Kurzfassung: BACKGROUND Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated reductions in splenomegaly and disease-related symptoms, as well as improved survival, in patients with MF and has proved superior to placebo and best available therapy in the 2 phase 3 COMFORT studies. JUMP (JAK Inhibitor Ruxolitinib in Myelofibrosis Patients) is a phase 3b, expanded-access trial for countries with no access to ruxolitinib outside a clinical trial and was designed to assess the safety and efficacy of ruxolitinib in patients with MF. As of 03 June 2014, 2027 patients have been enrolled in 25 countries, with a planned enrollment of 2500 patients. METHODS Eligible patients had MF classified as high risk, intermediate (Int)-2 risk, or Int-1 risk, with a palpable spleen (≥ 5 cm from the costal margin). Patients received starting doses of ruxolitinib based on platelet counts at baseline (5 mg twice daily [bid; ≥ 50 to 〈 100 × 109/L], 15 mg bid [100 to 200 × 109/L] , or 20 mg bid [ 〉 200 × 109/L]). The primary endpoint was assessment of safety and tolerability of ruxolitinib. Additional analyses included changes in palpable spleen length and symptom scores as measured by the FACT-Lymphoma Total Score (FACT-Lym TS). The final analysis will be performed after all patients have completed 24 months of treatment or ended treatment due to commercial availability. RESULTS This analysis includes results for 1144 enrolled patients (primary MF, 58.8%; n = 673) who started treatment ≥ 1 year before the data cutoff date (01 Jan 2014). At baseline, median age was 68 y (range, 18-89 y); 46.7% were female; median palpable spleen length was 13 cm below the costal margin; median hemoglobin was 105 g/L (range, 44-200 g/L) and 40.3% of patients had hemoglobin levels ˂ 100 g/L; median platelet level was 256 × 109/L (75-1910 × 109/L); mean FACT-Lym TS was 41.9. Most patients (69%) remained on treatment (35.5%) or completed treatment per protocol (33.5%; transition to commercial drug). Primary reasons for discontinuation included adverse events (AEs; 13.8%), disease progression (7.1%), and death (3.8%). Median exposure was 11.1 months; the median average daily dose was 37.2 mg for patients starting at 20 mg bid (64%; n = 728) and 23.4 mg for patients starting at 15 mg bid (33%; n = 374). The majority of patients (75.7%) had dose increases/decreases and 23.9% had a dose interruption. The most common hematologic grade ≥ 3 AEs were anemia (33.0%), thrombocytopenia (12.5%), and neutropenia (3.9%), which led to discontinuation in 2.6%, 3.2%, and 0.3% of patients, respectively. Mean hemoglobin levels declined from baseline (108 g/L) to a nadir of 85 g/L at 8 to 12 weeks and increased to near-baseline levels after week 12; mean platelet levels decreased from baseline (318 × 109/L) to a nadir of 139 × 109/L and remained stable over time. The most common nonhematologic AEs (≥ 10%) were diarrhea (14.5%), pyrexia (13.3%), fatigue (12.9%), and asthenia (12.5%) and were primarily grade 1/2; grade ≥ 3 AEs were low overall ( 〈 2%), except pneumonia (3.6%), which led to discontinuation in 6 patients (0.5%). Serious AEs were reported for 32.3% of patients. Rates of infections were low; all-grade infections ≥ 5% included nasopharyngitis (6.3%), urinary tract infection (6.0%), and pneumonia (5.3%). Tuberculosis was reported for 3 patients (0.3%; no grade 3/4); no hepatitis B was reported. At weeks 24 and 48, 55% (431/782) and 61% (301/497) of patients achieved a ≥ 50% reduction from baseline in palpable spleen length, respectively; 23% (181/782) and 18% (88/497) had 25% to 50% reductions. Most patients (69%; 733/1062) experienced a ≥ 50% reduction in spleen length from baseline at any time (Figure). Clinically significant improvements on the FACT-Lym TS were seen as early as week 4 and were maintained at week 48 (mean change from baseline: week 4, 11.0; week 48, 9.4; the range for the minimally important difference is 6.5 to 11.2 points). CONCLUSIONS The JUMP study includes the largest cohort of MF patients treated with ruxolitinib reported to date. Consistent with previous reports, the most common AEs were anemia and thrombocytopenia; however, they rarely led to discontinuation. As observed previously, the majority of patients experienced reductions in spleen length and clinically meaningful improvements in symptoms were observed with ruxolitinib treatment. Overall, the safety and efficacy profile of ruxolitinib in JUMP is consistent with that in the phase 3 COMFORT studies. Figure 1 Figure 1. Disclosures le Coutre: Novartis: Honoraria, Research Funding; BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Griesshammer:Shire: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria; Amgen: Honoraria. Schafhausen:Novartis: Membership on an entity's Board of Directors or advisory committees. Vannucchi:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. Foltz:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Janssen: Consultancy. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Tannir:Novartis: Employment. Ronco:Novartis: Employment. Ghosh:Novartis: Employment. Al-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Kurzfassung: Introduction: Published trial data shows that ruxolitinib improves both splenomegaly-related and nonsplenomegaly-related constitutional symptoms in patients with intermediate-2 and high risk myelofibrosis (MF). However, few trial-based assessments of ruxolitinib in lower-risk MF patients have been conducted and no studies to date have made such assessments in a real-world population. In this study, we assessed changes in spleen size and constitutional symptoms during ruxolitinib treatment for lower-risk MF patients in real-world clinical settings. Methods: This was a retrospective, observational review of anonymized medical record data collected in January 2014 by 49 hematologists and oncologists in the United States. Patient inclusion criteria were: (1) diagnosed with lower-risk MF (International Prognostic Scoring System score of 0 or 1); (2) first treated with ruxolitinib ≥3 months before the medical record abstraction date; (3) ≥18 years of age at ruxolitinib initiation; (4) complete medical history from MF diagnosis until the medical record abstraction date; and (5) never enrolled in an MF-related interventional trial. Minimum quotas of n=50 and n=25 were set for intermediate-1 and low-risk patients, respectively, with a predetermined maximum of 110 patients in the combined total. Spleen size and constitutional symptoms were retrospectively observed at MF diagnosis, at ruxolitinib initiation, and at best response while on ruxolitinib. Spleen size was captured via predefined categories of no splenomegaly (spleen not palpable), very mild or mild splenomegaly ( 〈 10 cm palpated), moderate splenomegaly (10-20 cm palpated), or severe splenomegaly ( 〉 20 cm palpated). Symptoms of interest included those captured in the MPN Symptom Assessment Form (MPN-SAF), which were categorized as mild, moderate, or severe based on medical notes recorded at each time point. For this abstract, we present findings on the 7 most commonly observed MPN-SAF symptoms in our sample. This study was exploratory and used only descriptive analyses. Results: A total of 108 patients were included in the study (25 low-risk and 83 intermediate-1 patients). Ruxolitinib start dates spanned January 2012 – November 2013. All low-risk patients were ≤65 years of age, and nearly 80% of intermediate-1 patients were ≤65 years of age. The majority of patients in both risk groups (60% and 69%, respectively) were male. A higher proportion of intermediate-1 patients were positive for JAK2 V617F mutation (72%) than low-risk patients (56%). Most patients (92% of low-risk, 77% of intermediate-1) were still receiving ruxolitinib treatment at the medical record abstraction date. Median observed ruxolitinib exposure time was approximately 8 months in both risk groups. In low-risk patients, the combined proportion of patients with moderate or severe splenomegaly (≥10 cm palpated spleen) decreased from 64% at MF diagnosis to 16% at best response during ruxolitinib treatment (Figure 1a). Similar findings were observed for intermediate-1 patients: the proportion with moderate or severe splenomegaly decreased from 53% at MF diagnosis to 10% at best response (Figure 1b). General fatigue was the most commonly observed constitutional symptom in both low-risk and intermediate-1 patients (Figures 2a and 2b). Shifts in symptom severity from more severe to less severe were observed in both low-risk and intermediate-1 patients. Among low-risk patients with fatigue, the proportion with moderate or severe fatigue decreased from 90% at MF diagnosis to 37% at best ruxolitinib response; in intermediate-1 patients, the decrease was from 76% at MF diagnosis to 42% at best response. For most other symptoms, similar improvements in severity distribution were observed. Conclusions: Both low-risk and intermediate-1 MF patients experienced a substantial decrease in spleen size from MF diagnosis through ruxolitinib treatment in real-world clinical settings. Furthermore, for most symptoms examined, there was a distinct improvement in the distribution of symptom severity at the time of best response during ruxolitinib treatment. These findings suggest that lower-risk MF patients may benefit clinically from ruxolitinib treatment. Further studies are needed to assess adverse effects and evaluate the benefit-risk tradeoff of ruxolitinib. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Davis: Novartis Pharmaceuticals Corporation: Research Funding. Kaye:Novartis Pharmaceuticals Corporation: Research Funding. Cote:Novartis: Employment. Off Label Use: The study discusses use of ruxolitinib in patients with lower-risk (IPSS 0 or 1) myelofibrosis (MF) in real-world practice; currently ruxolitinib is only indicated in higher-risk MF (IPSS 〉 1).. Gao:Novartis: Employment. Ronco:Novartis: Employment. Seifeldin:Novartis: Employment. Mendelson:Novartis: Employment.

Kurzfassung: BACKGROUND: Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated durable reductions in splenomegaly and myelofibrosis (MF)-related symptoms. Additionally, ruxolitinib proved superior to placebo and best available therapy in the phase 3 COMFORT studies and showed improved survival. In some patients (pts) receiving ruxolitinib, adverse events (AEs) may lead to treatment interruption; in such pts, AE management, dose optimization, and efficacy expectations may be balanced. This analysis provides further information about the efficacy and safety of ruxolitinib in pts who have restarted treatment after treatment interruption (cutoff date, 01 January 2014) in the JUMP (JAK Inhibitor Ruxolitinib in Myelofibrosis Patients) trial, a large, phase 3b, expanded-access program. METHODS: Pts with MF classified as high risk, intermediate-2 risk, or intermediate-1 risk, with a palpable spleen (≥ 5 cm from the costal margin), received starting doses of ruxolitinib based on their platelet counts at baseline (5 mg twice daily [bid; ≥ 50 to 〈 100 × 109/L], 15 mg bid [100 to 200 × 109/L] , or 20 mg bid [ 〉 200 × 109/L]). Endpoints included safety and tolerability, as well as changes in spleen length, symptoms, and laboratory values. This analysis included all pts who started study treatment ≥ 1 year before data cutoff and had ≥ 1 dose interruption of ≥ 7 days. RESULTS: This analysis included 207 pts (primary MF, 68.1%; female, 53.1%; median age, 69 years) presenting with baseline medians: spleen length, 13 cm (range, 1.0-35.0 cm); hemoglobin, 99 g/L (50.7% of pts with 〈 100 g/L); and platelets, 199.5 × 109/L. At data cutoff, most pts (60.9%) remained on treatment (38.2%) or completed treatment per protocol (22.7%); the main reasons for discontinuation included AEs (18.4%), death (6.8%), disease progression (5.3%), and other (8.7%). Overall, the median duration of exposure was 12.5 months: 1.9 months from baseline to interruption and 6.5 months after restart. The mean daily dose was 30.5 mg prior to treatment interruption and 19.4 mg after treatment restart. Dose interruptions lasted 7 to 14 days in 41.1% of pts (15 to 21 days, 26.6%; 〉 21 days, 32.4%) and were mostly due to AEs (92.3%). Most pts (67.1%) had only 1 dose interruption. At weeks 12, 24, and 48, overall 45%, 53%, and 54% of pts, respectively, achieved a ≥ 50% reduction from baseline in palpable spleen length. In addition, at the same time points, 29%, 23%, and 23% achieved reductions from 25% to 50%. 68.2% (133/195) of pts experienced a ≥ 50% reduction at any time; 77 pts (58%) achieved it before interruption and 56 pts (42%) after restart. From spleen length at restart, 24% of pts achieved a further 50% reduction, 9% experienced a spleen length increase ≥ 50%, and 67% remained stable in between. Clinically meaningful improvements in symptoms (the range for the minimally important difference is 6.5 to 11.2 points), as assessed by the FACT-Lymphoma Total Score, were observed as early as week 4 (mean change from baseline, 9.6), with a trend toward improvement at week 48 (6.1). The most common hematologic grade 3/4 AEs were anemia (43.5%) and thrombocytopenia (41.1%), leading to permanent discontinuations in 9 (4.4%) and 14 pts (6.8%), respectively. Rates of nonhematologic AEs grade ≥ 3 were low (≤ 2%), except for pneumonia (5.8%), abdominal pain (3.4%), urinary tract infection (3.4%), increased γ-glutamyltransferase (2.4%), asthenia (2.4%), and dyspnea (2.9%), but these rarely led to discontinuations (≤ 1%). Despite 〉 3-times longer exposure after restart, the rates of AEs before ruxolitinib interruption and after treatment restart were similar overall. CONCLUSIONS: In this cohort of pts, ruxolitinib provided reductions in spleen size and symptoms prior to and after treatment interruption. After restart of treatment, pts were able to stay on ruxolitinib at a median dose of ≈ 10 mg bid, and most pts did not require another interruption. Rates of AEs did not increase after treatment restart, with rates of some AEs decreasing; discontinuation rates after restart of treatment are comparable to those observed in the overall study population (Al-Ali et al. EHA 2014). Overall, ruxolitinib is generally safe and well tolerated and provides meaningful reductions in splenomegaly and symptoms in pts who have restarted ruxolitinib after treatment interruption. Disclosures Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Griesshammer:Shire: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria; Amgen: Honoraria. Foltz:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Janssen: Consultancy. Al-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Tannir:Novartis: Employment. Ronco:Novartis: Employment. Ghosh:Novartis: Employment. Vannucchi:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding.

Kurzfassung: 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.

Kurzfassung: Current data identifying COVID-19 risk factors lack standardized outcomes and insufficiently control for confounders. Objective To identify risk factors associated with COVID-19, severe COVID-19, and SARS-CoV-2 infection. Design, Setting, and Participants This secondary cross-protocol analysis included 4 multicenter, international, randomized, blinded, placebo-controlled, COVID-19 vaccine efficacy trials with harmonized protocols established by the COVID-19 Prevention Network. Individual-level data from participants randomized to receive placebo within each trial were combined and analyzed. Enrollment began July 2020 and the last data cutoff was in July 2021. Participants included adults in stable health, at risk for SARS-CoV-2, and assigned to the placebo group within each vaccine trial. Data were analyzed from April 2022 to February 2023. Exposures Comorbid conditions, demographic factors, and SARS-CoV-2 exposure risk at the time of enrollment. Main Outcomes and Measures Coprimary outcomes were COVID-19 and severe COVID-19. Multivariate Cox proportional regression models estimated adjusted hazard ratios (aHRs) and 95% CIs for baseline covariates, accounting for trial, region, and calendar time. Secondary outcomes included severe COVID-19 among people with COVID-19, subclinical SARS-CoV-2 infection, and SARS-CoV-2 infection. Results A total of 57 692 participants (median [range] age, 51 [18-95] years; 11 720 participants [20.3%] aged ≥65 years; 31 058 participants [53.8%] assigned male at birth) were included. The analysis population included 3270 American Indian or Alaska Native participants (5.7%), 7849 Black or African American participants (13.6%), 17 678 Hispanic or Latino participants (30.6%), and 40 745 White participants (70.6%). Annualized incidence was 13.9% (95% CI, 13.3%-14.4%) for COVID-19 and 2.0% (95% CI, 1.8%-2.2%) for severe COVID-19. Factors associated with increased rates of COVID-19 included workplace exposure (high vs low: aHR, 1.35 [95% CI, 1.16-1.58]; medium vs low: aHR, 1.41 [95% CI, 1.21-1.65] ; P   & amp;lt; .001) and living condition risk (very high vs low risk: aHR, 1.41 [95% CI, 1.21-1.66]; medium vs low risk: aHR, 1.19 [95% CI, 1.08-1.32] ; P   & amp;lt; .001). Factors associated with decreased rates of COVID-19 included previous SARS-CoV-2 infection (aHR, 0.13 [95% CI, 0.09-0.19]; P   & amp;lt; .001), age 65 years or older (aHR vs age & amp;lt;65 years, 0.57 [95% CI, 0.50-0.64]; P   & amp;lt; .001) and Black or African American race (aHR vs White race, 0.78 [95% CI, 0.67-0.91]; P  = .002). Factors associated with increased rates of severe COVID-19 included race (American Indian or Alaska Native vs White: aHR, 2.61 [95% CI, 1.85-3.69]; multiracial vs White: aHR, 2.19 [95% CI, 1.50-3.20] ; P   & amp;lt; .001), diabetes (aHR, 1.54 [95% CI, 1.14-2.08]; P  = .005) and at least 2 comorbidities (aHR vs none, 1.39 [95% CI, 1.09-1.76]; P  = .008). In analyses restricted to participants who contracted COVID-19, increased severe COVID-19 rates were associated with age 65 years or older (aHR vs & amp;lt;65 years, 1.75 [95% CI, 1.32-2.31]; P   & amp;lt; .001), race (American Indian or Alaska Native vs White: aHR, 1.98 [95% CI, 1.38-2.83]; Black or African American vs White: aHR, 1.49 [95% CI, 1.03-2.14] ; multiracial: aHR, 1.81 [95% CI, 1.21-2.69]; overall P  = .001), body mass index (aHR per 1-unit increase, 1.03 [95% CI, 1.01-1.04]; P  = .001), and diabetes (aHR, 1.85 [95% CI, 1.37-2.49]; P   & amp;lt; .001). Previous SARS-CoV-2 infection was associated with decreased severe COVID-19 rates (aHR, 0.04 [95% CI, 0.01-0.14]; P   & amp;lt; .001). Conclusions and Relevance In this secondary cross-protocol analysis of 4 randomized clinical trials, exposure and demographic factors had the strongest associations with outcomes; results could inform mitigation strategies for SARS-CoV-2 and viruses with comparable epidemiological characteristics.