Mesa, Ruben A.

Abstract Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for primary myelofibrosis (PMF). Reduced intensity conditioning (RIC) allows otherwise ineligible patients to proceed with HSCT. Host factors in PMF such as bone marrow (BM) fibrosis, massive splenomegaly, and transfusion related allo-immunization increase the risk of engraftment failure, especially with RIC. Spleen directed therapy (SDT) is often used in PMF patients with splenomegaly to help with engraftment, however little data exists supporting this practice. This study was carried out to investigate the role for SDT and the predictors of outcomes with RIC HSCT for PMF. Methods :After IRB approval, the Mayo Clinic HSCT registry was queried for patients with PMF that underwent RIC allo-HSCT from 2005-2014. Disease and transplant related data were retrospectively abstracted and analyzed for HSCT related outcomes. SDT was defined as a therapeutic strategy with specific intent to overcome an enlarged spleen prior to HSCT and included splenectomy, splenic artery embolization, splenic irradiation, or JAK inhibitor therapy that was stopped <30 days before HSCT. Survival estimates were calculated using the Kaplan-Meier method and means were compared using the log-rank test. Univariate and multivariate analyses were performed using Cox regression modeling. Results :51 patients (67% males) with WHO defined PMF with palpable splenomegaly that underwent RIC allo-HSCT were included in the study; median age 57 years (range, 35-68). The median follow-up was 12.2 months, and at last follow up, 19 deaths (37%) and 4 relapses (8%) were documented. The median OS for the group was not reached (mean 34.2 months); 88% at 100 days and 60% at 2 years. 17 deaths were attributed to non-relapse mortality (NRM). There were 3 engraftment failures (6%). 32 patients (63%) developed acute GVHD (grades II-IV) and 24 patients (47%) developed chronic GVHD (all grades). Twenty-one patients (41%) received SDT; 10 (48%) splenectomy, 2 (9%) splenic irradiation, and 9 (43%) JAK inhibitor therapy (ruxolitinib). The SDT group had a median spleen size of 14.5 cm (range, 1-29 cm) below the left costal margin (LCM) and 13 patients (62%) with spleen size >10 cm below LCM, while the no SDT group had a median spleen size of 7 cm (range, 1-19 cm) and 12 patients (40%) with spleen size >10 cm below LCM; p = 0.01. Seven (64%) of 11 patients receiving splenic irradiation (n = 1) or JAK inhibitor therapy (n = 6) were eligible for IWG-MRT spleen response, and 2 (29%) responded (both in JAK inhibitor group). Of the remaining 5 patients, 2 had a response not meeting IWG-MRT criteria. There were no differences in age (p = 0.09), gender (p = 1.0), DIPSS + score (p = 0.35), or HCT-CI (p = 0.61) between the two groups. There was a statistically significant difference in engraftment failure, with all 3 engraftment failures occurring in the SDT group (2 splenectomy patients, 1 splenic irradiation patient; p = 0.02). Engraftment failures were not attributable to insufficient cell dose, donor specific antibodies, or identifiable host factors. The patient with engraftment failure who underwent splenic irradiation had persistent massive splenomegaly. There were similar outcomes with regards to relapse rates, NRM, and acute and chronic GVHD. In the SDT group, the median OS was 13.3 months; 81% at 100 days and 33% at 2 years. In the no SDT group, the median OS was not reached; 94% at 100 days and 68% at 2 years; p=0.13. In a univariate survival analysis that included age, gender, SDT, DIPSS+ score, HCT-CI, CMV status, ABO status, HLA matching, donor source, graft source, engraftment status, and acute and chronic GVHD, predictors of survival were engraftment failure (p = 0.02) and major/bidirectional ABO incompatibility (p = 0.02). Similar results were obtained when JAK inhibitor therapy was considered separately from other forms of SDT. In a multivariate analysis, engraftment failure (HR 8.2, 1.8-27.2; p = 0.01) and major/bidirectional ABO incompatibility (HR 4.1, 1.4-10.9; p = 0.009) retained independent prognostic significance. Discussion:In patients with PMF and splenomegaly, there was no demonstrable benefit from SDT. Predictors of post-HSCT survival included engraftment failure and major/bidirectional ABO incompatibility. These findings need validation in a larger cohort of patients. Disclosures Al-Kali: Celgene: Research Funding. Mesa:Gilead: Research Funding; Incyte Corporation: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; CTI Biopharma: Research Funding; Promedior: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding.

Abstract Background: The Philadelphia chromosome negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) all have a time dependent risk of progression to either an advanced myelofibrotic state (post ET/PV MF) and/or to acute myeloid leukemia. The impact of disease duration upon the MPN symptom burden is not well understood, nor are the precise mechanisms of disease progression. We sought to better understand the impact of disease duration on MPN symptom burden. Methods: Symptom burden data was collected utilizing the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) amongst MPN patients, collected at the time of an office visit in an international cohort of MPN patients as previously described (Scherber et. al.). Symptom burden assessment was a previously validated 27-item symptom burden questionnaire scored on a 0-10 scale (0= as good as it can be, 10 = as bad as it could be). The patient or provider was asked to report the time since MPN diagnosis. MPN duration was determined to be early if the diagnosis was established between 0 to 5 years ago, intermediate if the diagnosis was established between 6 to 10 years ago, and late if the diagnosis was established 11 years ago or more. Anemia was defined as a red blood cell count less than 10 g/dL, leukopenia was defined as a white blood cell count was below 4 x 109, and thrombocytopenia if the platelet count was below 150 x109. Statistical significance was calculated using ANOVA f-test and chi squared. Results: Patient demographics and disease burden: A total of 1443 patients responded to the survey, including 592 (41%) ET, 549 (38%) PV, and 302 (21%) MF patients, including 181 (60%) primary MF, 67 (22%) post-ET MF, and 54 (18%) post-PV MF. Among MF patients, mean duration of MPN diagnosis was 9 years, and mean duration MF diagnosis was 4.7 years. Among respondents, 757 fit criteria for early disease duration, 353 fit criteria for intermediate disease duration, and 333 fit criteria for late disease duration. Respondent mean age was 62 years and approximately half of respondents were female (55%). Patients with longer diagnosis duration tended to be older (p=0.009) and were most likely to have anemia (0.02), leukopenia (p=0.01), or thrombocytopenia (p=0.03). These individuals were also most likely to have a history of hemorrhage (p=0.007) or require red blood cell transfusions (p<0.001). Combined cohort symptom burden: On average among the combined cohort of ET, PV and MF patients, symptoms tended to worsen with time with this effect being significant for symptom items of fatigue (BFI, p<0.04), concentration (p=0.007), insomnia (p=0.02), sexual difficulties (p=0.002), cough (p=0.03), night sweats (p=0.002), and pruritus (p=0.02). Symptoms of early satiety (p=0.004), concentration difficulties (p=0.01), insomnia (p=0.03), sexual difficulties (p=0.02), cough (p=0.01), and night sweats (p=<0.001) had significantly higher prevalence in those with longer disease duration. Similarly, the total calculated MPN-10 score (p=0.008) and quality of life assessment (0.03) demonstrated worsened outcomes with time (Table 1). No significant differences in symptoms for the combined cohort were observed among individuals diagnosed 0 to 1 years ago compared to those with a diagnosis established between 2 and 5 years ago. Symptom burden in MPN subtypes. When evaluating specific MPN types, patients with essential thrombocythemia experienced significantly greater sexual difficulties over time (p=0.03). The severity (p=0.01) and incidence (p=0.03) of pruritus and incidence of night sweats (p<0.001) were significantly increased over time for individuals with PV. For those with MF, the severity (p= 0.01) and incidence (p=0.009) of cough also significantly increased with longer diagnosis duration. Discussion Overall, significant worsening in symptom burden can be recognized over time for individuals diagnosed with MPNs. Diagnosis may not necessarily correlate with disease duration as the timing of diagnosis may be delayed from onset of disease. Given the intent of this abstract to evaluate changes with disease duration, we did not investigate correlations between symptom burden and cytopenias. We do know that risk factors for survival in the MPNs include older age and thrombosis, however, disease duration should be investigated as an alternative marker of burden in future survival studies. Disclosures Harrison: CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Shire: Speakers Bureau; Gilead: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Kiladjian:Incyte Corporation: Consultancy; Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Novartis: Consultancy. Zweegman:Celgene: Research Funding; Janssen: Research Funding; Takeda: Research Funding. Barbui:Novartis: Speakers Bureau. Etienne:Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; ARIAD: Consultancy, Honoraria, Speakers Bureau. te Boekhorst:CTI Biopharma: Consultancy; Novartis: Consultancy. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis. Research- incyte, Gilead, cti, Genentech, promedior, NS Pharma: Consultancy.

Abstract Abstract 1749 BACKGROUND: We have previously reported that transformation of a myeloproliferative neoplasm (MPN) to acute leukemia or blast phase (MPN-BP) is accompanied by a median survival of 2.6 months (range 0–24.2 months) (Mesa et. al. Blood 2005) despite treatment. Allogeneic stem cell transplantation (ASCT) offers a potential for cure. We reviewed 13 patients with MPN – BP who were candidates for ASCT, and 8 of those patients received ASCT after induction chemotherapy. METHODS: Retrospective analysis of individuals who had a clear antecedent myeloproliferative neoplasm (essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF) (either primary (PMF) or post ET/PV)), transformed to MPN-BP, and were candidates for ASCT. Clinical characteristics at each phase of illness, therapy at each phase of illness, and outcome of ASCT were assessed. RESULTS: Patients (MPN details): Thirteen patients (8 male, 5 female, median age at diagnosis of MPN 42 years in those who underwent ASCT and 64 years in those who did not receive ASCT (combined median 53 years, range 26–70)) were identified who met the inclusion criteria, of whom 2 had ET, 4 PV, 2 Post-ET MF, 1 Post-PV MF and 4 PMF. Jak2-V617F mutation was present in 7 of 8 patients tested. Treatments used during the MPN phase included hydroxyurea in 9 (+ busulfan in 1 and + anagrelide in 1), and thalidomide/prednisone in 2 (two patients received no treatment prior to MPN-BP). Patients (MPN-BP details): Transformation of an MPN to blast phase (from diagnosis of MPN) occurred after a median of 11 years in those who underwent ASCT and 8 years in non-ASCT (range 3 months to 30 years). At the time of MPN-BP diagnosis, 9 patients had an abnormal karyotype, 3 with complex karyotypes, 3 with trisomy 8 (sole abnormality), 1 with del(7q), 1 with del(13q). Leukemic induction consisted of standard anthracycline/cytarabine combination therapy (+/− etoposide), except for one patient received a study medication voreloxin. One patient who did not receive ASCT had remission after induction, but later expired from relapse, two expired soon after leukemic transformation, and two were too ill to receive induction. In the ASCT group (N=8), 5 patients achieved complete remission (CR) of their leukemia/return to MPN chronic phase (one of the five patients required a second induction to achieve CR), while 3 patients were considered primary induction failures due to persistence of > 5% blasts in the blood (2) or marrow (1) at the time of pre-transplant response assessment. The median time from diagnosis of MPN-BP to ASCT was 128 days. ASCT Details and Outcomes: Patients (median age of 55 years at time of ASCT; range 44–73) underwent ASCT (all HLA identical, 3 matched unrelated donors, 5 matched sibling donors) with either reduced intensity conditioning (n=6) or fully myeloablative conditioning (n=2). After a median follow-up of 488 days (range 127 – 1206), 6 of 8 patients are alive and free of disease. MPN-BP recurred in two patients at day 69 and 77 post-transplant; both patients eventually died of progressive leukemia, one after a second transplant. Acute GVHD occurred in 3 patients (1 grade III, 2 grade II), and chronic GVHD in 4 (2 mild, 2 moderate). All five patients who achieved CR (marrow and PB blasts < 5%) after induction therapy remain in continuous CR, while 2 of the 3 patients with evidence of persistent leukemia relapsed and died of MPN-BP. No patient died of transplant-related causes and all patients engrafted promptly. CONCLUSION: Rapid induction followed by ASCT can offer a curative path for individuals with MPN-BP. Although limited by small numbers, our data suggest that leukemic clearance (marrow blast percentage < 5%) prior to ASCT is associated with improved outcome. Disclosures: Mesa: Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding.

Abstract Abstract 1977 Introduction: Transplant options are limited for adult patients (pts) who lack a fully matched related or unrelated donor. We hypothesized that in-vivo T-cell depletion with r-ATG would allow safe allo-SCT from mismatched, unrelated donors, thus expanding the potential donor pool for pts with hematologic malignancies who require allo-SCT. Patients and Methods: Thirty seven adult pts (age 20 – 70, median 45) underwent a first unrelated, mismatched, allo-SCT between 1/1/2006 and 6/30/2011 at Mayo Clinic Arizona for hematologic malignancy (35 PBSC, 2 marrow). All pts had at least a one allele or one antigen mismatch (MM) at HLA-A, -B, -C, or -DRB1, and all except one pt received r-ATG as part of the GVHD prophylaxis strategy (dose range 2.5 – 10 mg/kg in daily dose of 2.5 mg/kg depending on degree of mismatch, with the last dose generally given on day −1). One pt received Campath after experiencing anaphylaxis to r-ATG. Pts were transplanted for acute myeloid leukemia (n = 19; 10 CR1, 6 CR2, 3 other), acute lymphoblastic leukemia (n = 8; 4 CR1, 4 CR>/= 2), chronic myeloid leukemia (n = 1), myelodysplastic syndrome (n = 5), or non-Hodgkin lymphoma (n = 4). Conditioning was myeloablative in 20, reduced intensity in 16, and non-myeloablative in 1. Mismatches were as follows: 1-allele MM (n = 7); 1 antigen MM (n = 15); 2 allele MM (n = 4); 1 antigen, 1 allele MM (n = 7); and 2 antigen MM (n = 4). Additional GVHD prophylaxis included tacrolimus plus either methotrexate (n =21), mycophenolate mofetil (n = 14), or other (n = 2). Results: The median follow-up for surviving pts is 12 months. As of 6/30/11, 31 pts were alive, and 6 had died of the following causes: multiorgan failure (n = 1), relapse (n = 3), and veno-occlusive disease (n = 2). To date, there have been no deaths related to acute or chronic GVHD. The 1- and 2-year estimated rates of overall survival are 84.5%/78.8% (Fig. 1); of progression-free survival 79.7%/72.0%. The estimated rate of relapse at 1 and 2 years is 11.8%/18.7%, and of non-relapse mortality 8.1%/10.5%. Four pts (10.8%) have developed severe (grades III-IV) acute GVHD by day 100 (days 19, 27, 30, 43; one pt after withdrawal of prograf due to transplant-associated microangiopathy). No late onset severe acute GVHD has been seen. Moderate to severe NIH-defined chronic GVHD occurred in a single pt at risk (cumulative incidence estimate 2.4% at 1 year, 4.7% at 2 years; Fig. 2). Four pts have reactivated EBV, with one developing PTLD (all have been treated with Rituximab). CMV reactivation was seen in 24 pts (65%), CMV disease in 4, with no deaths directly related to CMV. Conclusions: In vivo T-cell depletion with r-ATG abrogates severe acute and chronic GVHD, and allows use of mismatched unrelated donors for allo-SCT in adult pts with otherwise incurable hematologic malignancies. Long-term survivors are generally free of severe chronic GVHD, with good quality of life. There does not appear to be an increased incidence of disease relapse, and non-relapse mortality is low. This approach is safe, effective, and considerably expands the donor pool for adult pts who require allo-SCT. Disclosures: Reeder: Celgene: Research Funding; Millennium Pharmaceuticals Inc.: Research Funding; Novartis: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding.

Abstract Background Myeloid neoplasms (MN) occurring secondary to treatment of non-malignant disease, especially autoimmune diseases (AID), and the overlap between them, is an increasing clinically important observation. Confounding variables for myeloid transformation include the nature of autoimmune disease as an incessant, chronically activated inflammatory cascade that has been associated with an increased risk of myeloid malignancy, and disease modifying therapies, often with cytotoxic and immunosuppressive drugs. Thus, the addition of therapeutic agents for treatment of AID theoretically amplifies the opportunity for MN to develop in genetically susceptible individuals. To our knowledge, there is no large study evaluating a comprehensive primary AID population that developed MDS or AML with detailed assessment of therapeutic interventions for AID. The presented study queries the association of cytotoxic, anti-inflammatory, and immune-modulating agents to treat AID as risk factors for developing myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Methods In a 10-year period from 2004-2014, a total of 40,011 patients with an ICD-9 coded diagnosis of AID were seen at Mayo Clinic Arizona and Florida campuses; 311 patients from this population had a concomitant coded diagnosis of MDS and/or AML. In an IRB approved, retrospective chart review, we confirmed 86 cases meeting strict inclusion criteria for AID and confirmed MDS or AML. We performed a case-control match from the same primary autoimmune population for age, gender, and autoimmune specific diagnosis at a 2:1 ratio querying for therapeutic interventions. Results Myeloid neoplasm specifics in our case cohort of 86 patients were 55 MDS, 21 de novo AML, and 10 AML with history of MDS. Average age was 72 years with a slight male predominance (57%). Rheumatoid arthritis (26.4%), psoriasis (20.7%), systemic lupus (13.8%), was the most common autoimmune profiles. Median onset of autoimmune disease to diagnosis of myeloid neoplasm was 6 years (range 1-54 years). Up to 26% controls documented no systemic agent for treatment of autoimmune disease and similarly 12.8% of the case cohort (p=0.142). Case and control populations treated with systemic therapies had similar exposures by category for immune-modulating agents (33.7% and 37.8% respectively) and cytotoxic therapies (47.7 and 44.8% respectively). A total of 57/86 cases (66.3%) received either a cytotoxic or immune-modulating agent. In comparison, 105/172 (61.1%) controls received either agent; p=0.495. Azathioprine was the only statistically significant agent exposure observed more frequently in the study cohort than controls with an OR of 7.05 (p= < 0.001). There was no increased incidence of MDS or AML in TNF-antagonist treated patients. No significant correlation for duration of agent exposure by drug category was observed. Discussion In a large primary AID population, azathioprine exposure was associated with a 7 fold risk of MDS or AML (p=< 0.001). Notable, but not statistically significant case cohort trends among cytotoxic agents was exposure to cyclophosphamide (OR 3.58) followed by mitoxantrone (OR 2.73). Methotrexate, mercaptopurine, and mycophenolate had favorable odd ratios, but these were not statistically significant. No association was found for TNF-inhibitory agents. Finally, there was no association of drug exposure time to the incidence in development of MDS or AML. Disclosures Dueck: Bayer: Honoraria. Mesa:Gilead: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Incyte Corporation: Research Funding; Galena: Consultancy; Ariad: Consultancy; CTI: Research Funding; Promedior: Research Funding. Al-Kali:Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding. Foran:Millennium Pharmaceuticals, Inc.: Research Funding; novartis: Honoraria; karyopharm: Honoraria; medscape: Honoraria; pfizer: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding.

Abstract Abstract 4094 Background: Our group has previously reported the benefits of thalidomide-prednisone based regimens for improvement of anemia, thrombocytopenia, and splenomegaly for patients with MF; both primary myelofibrosis (PMF), and arising from essential thrombocythemia and polycythemia (Post ET/PV MF). We sought to evaluate the overall efficacy of these commonly used regimens by evaluating long-term outcomes and applying the IWG-MRT response criteria (Tefferi et. al. Blood 2006) which arose after completion of these trials. Methods: We retrospectively analyzed the long-term outcomes, and assessed the initial therapeutic responses using IWG-MRT criteria from three parallel completed trials of MF using a thalidomide (THAL-50 mg/day) and prednisone (3 month taper beginning at 40mg, stopped at 3 months) backbone. The trials had identical eligibility criteria including adequate organ function and need for MF therapy (defined as symptomatic: anemia and/or splenomegaly). The trials were 1) THAL-PRED alone, THAL only after 3 months 2) THAL-PRED-etanercept (ETAN - TNF- alpha inhibitor at 25 micrograms subcutaneously twice a week), THAL and ETAN only after 3 months and 3) THAL-PRED – oral cyclophosphamide (CTX 25mg daily orally), THAL alone after 3 months. Results: Patients: A total of 50 pts were enrolled in these 3 trials (Males n=36, 72%) with median age of 68.5 years (Range 43–85), with 79% having PMF. Patients had advanced disease in general with 88% having intermediate 2 or high risk MF by IWG criteria (Cervantes et. al. Blood 2009), 62% patients with red cell transfusion dependence and 50% with an abnormal karyotype. Therapy initial results: 80 % of patients reached the three month juncture on the trials, with 40% reaching 6 months. Initial toxicity was myelosuppression with 3 cases of grade 3 anemia, 3 cases of grade 3 neutropenia and 4 cases of grade 3 thrombocytopenia. There were no grade 4 or higher hematological toxicities noted. Initial neuropathy was uncommon and seen in only 4% of patients. No complete responses were observed and only 1 patient had partial response (by IWG-MRT criteria). 14 patients (28% overall) met the new IWG-MRT criteria for clinical improvement; 11 for anemia (22%), 2 for thrombocytopenia (4%) and 3 for splenomegaly (6%). Responses occurred relatively quickly at an overall median of 8 weeks (range 4–12) after enrollment. Long Term Outcomes: After a median follow-up of 36 months across this cohort we observed an overall median duration of response of 8.5 months (range 3–42). Responses to THAL based regimens can lead to periods of prolonged stabilization after cessation of therapy. We observed an overall median time to institution of next therapy of 3 months (range 1–50). At the time of this analysis 14 patients (28%) have expired of their MF and median survival across the entire cohort was 36 months (3-106). Comparison of Regimens: Comparison of these three independent trials (Table 1) suggests greater toxicity and inferior response rate, duration of response, and time to next therapy with the cyclophosphamide containing regimen. Conclusion: THAL-PRED based regimens are active in a subset of MF patients for therapy primarily of anemia, and for some patients a response of good duration (even after cessation of therapy) may be obtained. IWG-MRT response assessment demonstrates utilizing additional agents to a THAL-PRED regimen do not appear to augment (and may detract from responses). Newer agents such as pomalidomide may have similar to greater efficacy without neuropathy and less myelosuppression. Disclosures: Off Label Use: There is no FDA approved agent in Myelofibrosis. All the drugs discussed; Thalidomide, Prednisone, Etanarcept and Cyclophosphamide are off-label. Mesa:SBio: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Incyte: Research Funding; Roche: Research Funding; eisai: Research Funding; telik: Research Funding.

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 Abstract 5060 Background: The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) is a concise instrument of patient reported outcomes (PRO) designed to assess the unique spectrum of symptoms present in the majority of patients (Mesa et. al. Cancer 2007). We sought to validate the Italian Translation of the MPN-SAF which addresses 19 separate symptoms reported by MPN patients. Methods: Translation: We utilized the standard practice of PRO translation in which 3 independent translations are created by 3 independent translators fluent in both languages. A fourth translator then discussed the translations with the other translators and a consensus translation was obtained. Validation: Patients self completed the MPN-SAF: Italian at the time of a physician office visit and the Italian EORTC-QLQ-C30 (a widely used instrument of PRO for cancer patients) was co-administered for validation purposes. Results: Patients and Symptomatic Burden: 186 patients were prospectively enrolled (ET (N=88; 47%), PV (N=69; 37%) and MF (N=29; 16%)) a median of 6 years (range:0-29) from their diagnosis. Patients were of a median age (62; range 29–91 years) and gender (56% females) typical of the disease. 72% (N=135) had received some form of non-aspirin medical therapy for their disease, and 68% were on therapy at the time of completing the questionnaire. Patients frequently had a history of either thrombotic events (31%) and/or hemorrhagic events (13%). The MPN-SAF measured 19 items in the enrolled patients (data summarized in Table 1). Validation Analysis: EORTC-QLQ-C30: Consistent with our experience with the MPN-SAF:English, Pearson correlations between MPN-SAF:Italian individual symptom scores and the Italian EORTC-QLQ C30 showed excellent correlations with co-validation questions including fatigue, pain, insomnia, (all p<0.001). Excellent correlations were demonstrated between EORTC-QLQ-C30 subscales and corresponding MPN-SAF measurements. Comparison with MPN-SAF:English: Comparison with 102 patients prospectively completing the MPN-SAF: English (ET=20, PV=23, MF=59) in the USA indicated very strong correlations (when controlling for MPN subtype) in the prevalence of all 19 items assessed and only subtle differences in terms of symptomatic severity for fatigue, itching and insomnia. Conclusions: The MPN-SAF:Italian is an easy to administer, clear, 19-item inventory of patient-reported outcomes that is specific to MPNs. Additionally, the instrument is validated by 1) comparison to previously validated Italian instruments and 2) the correlation with the MPN-SAF:English. Utilization of the instrument in Italian MPN clinical trials will allow for useful comparison to patients completing the MPN-SAF in other countries and will serve as a valuable clinical marker of disease symptom severity. Disclosures: Vannucchi: Novartis: Membership on an entity's Board of Directors or advisory committees. Mesa:SBio: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Incyte: Research Funding; Roche: Research Funding; eisai: Research Funding; telik: Research Funding.

Abstract Abstract 4095 Background: Symptomatic burden in myeloproliferative neoplasms (MPNs) is present in over 70% of MPN patients (Mesa et. al. Cancer 2007). We sought to validate a broadly applicable instrument (MPN-SAF) to assess symptoms in myelofibrosis (MF), essential thrombocythemia (ET) and polycythemia vera (PV). Methods: Using the previously validated MF-SAF as a base instrument, we added several key additional symptoms previously identified as present in all subtypes of MPNs including headaches, concentration, dizziness, extremity tingling, insomnia, sexual problems and mood changes on a 0 (absent) to 10 (worst-imaginable) scale. Validation: The MPN-SAF was administered jointly with the EORTC-QLQ-C30 as the co-validation instrument using prospective cohorts in the USA, Sweden and Italy. The translated MPN-SAF (Swedish and Italian) was created through a standard approach using teams of 4 translators working in concert. Results: Compiled MPN-SAF: Patient data: 402 MPN-SAF surveys were administered (English (25%), Italian (46%) and Swedish (28%)) in 161 ET patients (40%), 145 PV patients (36%), and 96 MF patients (24%), an average of 7.8 years (range 0 – 43 years) from their MPN diagnosis. Participants were of typical age (64.9, range 26 – 91 years) and gender (53% female) characteristic of disease. Prior hemorrhage (10%) and thrombosis (25%) were frequent. 68% of patients currently received cytoreductive therapy and 84% received cytoreductive therapy in the past. Patients and Symptomatic Burden: 19 items assessed in the MPN-SAF demonstrated consistently that the most common symptoms were fatigue (93%), decreased quality of life (84%), insomnia (65%), sad mood (65%), and sexuality problems (58%). The least common symptoms (<50% prevalence) were fevers (20%), weight loss (35%), abdominal pain (46%), cough (46%), headache (48%), and bone pain (49%). Symptoms were most severe in MF, followed by PV, then ET patients. Although symptoms are present in all 3 MPN subgroups, itching is notably more burdensome in PV patients (65%, median score of 2.8 out of 10). Additionally, abdominal pain, abdominal discomfort, early satiety and inactivity all are most prevalent and severe in MF. Interestingly, night sweats (present in 56%) overall had similar prevalence and severity across all 3 MPNs. The majority found the MPN-SAF easy to understand (98%) and “addressed most of my MPN symptoms” (96%). Comparison to EORTC-QLQ-C30: Strong correlations existed between individual items represented on both the MPN-SAF and the EORTC-QLQC30 including pain, fatigue, appetite and insomnia (all p<0.001). Additionally key symptomatic elements were highly correlated with the EORTC QLQ-C30 functional subscales. Comparison to Physician Perceptions: Comparison of the results of the MPN-SAF to enrolling physicians' blinded opinion of patients symptoms (6 assessed - night sweats, fevers, fatigue, weight loss, bone pain, and pruritus) showed excellent correlation with corresponding patients' responses except bone pain (all p<0.001). Comparison across Countries: When controlling for MPN subtype, responses between the three different countries (and 3 different languages the MPN-SAF was administered) demonstrated great consistency and correlation for all but 1 item, bone pain. Serial MPN-SAF Results: 51 patients in the USA (ET (17.6%), PV (25.5%), and MF (56.9%)), responded to a repeat MPN-SAF survey sent via US mail (50% response rate, mean time between surveys 190±63 days (range 43 – 257)). Pearson correlations indicate that most MPN-SAF items are well correlated (r >0.5, p<.001) upon repeat survey administration. Items characteristic of advanced disease, including weight loss, fever, and cough displayed lower Pearson correlations (r=0.46, -0.08, and 0.38 respectively). Intra-class correlations for test-retest reliability indicated that common features of disease, including mean BFI, inactivity, insomnia, and night sweats, were highly reproducible upon serial survey administration (ICC>0.7, 2, k model used). Conclusion: The MPN-SAF is comprehensive and reliable instrument which is available in multiple languages to evaluate MPN-associated symptoms. The MPN-SAF is recommended as a uniform symptom assessment tool for MPN patients participating in clinical trials globally. Disclosures: Vannucchi: Novartis: Consultancy. Samuelsson:Roche Sweden:. Harrison:Incyte: Honoraria; Novartis: Honoraria. Mesa:SBio: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Incyte: Research Funding; Roche: Research Funding; eisai: Research Funding; telik: Research Funding.

Abstract Background: Patients with myeloproliferative neoplasms (MPNs), including myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET), report high symptom burden that may compromise activities of daily living and quality of life. Results from the MPN Landmark survey suggest that for gainfully employed patients, disease symptoms may impact work productivity or career opportunities. The objective of this study was to assess the effects of MPNs on employment status, work productivity, and daily activities of patients in the United States. Methods: Adult patients (18-70 years) diagnosed with MF, PV, or ET participated in an online survey conducted between April and July 2016. The survey asked about diagnosis, disease-related history, MPN-related symptoms, functional status, changes in employment status since diagnosis due to MPNs, and work productivity (assessed using the Work Productivity and Activity Impairment Specific Health Problem Questionnaire, WPAI-SHP V2). Descriptive statistics were used to report MPN-related symptoms, employment changes, and WPAI scores for patients with MPNs who were employed at diagnosis and currently. Results: A total of 595 patients (MF, n=148; PV, n=284; ET, n=163) completed the survey, with 387 (65.0%) employed full- or part-time at diagnosis (MF, n=90; PV, n=178; ET, n=119). Among patients who were employed at diagnosis, mean (SD) age was 54.3 (10.5) years, 70.0% were female, and 47.8% had a bachelor's degree or higher. Mean (SD) duration of disease was 6.4 (6.6) years. After diagnosis, almost half of the patients (49.9%) experienced ≥1 change in employment resulting from their MPN, one-third (34.1%) had ≥2 different types of changes, and almost one-quarter (22.7%) had ≥3 different types of changes (Table). Almost one-third of patients (31.3%) reported 'leaving a job' due to their condition, which was also the most common employment change. The mean (SD) time from diagnosis to first job change due to MPN disease was 2.4 (5.2) years. Among those currently employed, the mean percentage of overall effects on work productivity due to MPNs were 29.3% for work impairment (MF, 28.4%; PV, 30.0%; ET, 28.6%), 25.7% for impairment while at work (presenteeism; MF, 22.1%; PV, 26.5%; ET, 26.4%), and 6.4% for work time missed (absenteeism; MF, 9.4%; PV, 6.6%; ET, 4.9%). The mean (SD) number of hours of work missed per week was 2.0 (4.9). The mean percentage of daily activity impairment was 31.6% (MF, 32.1%; PV, 32.0%; ET, 30.8%). The effects of MPNs on work productivity and daily activities are similar to those reported by patients with other significant chronic conditions such as rheumatoid arthritis (work time missed, 19.1%; impairment while working, 24.0%; activity impairment; 33.3%; Bansback N, et al. Rheumatology. 2012;51:375-84). Conclusion: MPNs have a substantial negative impact on patients' employment status and work productivity. Half of the employed patients with MPNs surveyed had a change in employment status (eg, leaving job, medical disability leave, early retirement) due to their disease. Moreover, currently employed patients reported a meaningful loss in work productivity due to their MPNs. Disclosures Yu: Incyte Corporation: Employment, Equity Ownership. Parasuraman:Incyte Corporation: Employment, Equity Ownership. Paranagama:Incyte Corporation: Employment, Equity Ownership. Naim:Incyte Corporation: Employment, Equity Ownership. Dubinski:Incyte Corporation: Employment, Equity Ownership. Bai:Incyte Corporation: Employment, Equity Ownership. Mesa:Novartis: Consultancy; Galena: Consultancy; Ariad: Consultancy; Incyte Corporation: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Celgene: Research Funding; CTI: Research Funding.