Mascarenhas, John

Abstract Background: Patients (pts) with polycythemia vera (PV) and essential thrombocythemia (ET) suffer from difficult MPN associated symptoms which impact quality of life (QoL). The impact of initial cytoreduction on ET/PV symptoms, resulting toxicity and QoL have not been prospectively studied. Methods: MPD-RC 112 trial (NCT01258856) randomized 168 therapy-naive (hydroxyurea [HU] <3 mo) high risk ET/PV pts (<5 years of disease) to response adjusted pegylated interferon alpha 2a (PEG) or HU. MPN symptoms, in depth toxicity assessment, and QoL were measured by two symptom instruments (MPN-SAF, EORTC QLQ-C30: baseline,3, 6, 9, and 12 mo) and toxicity questions. Blinded response review by European Leukemia Net (ELN) hematological responses (HR) was conducted at 12 months. Individual time point and longitudinal group comparisons were based on mixed models adjusting for age. Results: Patients: Of 168 randomized pts (86 HU, 82 PEG), 164 (98%) completed the survey package at baseline and 151 (HU 83%; PEG 98%) completed at least 1 survey during treatment. Median age was 61 (range 18-87) with 70 (42%) females; 81 (48%) / 87 (52%) with ET / PV; 46 (27%) had a history of a thrombosis. 119 (71%) received prior HU (up to 3 months). Baseline characteristics were balanced between arms with the exception of age (median HU 63 vs. PEG 60 yrs; p=0.02). Baseline Symptom Burden /QoL: Mean MPN-SAF Total Symptom Score (TSS), scale 0 [absent]-100 [worst imaginable] was 15.8 (SD 12.6; range 0-62.0) with means of 15.1 (SD 12.6) / 16.5 (SD 12.6) for ET / PV which were slightly lower than reported means of a previous cohort receiving any line of treatment (Scherber RM, JCO 2012). Median number of moderate (defined as score >=3) symptoms in ET patients was 3.0 and PV 4.0. Most common moderate symptoms were fatigue (65.9%), insomnia (37.2%), numbness (33.5%) , itching (29.9%), dizziness (27.4%), early satiety (26.8%) , headache (23.2%), sad mood (23.2%), inactivity (22%), concentration (20.7%). 50.6% of patients had one or more symptom with a score >=6. Mean QLQ-C30 global health status/QoL (GHS/QoL) was 70.8 (SD 21.9) - comparable to a general population (mean 71.2, SD 22.4) and better than a general cancer population (mean 61.3, SD 24.2; QLQ-C30 Reference Manual 2008). At baseline, TSS, symptoms, and QoL were similar between treatment arms. In patients with TSS >20 at baseline (highly symptomatic, n=50; ET:20, PV:30), median TSS was 28.0 (range 20.0 to 62.0); the highest scored symptom was fatigue (median=7.0), itching (median=4.5) and insomnia (median=4.0). Impact of Therapy on Symptom Burden/QoL: On HU, pts experienced worsening QoL (physical, cognitive functioning, HRQoL) and some persistent or transient worsened symptoms (inactivity, concentration (p<0.05) (Table 1)). On PEG, pts experienced worsening of fever, dyspnea, appetite loss and PEG-related symptoms including flu-like symptoms, injection site irritation, blurry vision, and visual changes (all p<0.05), but not sad mood (not corrected for antidepressants). In comparing arms, change in TSS significantly differed (p=0.01) between arms with increasing symptoms on HU vs PEG at 3 and 6 mo, but lower symptom burden at 9 and 12 mos (Figure 1). In highly symptomatic pts (with a baseline TSS > 20, n=50), improvements in weight loss, abdominal discomfort, fatigue, itching, fever, early satiety (12 m.) were observed in pts on HU. For PEG, in highly symptomatic pts, improvements were observed for overall TSS score, fatigue, inactivity, night sweats, and itching (with similar toxicities to all PEG patients). ELN Response and Symptom Burden/QoL: Among the 133 pts with 12-mo symptom data, complete hematologic response (CHR) rate was 43%. Inactivity and sad mood were worse in those patient achieving a CHR (inactivity: CHR worsening 0.68 vs PHR/NR better 0.26; p=0.03; sad mood: CHR worsening 0.67 vs PHR/NR better 0.67, p=0.002)). These latter changes were not related to higher doses utilized (in either arm), suggesting obtaining CHR may have negative effects on patient symptoms. Conclusions:In pts with a significant baseline MPN symptom burden, cytoreductive therapy has both a beneficial impact on baseline MPN symptom burden but also leads to therapy associated toxicity, although different patterns of efficacy and toxicity between HU and PEG. Achievement of a CHR in PV/ET may be associated with higher rates of drug related toxicities, and the value of achieving CHR may need further validation. Disclosures Mesa: Incyte Corporation: Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment; Genentech: Research Funding; Pfizer: Research Funding. Mascarenhas:Merck: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Promedior: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Research Funding. Rambaldi:Omeros: Consultancy; Roche: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Amgen Inc.: Consultancy. Yacoub:Novartis: Honoraria, Speakers Bureau; Cara Therapeutics: Equity Ownership; Ardelyx, INC.: Equity Ownership; Inycte: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Dynavax: Equity Ownership. Harrison:Gilead: Honoraria, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Mead:Elstar: Research Funding; Celgene: Research Funding; ARIAD: Consultancy; Cell Therapeutics: Consultancy; Evotek: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy. Kessler:Sangamo: Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Research Funding; Dimension Advisory boards: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; DSMB: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Biomarin: Research Funding. Kremyanskaya:Incyte: Research Funding. Rampal:Incyte: Honoraria, Research Funding; Constellation: Research Funding; Jazz: Consultancy, Honoraria; Stemline: Research Funding; Celgene: Honoraria. Hoffman:Incyte: Research Funding; Janssen: Research Funding; Merus: Research Funding; Formation Biologics: Research Funding; Summer Road: Research Funding. Dueck:Pfizer: Honoraria; Bayer: Employment; Phytogine: Employment.

Abstract Background: The Philadelphia chromosome negative myeloproliferative neoplasms (MPN), including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), carry a propensity to evolve into an accelerated phase (MPN-AP, 10-19% blasts in the blood or marrow) and blast phase (MPN-BP, ≥20% in the blood or marrow). Such disease evolution carries a dismal prognosis with a median survival of 3-5 months, and thus the development of innovative treatment strategies represents an urgent unmet clinical need. Responses in patients with MPN-AP/BP to both hypomethylating agents and single-agent ruxolitinib (RUX) have been reported. In vitro, the combination of RUX and decitabine (DEC) are synergistically active in cells derived from patients with MPN-BP and from a murine model of MPN-BP. These observations led us to explore the safety of the combination in MPN-AP/BP in a phase I study. An MTD for RUX in combination with DEC 20mg/m2/d x 5 days was not reached in this study and the recommended Phase II dose of RUX was selected as 25mg BID for the first cycle of therapy followed by 10mg BID in subsequent cycles with a goal to minimize myelosuppression and maintain ambulatory administration (Rampal et al ASH 2016). Here we report the final results of the phase 2 combination of RUX + DEC in patients with MPN-AP/BP (NCT02076191). Methods: We conducted a multicenter, open label, phase II trial in patients with MPN-AP/BP, following a previous diagnosis of ET, PV or PMF. Patients enrolled were treated with the RPTD dose of RUX + DEC on a 28-day cycle until progression of disease, unacceptable toxicity or patient/physician withdrawal. Adverse events (AEs) were assessed using the NCI CTCAE v4.0. The primary endpoint was response rate by cycle 6 using modified Cheson criteria: CR required 0% peripheral blood blasts, ANC >1000/uL, hemoglobin ≥10g/L, and platelets ≥100x109/L; CRi required 0% peripheral blood blasts with incomplete count recovery; and PR required ≥50% decrease in peripheral blood blasts regardless of blood counts. Results: A total of 25 patients were accrued to study. The median age was 71 years (46.7-85.6). 10 patients (40%) had MPN-AP and 15 patients (60%) had MPN-BP. 6 patients (24%) had been previously been treated with single-agent RUX, and 2 patients (8%) had been treated with single-agent DEC. Median palpable spleen size was 7cm (range 0 - 20cm). The median number of cycles of treatment received on study was 4 (range 1 - 20). The most common grade 3/4 non-hematologic AEs observed were pneumonia (16%), febrile neutropenia (16%) and infection (8%). The most common grade 3/4 hematologic AEs were anemia (16%), neutropenia (12%) and leukopenia (8%). The most common reasons for study discontinuation were AEs in 9 patients (36%), disease progression in 5 (20%) patients and hematopoietic cell transplantation in 2 (8%) patients. Eighteen (72%) patients were evaluable for response. The overall response rate (CR+CRi+PR) was 61% (11/18 patients). CRi was observed in 2 patients (11%), PR in 9 patients (50%) and no response in 7 patients (39%). The median time to CR/PR was 3.4 mos (95% CI: 2.1 - not estimated). The median peripheral blood blast count reduction was 80.1% (range 71.4-100%) (Figure 1A). The median reduction in spleen size by palpation was 70.5% (range 0-100%) (Figure 1B). Median overall survival for all patients was 7.6 months (95% CI: 4.3 - Not estimated); 9.7 months (95% CI: 4.3 - Not estimated) for MPN-BP and 5.8 months (95% CI: 3.6 - Not estimated) for MPN-AP (Figure 2). Three patients (17%) were able to proceed to HCT. The results of ongoing genomic, histopathologic and cytokine profiling studies will be available for presentation at the meeting. Conclusions: The combination of RUX+DEC has activity in patients with MPN-AP/BP. The drug combination is generally well tolerated and can be administered as an outpatient, a distinct advantage over intensive induction therapies that have not shown significant benefit in these patients. Additional work is ongoing to assess the genomic and clinical variables predictive of response with this combination therapy approach. Given the tolerability and efficacy, this regimen may be of particular benefit to patients who are not candidates for intensive therapies. Disclosures Rampal: Constellation: Research Funding; Celgene: Honoraria; Stemline: Research Funding; Incyte: Honoraria, Research Funding; Jazz: Consultancy, Honoraria. Mascarenhas:Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Novartis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Promedior: Research Funding. Wang:Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Novartis: Speakers Bureau. Gerds:Celgene: Consultancy; Apexx Oncology: Consultancy; Incyte: Consultancy; CTI Biopharma: Consultancy. Heaney:Roche: Consultancy, Research Funding; Incyte: Research Funding; Blueprint: Research Funding; Novartis: Research Funding; Decipheral: Research Funding. Abboud:Agios: Honoraria; Jazz: Honoraria, Speakers Bureau. Kremyanskaya:Incyte: Research Funding. Odenike:ABBVIE: Honoraria, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI/Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncotherapy Science: Research Funding; Agios: Research Funding; Celgene: Research Funding; NS Pharma: Research Funding; Janssen: Research Funding; Astex: Research Funding; Gilead Sciences: Research Funding. Levine:Roche: Consultancy, Research Funding; C4 Therapeutics: Equity Ownership; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Epizyme: Patents & Royalties; Prelude: Research Funding; Qiagen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Loxo: Consultancy, Equity Ownership; Imago: Equity Ownership; Novartis: Consultancy; Isoplexis: Equity Ownership. Mesa:Novartis: Consultancy; NS Pharma: Research Funding; Genentech: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment; CTI Biopharma: Research Funding; Gilead: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; Incyte Corporation: Research Funding; Promedior: Research Funding. Dueck:Phytogine: Employment; Bayer: Employment; Pfizer: Honoraria. Hoffman:Incyte: Research Funding; Formation Biologics: Research Funding; Janssen: Research Funding; Merus: Research Funding; Summer Road: Research Funding.

Abstract Introduction HU is the treatment of choice for patients (pts) with high risk ET/PV, however, PEG has been proposed as an alternative option due to its proposed potential to modify disease course. An interim analysis of MPN-RC 112 (Blood 2016 128:479;) did not reveal a difference in PR/CR rates between HU and PEG therapy after 12 months in the first evaluable 75 pts treated. Here we present the results and long-term follow-up of all pts participating in this pivotal study [NCT01259856]. Methods MPN-RC 112 was a randomized, open label, phase 3 clinical trial comparing HU and PEG in pts with high risk ET/PV. Pts were treated for up to 12 months to achieve PR or CR (ELN/IWG-MRT response criteria). Pts who achieved a PR/CR continued therapy for up to a maximum of 6 years. Minimum follow up was 1 year from the time the last pt was randomized. The primary objective was to compare the CR rate following HU vs. PEG at 12 months with 3 month confirmation. Secondary objectives included a comparison of toxicity and tolerability; PR rates; incidence of specific pre-defined toxicities and tolerance to therapy; impact of therapy on key biomarkers; survival and incidence of myelodysplastic syndrome, myelofibrosis, or leukemic transformation; and incidence of major cardiovascular events. Bone marrow pathologic responses were evaluated by central blinded expert review at baseline, 12, 24 months and end of study. Results The study accrued 168 pts; 86 were randomized to HU and 82 to PEG. A summary of pt baseline characteristics by treatment arm is shown in Table 1 and were well balanced between the treatment arms except for median age which was higher in the HU arm (p=0.02). Median duration of follow up was 89.9 weeks (range, 0 to 292.3) and the median treatment duration was 86.0 weeks (range, 0 to 287.3). At 12 months, the overall response rate (ORR= PR+CR) was 69.8% and 78% for HU and PEG, respectively (p=0.22). Figure 1 shows the distribution of responses stratified by disease type. At 24 months, 59 pts were on treatment with an ORR of 22/25 (88%) for HU and 31/34 (91%) for PEG. When considering all 106 pts who were eligible to receive treatment for 24 months (due to study closure), the ORR was 22/54 (40.7%, PR: 11 (20.4%), CR: 11 (20.4%)) for HU and 31/52 (59.6%, (PR: 15 (28.9%), CR: 16 (30.8%)) for PEG, p=0.04. Best ORR at any time on study was seen in 70.9% and 81.7% of HU and PEG treated pts, respectively, p=0.10. The median maximum change from baseline spleen volume was -6% (-100.0 - +53.8) in 112 evaluable pts and was similar between arms, p=0.99. Bone marrow morphologic responses are shown in Table 2 and the best response (CR) seen at any time on study for ET treated with HU was 52% (12/23) vs PEG 32% (8/25) and for PV treated with HU 19% (6/31) vs PEG 6% (2/34). Cytogenetic analyses at diagnosis were available in 86% (144/168). An abnormal karyotype was seen in 15% (22/144). Five PV and one ET pt lost their chromosomal abnormalities: 3 after one year (HU=1, PEG=2) and three after two years of therapy (HU=2, PEG=1). AE information is available for 162 pts (HU: 80; PEG: 82) (Table 3). Six pts randomized to HU never received treatment due to study withdrawal prior to initiation of treatment. Sixty pts had a grade 3 or higher event [HU: 22 (27.5%) and PEG: 38 (46.3%)]. 28 PV pts had a grade 3/4 [HU: 10 (24.4%) and PEG: 18 (41.9%)]. Four pts had a grade 4/5 event [HU: 3 (7.3%) and PEG: 1 (2.3%)]. 32 ET pts had a grade 3/4 [HU:12 (30.8%) and PEG:20 (51.3%)]. Two pts had a grade 4/5 event [HU:1 (2.6%), PEG:1 (2.6%)]. Additional outcomes of interest on study include one death attributed to new diagnosis of lung cancer (HU:1), progression to myelofibrosis (HU:1), vertebral artery occlusion (HU:1), and cerebral vascular accident (PEG:1). Reasons for study discontinuation are shown in Table 4. The effect of therapy on symptom burden and quality of life will be presented in a companion abstract (Mesa et al). The impact of mutation status on therapeutic outcome as well as the molecular responses will be presented at the meeting. Conclusion The final analysis of MPN-RC 112 revealed that the CR rates in pts with high risk ET/PV treated with PEG and HU at 12 and 24 months were similar. PEG was associated with a higher rate of grade 3/4 toxicity. Each drug appeared equally capable of modifying the natural history of high risk ET/PV based upon their effects on spleen size, karyotypic abnormalities, histopathological parameters and the low incidence of thrombotic complications and disease evolution in both arms. Disclosures Mascarenhas: Novartis: Research Funding; Promedior: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Merck: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rambaldi:Amgen Inc.: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Omeros: Consultancy; Roche: Consultancy; Celgene: Consultancy. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Mead:Bristol-Myers Squibb: Consultancy; Elstar: Research Funding; Celgene: Research Funding; ARIAD: Consultancy; Evotek: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Cell Therapeutics: Consultancy. Kessler:Genentech: Research Funding; Sangamo: Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biomarin: Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; DSMB: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Research Funding; Dimension Advisory boards: Membership on an entity's Board of Directors or advisory committees. Kremyanskaya:Incyte: Research Funding. Rampal:Stemline: Research Funding; Incyte: Honoraria, Research Funding; Constellation: Research Funding; Jazz: Consultancy, Honoraria; Celgene: Honoraria. Mesa:CTI Biopharma: Research Funding; Novartis: Consultancy; Genentech: Research Funding; Promedior: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment; Pfizer: Research Funding; Celgene: Research Funding; Incyte Corporation: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding. Dueck:Pfizer: Honoraria; Bayer: Employment; Phytogine: Employment. Hoffman:Incyte: Research Funding; Formation Biologics: Research Funding; Merus: Research Funding; Janssen: Research Funding; Summer Road: Research Funding.

Abstract Abstract 2818 Background: Pegylated interferon alpha-2a (Peg INF2a) has been demonstrated to be active therapy for high-risk essential thrombocythemia (ET) and polycythemia vera (PV), as well as treatment for early myelofibrosis (MF). We retrospectively analyzed the outcomes of Peg INF2a therapy in MPN patients treated outside the constraints of a clinical trial in the USA and EU. Methods: Clinical records of MPN patients treated at the participating centers, receiving Peg INF2a outside of the context of a clinical trial, were analyzed for response (ET and PV by ELN criteria; MF by EUNMET and IWG-MRT criteria), toxicity, and duration of response. Results: Patients: 115 patients were identified (54 PV (47%), 44 ET (38%), 17 MF (15%)) with a median age at diagnosis (48) and gender distribution (59% females) typical for the disorders. The patients had been diagnosed with the MPN a median of 44 months (0.0–312 months) prior to initiation of the Peg IFN2a and 64% harbored the JAK2-V617F mutation. The majority of patients (81%) had received at least one prior cytoreductive therapy for their disease (73 hydroxyurea, 39 anagrelide, 37 aspirin, 21 prior interferon (non pegylated), 3 phlebotomy alone). Therapy: Median starting dose of Peg INF2a was 45 micrograms/week (range: 22.5–180) with peak starting doses ranging from 30 to 300 micrograms/week. A total of 84 patients (73%) remain on Peg IFN2a with median duration of treatment of 17 months (range: 1.0–92). Toxicity: Overall the Peg INF2a was well tolerated. Hematological toxicity was Gr 3 or lower. There were 6 cases with anemia (5%), 10 with thrombocytopenia (9%) and 8 had leukopenia (7%). Most common non-hematologic toxicities were Gr 1–3 fatigue in 27 (23%), Gr 1 LFT elevation in 6 (5%), Gr 2–3 skin/allergic reaction in 6 (5%), Gr 1–2 nausea in 5 (4%), and Gr 2 mood disorder in 5 (4%) patients. Twenty patients (17%) discontinued therapy secondary to toxicity. Response: ET-PV: By ELN criteria, 30 PV patients achieved CR (55%), 17 achieved PR (31%), 4 achieved NR (7%), and 3 patients (5%) were lost to follow up or were too early to evaluate for response. In ET, the responses were CR in 27 (61%), PR in 7 (16%), NR in 4 (9%), and 6 patients (14%) were lost to follow up or were too early to evaluate for response. MF: The responses by IWG criteria were 1 CR (6%), 2 PR (12%), 2 CI (12%) and 9 SD (53%). By EUNMET, there were 2 CR (12%), 4 major responses (24%), 4 moderate responses (24%), 1 minor response (6%), 2 no response (12%), and 3 patients (17%) were lost to follow up or were too early to evaluate for response. Conclusions: Peg INF2a used at doses consistent with published clinical trials is active and well-tolerated when administered in a clinical setting outside of the support of a clinical trial. Given the majority of patients had previously failed cytoreductive therapy these results substantiate prior reports of efficacy of Peg INF2a in MPNs. Upcoming randomized clinical trials through the Myeloproliferative Disorders Research Consortium will help further define the role of Peg INF2a as first line therapy in high-risk MPNs. Disclosures: Mesa: Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding.

Abstract Background: Patients with the myeloproliferative neoplasm (MPN) polycythemia vera (PV) require treatment to manage blood cell counts and reduce the risks of cardiovascular/thromboembolic events. Hydroxyurea (HU) is a common cytoreductive treatment; however, some patients discontinue HU treatment because of resistance, intolerance, or frequently a combination of both limitations. Patients may also continue to receive HU despite diminishing or nonexistent clinical benefit, sometimes in combination with persistent need for phlebotomy procedures. This analysis of MPN Landmark survey data examined patient-reported quality of life (QoL) outcomes in patients with PV who were naive to HU (HU-N), were continuing HU (HU-C), or had discontinued HU (HU-D). Methods: Patients with an MPN under active management in the US were eligible to complete an online survey (fielded May - July 2014). This is a report of responses given by patients with PV to questions about symptom burden, QoL, activities of daily living (ADL), and work/productivity. PV-related effects on patients feeling depressed/discouraged, patients feeling anxious/worried, or interference with ADLs were considered to be at high levels if the patient-reported score was ≥4 on a scale of 1 (not at all) to 5 (a great deal). Symptom severity was rated on a scale of 0 (absent) to 10 (worst imaginable). Results: The survey respondents included 380 patients with PV (HU-N, n=159; HU-C, n=181; HU-D, n=40). Mean age was 62.2 years, 65.1 years, and 64.2 years in the HU-N, HU-C, and HU-D groups, respectively. Mean duration of PV was 8.3 years, 10.3 years, and 13.9 years in the HU-N, HU-C, and HU-D groups, respectively. Patients who had not received HU were currently or previously treated with phlebotomy (87.4%), interferon (11.3%), or anagrelide (9.4%); 66.0% of HU-N patients were classified as high-risk based on information provided by the patients in the survey (ie, age 60 or older or history of thrombosis). Among HU-C and HU-D patients, treatment history included phlebotomy (89.5% and 100%, respectively), interferon (7.2% and 52.5%), or anagrelide (15.5% and 35.0%); 79.6% and 82.5%, respectively, were classified as high-risk. Ruxolitinib was not FDA-approved for PV at the time of this survey. Patients reported high levels of feeling anxious/worried and depressed/discouraged as a result of their PV across all subgroups: HU-N, 27.7% and 15.1%, respectively; HU-C, 22.7% and 15.5%; HU-D, 32.5% and 22.5%. Many patients also experienced a high level of PV-related interference with ADLs, which was more common in the HU-D group (30.0%) than the HU-N (11.3%) or HU-C (18.2%) groups. HU-D patients were more likely to have reported ever reducing their work hours (54.2% of the patients who responded) compared with the HU-N (33.3%) and HU-C groups (36.8%). Among all patients, HU-D patients reported a mean of 8.3 doctor visits in the past 12 months, compared with 5.6 in the HU-N group and 6.6 in the HU-C group. Most patients had experienced PV-related symptoms in the past 12 months (Table 1), particularly fatigue, itching, and day/night sweats; fatigue was ranked first as the symptom that patients would most like to resolve. Conclusion: Patients with PV in a large retrospective real-world survey across the US are found to experience burdensome PV-related symptoms and reduced QoL. The findings from this study also show that standard treatments do not address these aspects of PV in many patients, and patients who have discontinued HU may experience an even greater disease burden, possibly because of a lack of effective and/or safe alternative treatment options. Importantly, while 66.0% of the patients in the HU-N group were classified as high-risk, the majority of the high-risk patients in the HU-N group (81.0%) were not treated with cytoreductive agents, suggesting a potential knowledge deficit regarding recommendations for PV management. Collectively, these results illustrate the adverse impact of PV-related symptom burden on patient QoL and reinforce the importance of unmet control of PV-related symptoms in choosing PV therapy. Disclosures Mesa: Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Promedior: Research Funding; Gilead: Research Funding. Miller:Incyte Corporation: Honoraria, Research Funding. Mascarenhas:Promedior: Research Funding; Roche: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; Kalobios: Research Funding. Thyne:Incyte Corporation: Speakers Bureau. Paranagama:Incyte Corporation: Employment, Equity Ownership. Parasuraman:Incyte Corporation: Employment, Equity Ownership. Fazal:Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Naim:Incyte Corporation: Employment, Equity Ownership. Mangan:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Patients (pts) with polycythemia vera (PV) and essential thrombocythemia (ET) suffer from disease related events linked to risk of vascular events, splenomegaly, progression to myelofibrosis/acute leukemia, and disease related symptoms arising from both elevated cytokines and issues of vascular flow. Impact of front line therapy on ET/PV symptoms has not been reported in a systematic fashion. Methods: MPD-RC 112 trial (NCT01258856) enrolled cytoreductive therapy naïve (hydroxyurea [HU] <3 mo) pts with high risk ET or PV within 3 years of diagnosis. Pts were randomized (1:1, stratified by ET vs PV) to either response adjusted pegylated interferon alpha 2a (PEG) or HU. MPN symptoms, treatment toxicities, and quality of life (QoL) were measured by the MPN-SAF and EORTC QLQ-C30 at baseline and 3, 6, 9, and 12 mo. PEG related toxicities were assessed with 5 questions on PEG arm only. European Leukemia Net (ELN) complete hematological responses (CHR) at 12 mo were determined by central blinded review. Individual time point and longitudinal group comparisons were based on mixed models adjusting for age. T-tests were used to compare change scores at 12 mo between pts with and without CHR. Results: Patients: MPD-RC 112 enrolled 168 pts from 9/2011 to 7/2016, with 75 pts included in the interim analysis. 73 (97%; HU 37, 95%; PEG 36, 100%) completed surveys at baseline of which 66 (90%; HU 30, 81%; PEG 36, 100%) completed at least 1 survey during treatment. Median age was 60 (range 19-84) with 32 (44%) females; 30 (41%) / 43 (59%) with ET / PV; 19 (26%) had a history of thrombosis; and 16 (22%) had palpable spleen. Baseline characteristics where balanced between arms with the exception of age (median age: HU 66, PEG 54; p<0.001). Baseline Symptom Burden/QoL: Mean MPN-SAF Total Symptom Score (TSS, scale 0 [absent]-100 [worst imaginable]) was 15.4 (SD 12.5; range 0-52.2) with means of 12.6 (SD 11.7) / 17.3 (SD 12.7) for ET / PV which were somewhat better than reported means of a previous cohort receiving any line of treatment (ET mean 18.7, SD 15.3; PV mean 21.8, SD 16.3; Emanuel RM, JCO 2012). Symptoms (scale 0 [absent]-10 [worst imaginable]) with the highest prevalence (score >0) included fatigue (65/73, 89%) and insomnia (47/73, 64%). The symptom with the lowest prevalence was fever (8/72, 11%). Mean QLQ-C30 global health status/QoL (GHS/QoL) was 73.3 (SD 19.1) which is comparable to a general healthy population (mean 71.2, SD 22.4) and better than a general cancer population (mean 61.3, SD 24.2; QLQ-C30 Reference Manual 2008). TSS, symptoms, and QoL did not differ between arms. Impact of Therapy on Symptom Burden/QoL: On HU, pts initially experienced worsening of TSS, fatigue, early satiety, itching, bone pain, and fever (all p<0.05) with some symptoms returning to baseline after 6 mo (Table 1). On PEG, pts experienced improved abdominal pain and discomfort, but worsening of headache, cough, injection site irritation, blurry vision, and vision change (all p<0.05). Sad mood did not worsen on PEG, although this may be confounded by concurrent use of mood stabilizers. Concentration problems on PEG were significantly worse at 9 mo (p=0.04). Both arms experienced worsened QoL (MPN-SAF single item: HU p=0.009, PEG p=0.003). In comparing between arms, TSS significantly differed (p=0.009) with higher symptoms on HU vs PEG at 3 and 6 mo, but lower symptoms at 9 and 12 mo (Figure 1). Similar descriptive profiles were observed for most individual symptoms; however, the only symptom profiles which significantly differed between arms was early satiety (p=0.03). ELN Response and Symptom Burden/QoL: Among 62 pts with symptom and response data at 12 mo, CHR rate was 37% (23/62). Change in sad mood and sexuality were the only significant differences between pts with and without CHR regardless of arm though in the unanticipated direction (sad mood: mean change 1.5 vs -0.8, p<0.001; sexuality: mean change 2.33 vs 0.3, p=0.03). Conclusions: PEG was associated with an initial decrease in MPN symptom burden when compared to HU. However, with longer duration of therapy, this superiority dissipated. Patient-reported PEG toxicities worsened over time. On both arms, symptom worsening was observed in pts achieving an ELN CHR, possibly leading to the observed negative impact on mood and sexuality. Future research on the impact of PEG on disease progression and molecular features will be important to assess whether increased side effects with PEG are justified. Disclosures Mesa: CTI: Research Funding; Celgene: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Harrison:Incyte Corporation: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. McMullin:Novartis: Honoraria, Speakers Bureau. Yacoub:Alexion: Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mead:Novartis: Honoraria, Research Funding, Speakers Bureau. Kessler:Pfizer: Consultancy; Octapharma: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Grifols: Consultancy; Genentech: Consultancy, Research Funding; Biogen: Consultancy; Bayer: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; LFB: Other: Member of DSMB. Ritchie:Pfizer: Honoraria; Novartis: Honoraria; Arian: Speakers Bureau; Celgene: Speakers Bureau; Incyte: Speakers Bureau. Schlenk:Pfizer: Honoraria, Research Funding; Amgen: Research Funding. Mascarenhas:Promedior: Research Funding; Janssen: Research Funding; CTI Biopharma: Research Funding; Novartis: Other: DSMB , Research Funding; Roche: Research Funding; Incyte: Other: Clinical Trial Steereing Committee, Research Funding.

Abstract Background: PRM-151 (PRM) is a recombinant form of pentraxin-2, an endogenous human protein that acts at sites of tissue damage, inducing macrophage differentiation to prevent and reverse fibrosis. 27 patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, or post-polycythemia vera MF and Grade 2 or 3 bone marrow (BM) fibrosis enrolled in the first stage of a 2-stage adaptive trial in which PRM-151 10 mg/kg IV was administered for 24 weeks in four different arms: PRM-151 QW (n=8), PRM-151 Q4W (n=7), PRM-151 QW + ruxolitinib (RUX) (n=6), or PRM-151 Q4W + RUX (n=6). At 24 weeks, reductions in BM fibrosis, improvements in hemoglobin (Hgb) and platelets (PLT), decreases in symptoms (MPN-SAF Total Symptom Score [TSS]), and modest reductions in spleen size by palpation were observed in all arms, with a favorable safety profile (Verstovsek, ASH 2014, Abstract 713). Patients experiencing clinical benefit were allowed to continue beyond 24 weeks. We now report efficacy and safety in 13 patients who have completed at least 72 weeks of treatment. Bone marrow fibrosis status by morphologic WHO grading and computer-assisted image analysis (CIA) are available up to 48 weeks in some patients, as assessed by central hematopathologist reviewers blinded to patient, treatment, and timepoint. BM data through 72 weeks is pending. WHO response was defined as ≥1 grade reduction in MF grade at any time and CIA response was defined as a decrease in the % fibrosis compared to baseline with a negative slope > 1. (Pozdnyakova, EHA 2015, Abstract P677). Baseline Demographics (N=13): Median age 60 (51-76); 46% DIPSS Int-1, 54% DIPSS Int-2; 62% PMF, 15% post-ET MF, 23% post-PV MF; 46% grade 3 BM fibrosis, Hgb < 100 g/L in 38%, PLT < 100 x 109/L in 69% and <50 x 109/L in 38%; 31% JAK inhibitor-naive and 69% received a prior or current JAK inhibitor. Study treatment (N=13): In the first 24 weeks, treatment was PRM-151 QW (n=5), PRM-151 Q4W (n=3), PRM-151 QW + RUX (n=2), PRM-151 Q4W + RUX (n=3). At 28 weeks, treatment changed to PRM-151 QW (n=2), PRM-151 Q4W (n=7), and PRM-151 Q4W + RUX (n=4), with 1 patient stopping RUX for thrombocytopenia. Both PRM-151 QW patients switched to PRM-151 Q4W after 40 and 52 weeks. Two patients missed weeks 64 and 68 due to complications of a motor vehicle accident and abdominal surgery, respectively, but are continuing treatment as of week 72. BM (n=13): 54% had a morphologic response, and 85% had a CIA response. Hgb (g/L): In 5 pts with baseline Hgb < 100, median Hgb increased by 24% from 86 (range 77-97) at baseline to 107 (range 71-113) at Week 72. 3 of 5 patients who were receiving transfusions at baseline became transfusion independent, with durations of 32-60 weeks. (Figure 1) PLT (x 109/L): In 9 pts with baseline < 100, median PLT count increased by 37% from 38 (range 10-89) at baseline to 52 (range 26-159) at Week 72. All 4 patients who were receiving PLT transfusions at baseline became transfusion independent, with durations of 24-44 weeks. (Figure 2) Symptoms (N=13): 69% and 38% of patients had ≥ 50% and 100% reductions from baseline in TSS between 24 and 72 weeks, with durations of up to 48 and 12 weeks, respectively. (Figure 3) Spleen (N= 9 with palpable spleens at baseline): 50% of pts had ≥25% reduction, 2 of whom had ≥50% reduction lasting > 12 weeks. (Figure 4) Safety (N=13): Most common adverse events (AEs) regardless of relatedness were fatigue (4), nausea (3), fever (3), cough (2), diarrhea (2), tooth infection (2), headache (2), upper respiratory infection (2), hyperglycemia (2), and hyperuricemia (2). There were 13 possibly or probably related adverse events in 3 patients from beginning of study through 71 weeks, 11 Grade 1, 1 Grade 2 and 1 Grade 3, with no event occurring in > 1 patient. There were no related serious AEs in these patients. Conclusion: In 13 patients completing at least 72 weeks, PRM-151 treatment was well tolerated, and improvements in Hgb, PLT, symptoms and spleen appeared to increase with longer treatment duration. Disclosures Mesa: Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Genentech: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Pfizer: Research Funding. Foltz:Promedior: Research Funding. Gupta:Incyte Corporation: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Promedior: Research Funding. Mascarenhas:Kalobios: Research Funding; Roche: Research Funding; Promedior: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding. Ritchie:Incyte: Speakers Bureau; Celgene: Speakers Bureau. Hoffman:All Cells, LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding. Silver:Promedior: Research Funding. Pozdnyakova:Promedior: Consultancy. Hasserjian:Promedior: Consultancy. Trehu:Promedior: Employment, Equity Ownership. Salama:Promedior: Consultancy. Gotlib:Allakos, Inc.: Consultancy.

Abstract Introduction: Most myelofibrosis (MF) patients develop anemia during evolution of the disease process predicting decreased survival. Previous studies exploring the effect of danazol for the treatment of anemia in MF demonstrate responses in anemia. In prior randomized-controlled studies, ruxolitinib demonstrated improvements in splenomegaly, symptom burden, and even survival yet improvements in cytopenias were uncommon. We designed a phase II multicenter pilot study to evaluate the efficacy and tolerability of combination therapy with ruxolitinib and danazol in MF patients with anemia. Methods: This was a Simon optimum two-stage phase II trial. Eligible subjects received ruxolitinib, a JAK 1/JAK2 inhibitor, at 10mg (plat >75 x10x9) BID or 5mg (plat <75 x10 x9) BID) representing initial dose reduction for JAK inhibitor naïve patients to minimize cytopenias, in combination with tapered danazol up to 200mg orally TID. Dose escalation was allowed after completion of 28 days for lack of response or for disease progression. Pts without progression continued for 6 cycles at 56 days each. Treatment modifications were allowed for either medication based on emergent adverse events (AE). Treatment responses were evaluated every cycle by IWG-MRT criteria (Blood 2006). Patient reported outcome questionnaires (MPN-SAF, EORTC QLQ-C30) were administered at baseline, prior to treatment cycles, and at study discontinuation. Results: Patients: Fourteen pts enrolled (9 Mayo Arizona, 5 Mount Sinai). Median (Med) age 70.5 (range 43-78), M:F ratio 1.8:1. Ten primary MF, 2 post-essential thrombocythemia MF, and 2 post-polycythemia vera MF. JAK2 V617F positive in 42.9%. DIPSS Low in 1 pt, Int-1 in 1pt, Int-2 in 8 pts, High in 2 pts, and unknown in 2pts. Transfusion dependence in 35.7% at baseline. Med baseline hemoglobin (hgb) was 9.0 g/dL (R: 8.3 - 12.4), platelet (plt)157 x109/L (R:143 - 520). Thirteen pts received prior therapy, with 9 pts (64.2%) on a JAK inhibitor within 3 months of study entry. Tolerability: Nine pts (64.2%) ended active treatment, due to progression of disease in 2 pts (22.2%), adverse event (AE) in 2, pt preference in 2, stem cell transplant in 1, unrelated death in 1, and comorbidity in 1. Med duration of therapy: 91 days (range 24-287). AEs regardless of attrition included: hematologic grade 3 or >: anemia in 7 pts (50%), neutropenia in 2 (14.3%), leukopenia in 1 (7.1%), and thrombocytopenia in 2 (14.3%). Non-hematologic grade 3 or >: electrolyte abnormalities in 3 pts (21.4%), infection in 2 (14.3%), edema in 1(7.1%), hypertension in 1 (7.1%), and intracranial hemorrhage in 1 (7.1%). Efficacy: Of the 5 JAK inhibitor naïve pts, 4 had stable or increasing hgb levels with therapy despite new ruxolitinib therapy. Of the 9 pts on prior JAK inhibitor (5 ruxolitinib, 4 other), 5 (55.5%) and 7 (77.7%) patients had stable or increasing hgb or plt levels, respectively. See Table #1. Four pts (28.6%) had at least 50% improvement from baseline on MPN-SAF TSS (95% CI 8.4%-58.1%). Overall treatment response: (IWG-MRT) stable disease (SD) in 10 pts (71.4%), clinical improvement (CI) in 3 (21.4%) all of which were spleen responses, and progressive disease (PD) in 1 (7.1%). Trial was halted secondary to lack of anemia response. Table 1. Patient Specific Response Patient IWG-MRT Response: Study Cycles (N): Prior therapy (within 3 mo) Hemoglobin Response*: (initial, final g/dL) Platelet Response*: (initial, final 10(9)/L) Ruxolitinib 1 CI-Spleen 5 D (8.8, 7.6) S (221,212) 2 SD 4 D (10.3,7.9) S (54,46) 3 SD 2 S (8.8,8.9) S (82,101) 4 SD 3 I (8.9,9.8) S (441,458) 5 SD 3 S (9.6, 9.5) I (161, 231) JAK Inhibitor: 6 SD 5 Momelotinib S (9.0, 9.2) S (132,113) 7 SD 1 NS-018 D (8.3, 7.1) D (120,43) 8 SD 3 NS-018 D (10.1,9.0) D (138,111) 9 SD 2 LY2784544 S (8.7,9.1) S (56,21) Other: 10 CI-Spleen 9 Procrit I (10.5,11.9) S (153,198) 11 CI-Spleen 7 None I (8.9,10.2) D (338,133) 12 PD 1 Hydroxyurea S (12.4, 12.2) D (310, 82) 13 SD 1 Procrit D (10.1, 8.6) D (192, 71) 14 SD 1 Hydroxyurea S (9.1,8.9) D (346,119 *S=stable (Hgb +/- 0.5g/dL, Plt +/- 50x109, D=decreasing, I=increasing. Conclusions: Although overall well tolerated, the addition of danazol to ruxolitinib therapy has modest incremental efficacy by IWG-MRT criteria. Clinical improvement was observed in 21.4% of treated patients, however responses were limited to spleen reduction. The degree to which danazol may stabilize expected cytopenias is interesting and may require further investigation. Disclosures Hoffman: Promedior: Research Funding; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; All Cells, LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mesa:Gilead: Research Funding; Genentech: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; CTI Biopharma: Research Funding; Pfizer: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Incyte Corporation: Research Funding.

Abstract Background: Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms (MPNs). Patients across all 3 MPNs experience marked disease burden in terms of symptoms and negative effects on quality of life (QoL), productivity, and activities of daily living (ADL). To improve the lives and health of patients with MPNs, it is also important to have a current understanding of these burdens from a financial standpoint. This analysis of MPN Landmark survey data examined the financial burden of patients who reported that their MPN affected their employment (ie, reduced work hours, discontinued employment, or went on medical disability) or experienced no such effects on their employment. Methods: Patients diagnosed with MF, PV, or ET were recruited to participate in a real-world retrospective study (MPN Landmark survey) in the US (fielded May - July 2014). Only respondents who were diagnosed before 2013 and were 16 to 65 years of age at the time of diagnosis were eligible for this analysis. Participants were asked if their MPN had an impact in terms of reduced work hours, discontinued employment, medical disability, or no impact; the first 3 categories were not mutually exclusive. Participants provided information on their annual household income in 2013 before taxes by selecting from the following categories: ≤$15,000, $15,001-$25,000, $25,001-$35,000, $35,001-$50,000, $50,001-$75,000, $75,001-$100,000, and >$100,000. The mid value of each range was used to calculate mean income levels within each subgroup evaluated. Results: A total of 813 patients completed the web-based Landmark survey and 369 eligible patients were included in this analysis (MF, 85; PV, 172; ET, 112). Median age among patients with ET was slightly lower than among patients with MF and PV at time of MPN diagnosis (ET, 48 years; MF, 56 years; PV, 53 years). The majority of respondents were women (MF, 62%; PV, 52%; ET, 75%). Almost all patients (99%) had health insurance, primarily group commercial insurance through an employer (MF, 46%; PV, 53%; ET, 57%) and Medicare (MF, 40%; PV, 34%; ET, 24%). Most patients had at least some college education (ie, some college, 4-year degree, or postgraduate degree): MF, 86%; PV, 90%; ET, 88%. The mean 2013 household income of patients with MF, PV, and ET were similar to each other ($79,800, $80,200, and $80,400, respectively) and slightly higher than the total 2013 US mean household income of $75,839. A notable proportion of patients in each MPN group reported that their disease led to reduced work hours, discontinued employment, and medical disability: MF, 38%, 35%, and 33%, respectively; PV, 33%, 28%, and 15%; ET, 28%, 21%, and 4%. Patient demographics, such as age and health insurance status, were similar among patients who reported MPN-associated effects on employment and patients who did not within each MPN. In each MPN group, the mean percentage household income loss in patients with reduced work hours, discontinued employment, and medical disability were: MF, 16%, 18%, and 28%, respectively; PV, 15%, 24%, and 17%; and ET, 0%, 24%, and 37%, compared with patients who did not experience any effects of their MPN on employment (Figure 1). Discontinued employment and medical disability tended to have a greater impact compared with reduced work hours across MPNs. Conclusion: Patients withMPNs may experience a considerable negative impact on their employment status, which in turn may be associated with reduced annual household income. Therefore, across all MPNs, forestalling or reversing discrete aspects of the diseases that negatively impact individual productivity is an important factor in the management of these chronic neoplasms. Disclosures Parasuraman: Incyte Corporation: Employment, Equity Ownership. Naim:Incyte Corporation: Employment, Equity Ownership. Paranagama:Incyte Corporation: Employment, Equity Ownership. Thyne:Incyte Corporation: Speakers Bureau. Mascarenhas:Incyte Corporation: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; Promedior: Research Funding; Roche: Research Funding; CTI Biopharma: Research Funding; Kalobios: Research Funding. Mangan:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Fazal:Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Miller:Incyte Corporation: Honoraria, Research Funding. Mesa:Promedior: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; NS Pharma: Research Funding; CTI Biopharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Genentech: Research Funding; Pfizer: Research Funding.

Abstract The inhibitory effects exerted by transforming growth factor-β (TGF-β) on adult erythropoiesis has been well established. Canonical SMAD-depedent TGF-β signaling inhibits erythroid differentiation at multiple levels: it induces hematopoietic stem cells into quiescence (Chabanon et at Stem Cells. 2008;26:3150), it elicits a Smad5-dependent inhibition of progenitor cell proliferation (Bruno et al, Blood 1998; 91:1971) by increasing the length of G1 through reduction of G1 cyclin and cyclin-dependent protein kinases (Jacobsen et al, Blood 1995; 86:2957; Geng and Weinberg, PNAS 1993; 90:10315) and triggers Smad4-signaling accelerating terminal erythroid maturation (Zermati et al, Exp hematol 2000; 28:885; Choi et al MCB 2005;271:23). TGF-β is expressed by almost every cell type, but is produced in the greatest amount by megakaryocytes (Assonian et al, JBC 1983;258:7155; Massague, Cell 2008;134, 215). TGF-β has been implicated in the pathogenesis of primary myelofibrosis (PMF) by Schmitt et al (Blood. 2000;96:1342). Plasma, bone marrow and spleen washes of PMF patients, as well as those from murine PMF models, contain 2 fold-greater levels of total and bioactive TGF-β than those from normal controls (Zingariello et al, Blood 2013;121:3345). In addition, megakaryocytes from PMFpatients contain greater amounts of TGF-β than those from other MPNs such as polycythemia vera (PV) and essential thrombocythemia (Ciurea et al, Blood 2007;110:986). Published data, however, also suggest that malignant MPN cells are insensitive to TGF-β. Microarray analyses of PMF bone marrow and spleen cells revealed TGF-β signaling abnormalities which predict activation of non-canonical p38/ERK-dependent rather than canonical SMAD-dependent signaling (Ciaffoni et al, BCMD 2015;54:234). In addition, by phosphoproteomic profiling of PV erythroblasts (Erys) expanded in vitro express lower levels of pSmad2 as compared to Erys from healthy controls (Hricik et al. AJH 2013;88:723). The hypothesis that malignant MPN cells are insensitive to TGF-β was tested here by evaluating the effect of SB431542 [1,3,10 and 26µM], a small molecule inhibitor of TGF-β receptor 1, on ex vivo erythropoiesis in cultures generated by peripheral blood mononuclear cells from patients with JAK2 V617+-PV (n=2) and JAK2 V617F+ or CALR pQ365f+-PMF. Identical experiments were performed with Erys generated from adult peripheral blood (AB, n=3) and cord blood (CB, n=2) of healthy controls. All cultures were stimulated with SCF, IL-3 and EPO with and without dexamethasone (Dex). In cultures of JAK2 V617F+ -PV, SB431542 increased by 2-fold the numbers of progenitor cells observed by day 6, but had no effect on that of Erys observed by day 12-17 [fold increase (FI) ~4 fold in all cases]. Moreover, neither the number of progenitor cells nor that of Erys were affected by SB431542 treatment in cultures generated from JAK2 V617F+ (n=1) and CALR pQ365fs+ -PMF (n=1) patients (Fig. 1). This lack of effects was observed in cultures with and without Dex. By contrast, as expected, in cultures of AB, SB431542 significantly increased by 2.5-fold the number of progenitor cells observed by day 6 and that of Erys observed by day 14-17 (Fig. 1). This increase was associated with greater retention of an immature erythroid phenotype (CD36+ CD235a+ cells 16% vs 3%) and an increased proliferative index (>3 Erys in metaphases per field vs 0). This was observed up to day 17 in cultures both with and without Dex. The effects of SB431542 in cultures of CB were, however, affected by the presence of Dex. In cultures without Dex, SB431542 increased by 2-fold the number of progenitor cells by day 6 but had no effect on that of Erys by day 12-17 (FI=10-15 and CD36+CD235a+ cells >60%). In the presence of Dex, SB431542 did not affect the number of progenitor cells at day 6 but reduced that of Erys by 3-fold on day 12-17. These results suggest that in the case of CB, TGF-β promotes erythroid maturation in synergy with Dex. In conclusion, SB431542 promoted proliferation and maturation of normal adult progenitor cells but had no effect on PMF progenitor cells suggesting that treatments with TGF-β receptor 1 inhibitors may reactivate normal hematopoiesis in PMF patients by providing a proliferative advantage to the resident non-diseased hematopoietic stem cells over the malignant clone. This therapeutic approach will be explored in a MPD-RC, multi-center, phase II trial in patients with PMF. Disclosures Hoffman: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; All Cells, LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding. Mascarenhas:Roche: Research Funding; Incyte Corporation: Research Funding; Kalobios: Research Funding; CTI Biopharma: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; Promedior: Research Funding.