Abstract: Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with disabling symptoms and a heightened risk of life-threatening complications. Recent studies have demonstrated the effectiveness of JAK inhibitor therapy in patients with PV patients who have a history of prior hydroxyurea (HU) use (including resistance or intolerance), phlebotomy requirements, and palpable splenomegaly. We aimed to determine how these features contribute alone and in aggregate to the PV symptom burden. Patients and Methods Through prospective evaluation of 1,334 patients with PV who had characterized symptom burden, we assessed patient demographics, laboratory data, and the presence of splenomegaly by disease feature (ie, known HU use, known phlebotomy requirements, splenomegaly). Results The presence of each feature in itself is associated with a moderately high symptom burden (MPN symptom assessment form [SAF] total symptom score [TSS] range, 27.7 to 29.2) that persists independent of PV risk category. In addition, symptoms incrementally increase in severity with the addition of other features. Patients with PV who had all three features (PV-HUPS) faced the highest total score (MPN-SAF TSS, 32.5) but had similar individual symptom scores to patients with known HU use (PV-HU), known phlebotomy (PV-P), and splenomegaly (PV-S). Conclusion The results of this study suggest that patients with PV who have any one of the features in question (known HU use, known phlebotomy, or splenomegaly) have significant PV-associated symptoms. Furthermore, it demonstrates that many PV symptoms remain severe independent of the number of features present.

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 4075 Introduction. The association of Melphalan-Prednisone and Thalidomide (MPT) is approved as first-line treatment in elderly patients with Multiple Myeloma (MM). This treatment demonstrated significant benefit in terms of overall survival (OS) and Progression Free Survival (PFS) as opposed to MP alone. Lenalidomide (Len), used in combination with Dexamethasone (Len/Dex), is recommended to treat patients with relapsed MM who received a prior therapy. Len is an oral immunomodulator similar to Thalidomide (T). Both these drugs have identical activity but their safety profiles are different. So, in case of successive use of MPT and Len/Dex, it is legitimate to think that the efficacy of Len is affected by the previous use of T, probably because of the resistance to Len developed by relapsed or refractory patients. Therefore, we carried out a retrospective, multicentric study in order to assess the efficacy and safety of Len in patients with relapsed MM previously treated by MPT. Method. Our survey included 64 elderly patients with symptomatic MM from three French hematology centers. All the patients showed a relapsed MM treated with first-line treatment of MPT. Len was administered at first or second relapse. The main objective was to assess the efficacy of Len in terms of response rate, OS and PFS. Another objective was to evaluate the tolerance to Len and MPT treatments and to identify the predictive factors of efficacy of Len like the response rate, the duration of remission after MPT treatment and the line number of treatment before using Len. Results. The median age of patients at diagnosis was 73.5 years old and the sex ratio was 1. The M-protein was IgG for 64% of patients, IgA for 20%, light chains for 14% and IgD for 2%. Concerning the International Staging System, 35% of patients were stage I, 28% were stage II and 37% were stage III. MPT was administered with a 100mg/d thalidomide dose to 83% of patients. The median duration of T treatment was 13 months [range: 0.1 – 29.5]. The overall response rate (ORR) was 90% with 53% of partial response (PR), 27.5% of very good partial response (VGPR) and 9.5% of complete response (CR). Five patients stopped T because of progression on therapy, 36 because of toxicity out of which 26 because of peripheral neuropathy and 2 thromboembolic events. The median response duration after MPT was 25.5 months. Len was administered at first relapse to 47 patients (73.5%) and at second relapse for the others (n=17). The second-line treatment for these 17 patients was bortezomib-based regimen treatment. The daily dose of Len was 15 to 25 mg, always associated with low dose of Dex, for 83% of patients. Ten cycles of Len/Dex were administered on average. For 23/64 patients, the Len/Dex treatment is going on, 21/41 patients stopped because of progression and 17/41 because of toxicity (hematologic toxicity: 8/17, thromboembolic events: 2/17, general and gastrointestinal disorder: 7/17). The Len ORR was 78% (CR: 3.5%, VGPR: 27.5%, PR: 47%). The median SSP after initiation of Len is 12.8 months. The median OS after initiation of Len is 43 months and the OS rate is 58% at 3 years. Since the diagnosis, No predictive factor has a significant impact on the efficacy of Len. No second primary malignancies were reported. Conclusion. Our study shows that the efficacy and safety of Len is satisfactory, even after a Thalidomide treatment. The ORR and median PFS are similar to published data. There is no increase of toxicity for patients on Len, especially concerning thromboembolic events. With the development of new drugs like Carfilzomib, Pomalidomide and Eculizumab, the perspective of treatment increased as well as the number of lines. The choice of therapeutic sequences must be taken into account. In this study, we show that the MPT – Len/Dex sequence is effective and safe for elderly MM patients. Disclosures: Roussel: celgene: Honoraria; janssen: Honoraria. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Leleu:celgene: Honoraria; janssen: Honoraria. Facon:onyx: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Hulin:celgene: Honoraria; janssen: Honoraria.

Abstract: Background Ruxolitinib is a current therapeutic option, which has demonstrated rapid and durable reduction in splenomegaly and improved disease-related symptoms in patients (pts) with primary myelofibrosis (PMF), post-polycythemia vera-MF (PPV-MF), and post-essential thrombocythemia-MF (PET-MF). Anemia is another frequent issue in MF, which may be managed by the use of ESA, leading to a 40-50% response rate in small studies. Consistent with its JAK2 signalling inhibition, ruxolitinib therapy has been shown to be detrimental on the hemoglobin level, increasing the depth of anemia or transfusion need, especially during the first 12-24 weeks of treatment in the COMFORT studies. Despite potential antagonistic mechanisms of action on JAK2, some responses on anemia have been reported with the addition of ESA to ruxolitinib in a small subset of pts in the COMFORT II study. The present study aimed to better assess the efficacy of ESA on anemia related to ruxolitinib and tolerance of this combination in a larger cohort of pts treated for MF in general practice. Methods We performed an observational study on patients with MF previously or currently treated with concomitant ESA and Ruxolitinib in French centers members of the FIM. Informed consent was provided by the pts. Data collected included characteristics of the disease, treatment, responses to ruxolitinib and ESA. They are reported according to the IWG-MRT/ELN 2013 criteria. Results This analysis was performed in July 2016, on the 45 first consecutive pts in 11 centers. Median age at diagnosis was 73 (range 42- 89), 30 (67%) were men. Twenty-five pts (56%) had primary MF, 11 (24%) PET-MF and 9 (20%) PPV-MF, overall diagnosed between 2004 and 2016. IPSS risk categories were low/int-1 and int-2/high in 16 (36%) and 28 (64%) pts, respectively. Twenty-nine (64%) were JAK2V617F positive, 5 harbored MPL mutation and 8 had CALR mutations. Median time between MF diagnosis and ruxolitinib was 21 (0-109) months and median follow-up from ruxolitinib starting was 13 (2 - 53) months. At time of ruxolitinib initiation 32 (71%) pts were transfusion independent and 13(29%) had transfusion need. Ten additional pts became transfusion dependent after ruxolitinib initiation. Other causes of anemia were renal insufficiency n=7, surgery n=1, 1 cytoreductive therapy with hydroxyurea. Type of ESA were darbepoetin alfa, [n=26]; epoetin alfa, [n=3] , epoetin beta [n=8], epoetin zeta [n=4] , epoeitin theta [n=4], with a median duration of exposure to ESA of 15 months [1-92mo] . ESA was introduced either before ruxolitinib (n= 17), simultaneously (n= 4) or afterward (n= 24) after a median of 2 months [1-26mo]. Response rate to ruxolitinib were in accordance with previous reports: For splenomegaly, 33 (73%) of pts achieved at least a partial response, 8 (17%) were stable and 4 (9%) were progressive. Thirty pts (67%) had at least partial response on constitutional symptoms. Response assessment of anemia according to IWG-MRT/ELN 2013 criteria: 7 pts (16%) achieved a RBC transfusion independency, 13 (29%) pts had an increase in hemoglobin level of Hb 〉 2g/dl (2 pts achieved both criteria), which results in 40% of objective responses. The median time to best response on anemia after ESA initiation was 3 [1-84] months. For safety, a pulmonary embolism occurred in one patient possibly related to ESA, no other adverse event occurred, in particular no spleen enlargement was described. At time of analysis, 36/45 pts were still alive: 1 underwent allogeneic bone marrow transplant, 34 were still treated with ruxolitinib whereas 28 patients were still undergoing ESA therapy. Conclusions This retrospective analysis is the largest cohort describing the use of concomitant ESA with ruxolitinib therapy in "real life". We report 40 % of objective responses, consistent with ESA response rates without ruxolitinib for MF related anemia. Tolerance seemed acceptable without hampering efficiency of ruxolitinib. Our results suggest that ESA should be considered as a possible therapeutic for anemia in myelofibrosis patients treated with ruxolitinib. Disclosures Malak: Novartis: Membership on an entity's Board of Directors or advisory committees. Ugo:Novartis: Membership on an entity's Board of Directors or advisory committees. Kiladjian:Novartis: Research Funding; AOP Orphan: Research Funding. Roy:AOP: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: congress travel, Research Funding.