Support of parent study and funding of editorial support. Burbury:Roche: Other: Support of parent study and funding of editorial support. El-Galaly:F. Hoffmann-La Roche: Current Employment, Other: Support of parent study and funding of editorial support. Gerds:Roche/Genentech: Research Funding; Apexx Oncology: Consultancy; AstraZeneca/MedImmune: Consultancy; Pfizer: Research Funding; Imago Biosciences: Research Funding; Gilead Sciences: Research Funding; Incyte Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding; CTI Biopharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Gupta:Pfizer: Consultancy; Incyte: Honoraria, Research Funding; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kovic:Roche: Other: Support of parent study and funding of editorial support. Maffioli:Roche: Other: Support of parent study and funding of editorial support. Mesa:AbbVie: Research Funding; Sierra Oncology: Consultancy; CTI BioPharma: Research Funding; LaJolla Pharmaceutical Company: Consultancy; Bristol Myers Squibb: Research Funding; Genentech: Research Funding; Samus Therapeutics: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Incyte: Research Funding. Rambaldi:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.. Vannucchi:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yacoub:Roche: Other: Support of parent study and funding of editorial support; Dynavax: Current equity holder in publicly-traded company; Novartis: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company.

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