Abstract: Anemia is a frequent manifestation of myelofibrosis (MF) and there is an unmet need for effective treatments in anemic MF patients. The REALISE phase 2 study (NCT02966353) evaluated the efficacy and safety of a novel ruxolitinib dosing strategy with a reduced starting dose with delayed up-titration in anemic MF patients. Fifty-one patients with primary MF (66.7%), post-essential thrombocythemia MF (21.6%), or post-polycythemia vera MF (11.8%) with palpable splenomegaly and hemoglobin 〈 10 g/dl were included. Median age was 67 (45–88) years, 41.2% were female, and 18% were transfusion-dependent. Patients received 10 mg ruxolitinib b.i.d. for the first 12 weeks, then up-titrations of up to 25 mg b.i.d. were permitted, based on efficacy and platelet counts. Overall, 70% of patients achieved a ≥50% reduction in palpable spleen length at any time during the study. The most frequent adverse events leading to dose interruption/adjustment were thrombocytopenia (17.6%) and anemia (11.8%). Patients who had a dose increase had greater spleen size and higher white blood cell counts at baseline. Median hemoglobin levels remained stable and transfusion requirements did not increase compared with baseline. These results reinforce the notion that it is unnecessary to delay or withhold ruxolitinib because of co-existent or treatment-emergent anemia.

Abstract: Background Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPNs) whose associated disease burden includes a range of debilitating symptoms, thrombosis, hemorrhage, and shortened survival. To enhance patient care, it is important to understand the impact of MPNs in patients' lives; however, little is known regarding how these conditions affect patients' quality of life (QOL), activities of daily living, productivity, and emotional well-being. The US LANDMARK survey (Mesa et al. BMC Cancer 2016) captured data for US patients. Here, we present an interim analysis of results of another MPN LANDMARK survey conducted in the rest of the world. Methodology MPN LANDMARK survey is a cross-sectional survey of MPN patients across 6 countries (Australia, Canada, Germany, Japan, Italy, and UK). Patients completed an online questionnaire to measure MPN related symptoms experienced over the past 12 months and the impact of their condition on their QOL and ability to work. Additional questions related to employment productivity and activity impairment (including absenteeism and loss of productivity over the past 7 days). Patients included in this interim analysis had completed the survey by July 18, 2016, with enrollment continuing in all countries. Results Patients: Overall, 437 patients had completed the survey (98 MF, 121 PV, 218 ET). For MF and PV, the male to female gender split was relatively even (54% male for each), whereas an expected greater proportion of ET patients was female (70%). Patients with MF were significantly older than PV and ET patients (mean ages, 62, 59, and 55 years, respectively) and more had been diagnosed within 2 years of experiencing their symptoms (83% MF, 67% PV, 71% ET). MPN Symptoms (Table): Most patients (94%) experienced MPN-related symptoms in the past 12 months. The most commonly reported symptom among all subtypes was fatigue (69% MF, 62% PV, 73% ET), incidence of other common symptoms varied depending on disease subtype (MF: shortness of breath [38%], bruising [36%] , night sweats [35%], early satiety [33%] ; PV: night sweats [36%], trouble concentrating [36%] , trouble sleeping [34%], dizziness [34%] ; ET: trouble sleeping [37%], dizziness [37%] , bruising [35%], night sweats [35%] ). When asked which symptom patients would most like to have resolved, most patients preferred to have feeling of fatigue/tiredness improved across all disease subtypes (31% MF, 30% PV, 33% ET). Patients experienced an average of 6.4 symptoms at diagnosis but this progressed to an average of 7.6 symptoms since diagnosis after a median time of 6 years. QOL: A majority of patients indicated that they experienced a reduction in QOL due to MPN symptoms (87% MF, 71% PV, 73% ET) with 33% and 26% of MF and ET patients expressing that their condition has caused emotional hardship, and one-third of patients with PV reporting that they have felt worried or anxious about their disease (39%). MPN Impact on Activity/Employment: Patients reported a high impact on their ability to work, 12% reported voluntarily leaving their job, 10% had taken early retirement, 10% had moved onto disability living allowance, 8% moved to a lower paid job, and 2% experienced involuntary loss of work (Table). Of the patients who were in full-time or part-time employment at the time of the survey (MF [n=17]), PV [n=41] , ET [n=98]), approximately, 40% had been absent from work within the past 7 days; this was the highest in MF patients (41% MF, 38% PV, 33% ET). On an average, over the past 7 days, MF patients had missed 3.1 hours from work, PV patients 2.3 hours and ET patients 2 hours. Across all subgroups, a substantial proportion of patients reported impairment in work (mean: 34% MF, 33% PV, 31% ET) and overall activity (mean: 46% MF, 42% PV, 39% ET). Conclusions This interim analysis from the MPN LANDMARK survey indicates that MPN patients experience a high burden of disease, including a high prevalence of symptoms, an increase in the number of symptoms from diagnosis and reduction of their emotional well-being, QOL, and ability to work. These results are consistent with those from the previous US LANDMARK survey with the addition of novel data on how MPNs impact work. When treating MPN patients, care should be taken in trying to manage a patient's disease burden, so as to minimize the impact on a patient's daily life. Further results from additional survey responses will be presented at the congress. Disclosures Harrison: Baxaltra: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau. Koschmieder:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Foltz:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Koehler:Novartis Inc. (Germany): Consultancy, Other: Training. Komatsu:Shire: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Boothroyd:Novartis: Employment, Equity Ownership. Spierer:Novartis: Employment. Ronco:Novartis: Employment. Taylor-Stokes:Adelphi Real World: Employment. Waller:Adelphi Real World: Employment. Mesa:Celgene: Research Funding; Galena: Consultancy; Novartis: Consultancy; CTI: Research Funding; Ariad: Consultancy; Incyte: Research Funding; Gilead: Research Funding; Promedior: Research Funding.

Abstract: Background: The Janus kinase (JAK) inhibitor ruxolitinib (RUX) is approved for the treatment of disease-related splenomegaly and symptoms in patients with myelofibrosis (MF). Treatment with RUX has been shown to significantly reduce splenomegaly and provide marked improvements in MF-related symptoms and quality-of-life. A number of mutations have been identified with known or likely functional significance in patients with MF (Vannucchi AM, et al. Leukemia. 2013), which may therefore have the potential to affect treatment response. This exploratory analysis aimed to investigate the mutational status of patients in the REALISE trial and to assess the relationship between baseline mutational status and outcome. Methods: REALISE was a multicenter, open label, single arm phase 2 study (NCT02966353). Eligible patients (N=51) had primary MF, post-essential thrombocythemia (ET) MF or post-polycythemia vera (PV) MF, with palpable (≥5 cm) spleen and hemoglobin level 〈 10 g/dL. Patients started RUX at 10 mg bid with up titrations to 15 or 20 mg bid allowed after 12 weeks based on efficacy and platelet counts. The primary endpoint was achievement of ≥50% reduction in spleen length at Week 24. Secondary endpoints included transfusion requirements/dependence over time, adverse events, and patient-reported outcomes (PRO) (7-point MF score [MF-7], MF Symptom Assessment Form [MFSAF] version 2.0). Next generation sequencing (NGS) analysis using a 236 gene panel (Navigate BioPharma, Carlsbad, CA, USA) was performed on whole blood samples to identify genetic alterations. Results: NGS analysis data were available for 49/51 patients, median age was 67 years, 67.3% (33/49) had primary MF, 10.2% (5/49) had post-PV MF and 22.4% (11/49) had post-ET MF. DIPSS was available for 45 patients, 16.3% (8/49) were intermediate (Int)-1, 57.1% (28/49) were Int-2 and 18.4% (9/49) were high risk. The most frequent baseline mutations are shown in Figure 1. Classic driver mutations were found in JAK2 (n=33), CALR (n=11) and MPL (n=7), and did not affect response to RUX treatment. Two patients (4.1%) were triple negative for JAK2/CALR/MPL mutations, both responded to RUX treatment. The most commonly found non-driver mutations in patients with ≥50% reduction in spleen length at Week 24 (n=28) were TET2, ASXL1, U2AF1 and SRSF2; in non-responders, the most common non-driver mutations were TP53, FAT1 and ASXL1. The median number of mutations per patient was 2 (range 1-7); 35.7% (10/28) of patients with a response had ≥3 non-driver mutations vs 14.3% (3/21) of non-responders. Overall, no difference was seen in mutational distribution by change in spleen length at Week 24. In general, similar findings were seen for transfusion dependence status at baseline and improvements in symptom score with treatment (Table 1). However, there was a higher incidence of U2AF1 mutation in patients who were transfusion-dependent at baseline vs. non-transfusion dependent patients (4/8 [50%] vs 3/41 [7.3%] , respectively). U2AF1 mutation is known to be associated with anemia and/or thrombocytopenia in myelodysplastic syndromes (Li B, et al. Genes Chromosomes Cancer. 2018). Mutations in TP53 were present in 6 patients. One patient showed a response to treatment at Week 24, and 5 were classified as non-responders. None of these 5 patients completed 24 weeks of treatment and 3 died during the study or safety follow-up period. Two progressed to acute myeloid leukemia prior to death. All patients were ≥60 years old, 4 were male and 4 were DIPSS Int-2 risk. Four patients had primary MF, 1 had post-ET MF and 1 had post-PV MF. Conclusions: Though these data should be interpreted with caution due to the small patient numbers, patients in the REALISE study showed variation in the type and number of genetic alterations with known/likely functional significance in MF. Compared with published mutational data on MF patients treated with RUX (Spiegel, et al. Blood Advances. 2017; Pacilli et al. Blood Cancer Journal. 2018) 12.2% of patients had a TP53 mutation compared to 4% and 4.2% respectively. This molecular difference may reflect the anemic study population. Despite the higher TP53 mutational burden, and alternative dosing strategy, 57.1% (28/49) patients had a response to RUX at Week 24. Although there was no strong association between mutation patterns and response, patients with TP53 mutations tended to have a poor outcome overall. Disclosures Al-Ali: Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CTI: Honoraria. Gisslinger:Novartis Pharma GmbH: Consultancy, Honoraria, Research Funding; Roche Austria GmbH: Consultancy; Myelopro GmbH: Consultancy; Celgene GmbH: Honoraria; Pharma Essentia: Other: Personal fees; Janssen-Cilag: Honoraria; AOP Orphan Pharmaceuticals: Consultancy, Honoraria, Research Funding. Passamonti:Janssen: Honoraria, Other: Advisory board , Speakers Bureau; Novartis: Honoraria, Other: Advisory board , Speakers Bureau; Celgene: Honoraria, Other: Advisory board , Speakers Bureau. Foltz:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; Amgen: Other: Spouse Employment; Incyte: Research Funding; Constellation Pharma: Research Funding. Ross:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vannucchi:Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Komatsu:Pharma Essentia: Research Funding, Speakers Bureau; Novartis K.K: Speakers Bureau; Wako Pure Chemical Industries, Ltd.: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding, Speakers Bureau; Fuso Pharmaceutical Industries, Ltd.: Research Funding. Tiwari:Novartis: Employment. Zor:Novartis: Employment. Chaturvedi:Novartis Pharmaceuticals: Employment. Gilotti:Novartis Pharmaceuticals: Employment. Cervantes:Novartis: Honoraria, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.