Approval Of Ruxolitinib Research Articles

Socio-demographic determinants of myelofibrosis outcomes in an underserved center and the SEER national database

The influence of demographic characteristics and social determinants on cancer outcomes is widely recognized in various malignancies but remains understudied in myelofibrosis (MF). This study aims to investigate social and demographic variables associated with MF survival. We retrospectively reviewed data of biopsy-proven MF patients from the Surveillance, Epidemiology and End Results (SEER) database (2000–2021) and Montefiore Medical Center (2000–2023), an underserved inner-city hospital. The SEER cohort included 5,403 MF patients and was predominantly Non-Hispanic (NH) White (82%) with a median age of 69 years. The age-adjusted incidence rate of MF was 0.32 cases per 100,000 person-years, increasing annually by 1.3% from 2000 to 2021. Two- and five- year overall survival rates were 69% and 42%, respectively. Worse cause-specific survival was associated with older age, male sex, and diagnosis before 2011 (year of Ruxolitinib approval). NH-Black ethnicity, unmarried status and lower median income were independent predictors of worse overall survival. The single-center analysis included 84 cases, with a median age of 66 years. NH-White patients comprised 37% of the sample, followed by NH-Black (28.5%). Two- and five- year overall survival rates were 90% and 61%, respectively, with NH-Black patients exhibiting the lowest median survival, although the difference was not statistically significant. Age was a significant predictor of worse survival in this cohort. NH-Black and Hispanic patients lived in areas with higher socioeconomic and demographic stress compared to NH-White patients. Overall, this study highlights the association of social and demographic factors with MF survival and emphasizes the need for equitable healthcare and further exploration of social-demographic factors affecting MF survival.

Cardiovascular-Related Mortality Risk in Primary Myelofibrosis in Pre-Ruxolitinib and Ruxolitinib Eras

Background Ruxolitinib, a Janus Kinase inhibitor, was approved in 2011 for the treatment of primary myelofibrosis (PMF) and has shown improved survival since its introduction. However, there are reports of possible cardiotoxicity linked to the medication. 1,2 Previous studies have shown that cardiovascular disease (CVD) was the third most common cause of death in PMF. 3 Given that patients with PMF may need therapy for several years, the cardiovascular safety profile of ruxolitinib has been the subject of increased scrutiny. Our goal was to compare the cardiovascular-related mortality (CVM) risk in patients with PMF in the pre-ruxolitinib (pre-Rux) and ruxolitinib (Rux) eras. Methods Using the Surveillance, Epidemiology, and End-result (SEER) Research Plus Data, 17 Registries and Multiple Primary Standardized Incidence Ratio (MP-SIR) registries (2000 - 2020), a retrospective study of patients diagnosed with PMF between 2003 and 2019 was conducted. This period was split into the pre-Rux (2003-2010) and post-approval Rux eras (2012-2019) and compared the standard mortality ratios (SMRs) of CVD in both periods. SMR was expressed as the ratio of cardiovascular deaths observed in PMF to those expected in the general population. Descriptive statistics (frequencies) were compared with Chi-square. The Kaplan-Meier method was used to estimate cumulative relative survival (CRS), and the sub-distribution hazard model for competing risk analysis was used to predict CVM; the significance test was set at <0.05. Results 4,509 patients with PMF were identified between the two study periods (2003-2010 and 2012-2019). As shown in Table 1, a higher proportion of older patients aged 65+ years (67.2% vs. 62.9%, p=0.003) and Non-Hispanic Blacks (8.9% vs. 7.5%, p=0.025) were diagnosed in the Rux era. More patients were alive (49.6% vs. 16.6%, p<0.001), and 5-year CRS was higher in the Rux period (57.1% vs. 47.6%). There was no significant difference in the proportion of deaths due to cardiovascular disease between the two periods. Compared to the general population, patients with PMF had a higher overall CVM independent of the era of diagnosis ( Figure 1). However, there was a decrease in SMR of overall CVD in the post-Rux period (SMR=2.67; 95% CI: 2.28-3.10) compared to the pre-Rux (SMR: 3.42; 95% CI: 2.79-4.15). In terms of specific CVD, the SMRs of diseases of the heart, hypertension without heart diseases, and cerebrovascular disease were higher in the pre-RUX period compared to the Rux era, where SMR was higher only in diseases of the heart, which was still lower than the pre-Rux period (SMR: 2.73 [2.28-3.24] vs. 3.57 [2.84-4.44]). There was no significant difference in the mortality risk from other CVD compared to the general population in both periods. On multivariate analysis, after adjusting for age, sex, race and era of diagnosis, factors associated with reduced odds of CVM were diagnosis of PMF in the RUX era ( HR=0.76; 95% CI: 0.61-0.94, p=0.012), female gender ( HR=0.72; 95% CI: 0.58-0.89, p=0.002) and younger age (<65 years, HR= 0.12; 95% CI: 0.09-0.17, p<0.001. Non-Hispanic Black race was an independent predictor of increased CVM. Conclusion The risk of CVM in PMF compared to the general population did not seem to have increased in the era following the approval of ruxolitinib. The SMRs for overall and some specific cardiovascular diseases appear to be lower in the ruxolitinib era compared to the period before its approval. Lastly, the period following the introduction of ruxolitinib was associated with reduced death from cardiovascular diseases. Hence, ruxolitinib may have had some mortality benefits from cardiovascular disease in PMF; however, further studies are needed to examine and validate this observation.

Meter: A Multi-Country, Real-World Chart Review Study to Explore Treatment Patterns, Effectiveness and Healthcare Resource Utilization for Patients with Myelofibrosis

Background : Myelofibrosis (MF) is a rare myeloproliferative disorder associated with significant morbidity and mortality. The hallmarks of MF pathobiology include aberrant myeloproliferation, cytokine-induced inflammation, bone marrow reticulin fibrosis, extramedullary hematopoiesis, cytopenias, and constitutional symptoms. Hydroxyurea was the most commonly used drug in patients with MF prior to the approval of ruxolitinib (RUX), a first-in-class Janus kinase 1/2 inhibitor (JAKi) that is widely approved for symptomatic patients with MF. In addition to RUX, the JAKis fedratinib and, more recently, pacritinib have also been approved by the US Food and Drug Administration. Real-world treatment patterns and impact of currently available JAKis on patients with MF are not well understood. Several novel agents are in advanced development and will further reshape the treatment landscape of MF. A better understanding of current treatment patterns will assist in positioning novel treatments within the MF therapeutic landscape. Methods : The METER study (NCT05444972) is an ongoing multicountry noninterventional retrospective chart review assessing treatment patterns, effectiveness, and healthcare resource utilization (HCRU) in patients diagnosed with MF. Data from patients aged ≥18 years with primary or secondary MF treated on or after the local first date of RUX approval until December 31 , 2021 were assessed. Patients who received treatment for MF in a clinical trial were excluded. The primary objective is to describe real-world MF treatment patterns, including patient characteristics, time from MF diagnosis to first-line (1L) therapy, choice, duration and reason for change/discontinuation of initial and subsequent treatments for MF, and treatment procedures. Secondary objectives include assessments of days hospitalized as part of HCRU. Results : As of June 1, 2023, 928 patient charts were included, met eligibility criteria, and had initial treatment information available. Most patients were male (54%) and White (65%), and the median (range) age for patients ≤89 years of age was 66 (58-73) years; the most common geographic locations were Europe (53%), Latin America (23%), and North America (13%). Of patients, 66% (614/928) had primary MF, and 10% (97/928) were transfusion-dependent. Of patients tested for high molecular risk mutations, 50% (81/162) were positive. Of patients with available bone marrow fibrosis data, 82% (554/680) had grade ≥2 bone marrow fibrosis at diagnosis. The average interval from MF diagnosis to start of initial treatment (index date) was approximately 8.5 months. RUX was the most commonly used 1L therapy (47%; 437/928) followed by hydroxyurea (41%; 380/928). RUX was also the most common therapy used in second-line (2L), third-line, fourth-line, and fifth-line treatment for 62% (217/353), 63% (107/171), 66% (56/85), and 59% (24/41) of patients, respectively. Mean (SD) time from index date to procedural intervention was 556 (519) days; the most common procedure was stem cell transplant (n = 71) followed by splenectomy (n = 20). Of the 927 patients who received 1L therapy, 98% remained on 1L therapy through Week 24, and 66% did not initiate 2L therapy until Week 156. Median (95% CI) duration of 1L therapy was 48 (45-52) months (Figure). Median (95% CI) survival from the start of 1L therapy was 79 (71-NR) months. The estimated survival rate (95% CI) was 76% (73-79) at Week 156. Median (95% CI) overall survival was 120 (93-147) months. Median (Q1-Q3) total number of days hospitalized after the index date was 2 (0-19), and median (Q1, Q3) total number of days in the intensive care unit after the index date was 0 (0, 0). Analyses will be updated for presentation. Conclusions : In patients with MF, RUX was the most commonly used agent in all lines of therapy. The greatest reduction in duration of MF treatment occurred from 1L to 2L. Most patients remained on 1L therapy through Week 24 and did not initiate 2L therapy until Week 156. Median survival time from start of 1L therapy to death was 79 months (approximately 6 years). There was a high degree of advanced bone marrow fibrosis as well as transfusion dependence among this real-world patient population. Together, these results highlight the importance of optimizing 1L therapy.

Trends in overall mortality among US veterans with primary myelofibrosis

BackgroundPrimary myelofibrosis [PMF] is a myeloproliferative neoplasm associated with reduced overall survival (OS). Management strategies for PMF have evolved over the last two decades, including approval of ruxolitinib as the first Janus kinase 1 (JAK1)/JAK2 inhibitor for patients with intermediate or high-risk myelofibrosis. This study assessed changes in mortality before and after ruxolitinib approval, independent of ruxolitinib treatment.MethodsThis retrospective study investigated mortality trends among US veterans with PMF in 2 time periods, pre-ruxolitinib approval (01/01/2007–12/31/2010) and post-ruxolitinib approval (01/01/2015–09/30/2018). Deidentified patient-level data were extracted from US Veterans Health Administration (VHA) databases using PMF diagnosis codes; index was the first PMF diagnosis date. The analysis included adults with ≥2 PMF claims during the analysis periods who were continuously enrolled in the VHA plan 1 calendar year prior to and 6 months post-index and had ≥1 available International Prognostic Scoring System (IPSS) risk factor (available factors were age > 65, hemoglobin < 10 g/dL, and white blood cell count > 25 × 109/L; each counted as one point). Patients with ≥1 MF diagnosis for 12 months before the index period were excluded. Ruxolitinib treatment was not a requirement to be included in the post-ruxolitinib approval cohort. Mortality rates and OS were estimated using the Kaplan-Meier approach; all-cause mortality hazard ratio was estimated using univariate Cox regression.ResultsThe pre- and post-ruxolitinib approval cohorts included 193 and 974 patients, respectively, of which 80 and 197 had ≥2 IPSS risk factors. Ruxolitinib use in the post-ruxolitinib cohort was 8.5% (83/974). At end of follow-up, median (95% CI) OS was significantly shorter in the pre-ruxolitinib cohort (1.7 [1.2–2.6] years vs not reached [3.4–not reached]; P < 0.001). Overall mortality rates for the pre- versus post-ruxolitinib approval cohorts were 79.8% versus 47.3%, respectively, and overall risk of death was 53% lower in the post-ruxolitinib period (hazard ratio, 0.47; 95% CI, 0.37–0.58; P < 0.001). Mortality rates were lower among patients with < 2 vs ≥2 IPSS risk factors.ConclusionsAlthough veterans with PMF have high overall mortality rates, and results in this population might not be generalizable to the overall population, there was a significant lowering of mortality rate in the post-ruxolitinib period.

Comprehensive Profiling of Clinical JAK2 Inhibitors in Myeloproliferative Neoplasms

Since the approval of ruxolitinib (JAK1/JAK2) in 2011, two additional inhibitors, fedratinib (JAK2/FLT3) and pacritinib (JAK2/FLT3/IRAK1/CSF1R), have received FDA approval for myelofibrosis, and a new drug application for a fourth inhibitor, momelotinib (JAK1/JAK2/ACVR1/TBK1) has been submitted in June 2022. Although all four inhibitors potently suppress JAK2, the targeting of additional auxiliary targets may contribute to distinct responses observed in the clinic. Here, we take a comprehensive approach to assess the unique proliferative, transcriptional, and signaling pathways altered by these four JAK2 inhibitors in myeloproliferative neoplasms (MPN). In three human JAK2 mutant leukemic cell lines (HEL, UKE-1, SET2) and murine Ba/F3 EpoR-JAK2VF cells, ruxolitinib consistently showed the lowest IC50. Following, CD34+ hematopoietic stem/progenitor cells (HSPCs) from 8 MPN patients and 3 healthy donors were seeded for colony formation assays. Erythroid colonies were highly sensitive to ruxolitinib, fedratinib, and pacritinib inhibition. In contrast, momelotinib demonstrated greater relative sparing of erythroid colonies, consistent with clinical anemia amelioration, albeit potentially via a ACVR1/ALK2 and hepcidin-independent manner. Overall, greatest potency was demonstrated by pacritinib ex vivo, followed by ruxolitinib, fedratinib, and momelotinib. These findings were somewhat distinct from in vitro assays, likely reflecting additional underlying biology of human HSPCs. We then performed high dimensional mass cytometry to assess signaling changes at single cell resolution across different cell populations in 9 MPN patient samples and 3 healthy donors treated ex vivo with JAK inhibitors. We observed potent suppression of pSTAT1, pSTAT3, and pSTAT5 in CD34+ cells, with the 4 JAK2 inhibitors exerting similar degrees of inhibition. In B cells, pacritinib suppressed IκBα, pERK, and pCREB levels, while momelotinib inhibited pTBK1. Similar observations were noted in T cells, which in addition exhibited suppression of pSTAT1 and pSTAT3. These findings indicate distinct suppression responses across specific cell types and further highlight nuances beyond sole suppression of JAK-STAT signaling by these inhibitors. RNA-sequencing of HEL cells treated with the 4 JAK2 inhibitors also identified unique alteration of expression profiles and pathways (Fig. A). Differential gene expression (DEG) analysis revealed pacritinib inducing the greatest transcriptional alterations after 4 hours (3,121 genes) and ruxolitinib (1,969 genes) following 48 hours treatment duration. Only 82 and 103 DEGs relative to control were shared across the 4 JAK2 inhibitor treatment at 4 and 48 hours, respectively. Additional pathway analysis revealed at least 3 out of 4 inhibitors demonstrating capacity to suppress 1) JAK-STAT signaling, 2) inflammatory response, and 3) TNF signaling via NFκB pathways. Upregulation of multiple metabolic pathways was observed such as oxidative phosphorylation by momelotinib and pacritinib, potentially reflecting adaptive transcriptional feedback, as Seahorse Mito Stress assays revealed strongest suppression of oxygen consumption rate of PBMCs mediated by pacritinib and fedratinib. Lastly, we compared the in vivo potency of JAK2 inhibitors using patient-derived xenograft (PDX) models (Fig. B). Engrafted immunodeficient NSGS mice were treated with JAK2 inhibitors for 4 weeks across 2 sets of PDX experiments with CD34+ cells from unique JAK2 and CALR mutant donors. Pacritinib demonstrated greatest potency in reduction of peripheral blood and bone marrow human CD45+ leukemic cells, followed by ruxolitinib, and fedratinib/momelotinib. Vehicle treated mice were moribund by week 3 of treatment and survival was significantly prolonged with all JAK2 inhibitor treatments, with all animals surviving in the pacritinib treatment group after 4 weeks of treatment at end point. Despite all four JAK2 inhibitors demonstrating affinity in suppressing JAK-STAT signaling, our assays reveal varying degrees of alteration of transcriptional, proteomic, and metabolic profiles. In conjunction with comparative assessment of in vivo activity in PDX models, these findings provide insights with potential relevance to distinct responses observed with these inhibitors in the clinic and may help guide the use of specific JAK2 inhibitors in combination studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Leukemic Transformation of Myeloproliferative Neoplasms in the Post-Ruxolitinib Era: Analysis of 103 Consecutive Cases Diagnosed 2011-2021

Background: JAK2 inhibitors (JAK2i) are now part of the expanding therapeutic armamentarium for myeloproliferative neoplasms (MPNs), specifically for myelofibrosis (MF) and polycythemia vera (PV). In this regard, ruxolitinib has paved the way with its FDA approval in 2011. There is general agreement on the efficacy of JAK2i in controlling splenomegaly and constitutional symptoms whereas there is limited evidence for value in modifying disease natural history, including impact on progression into acute myeloid leukemia (AML), also referred to as blast phase (BP) MPN. We have previously published our pre-ruxolitinib era experience with MPN-BP and underscored its dismal prognosis with median survival of 3.6 months and 3-year survival rate of only 1%, in the absence of treatment response and consolidation with allogeneic hematopoietic stem cell transplant (AHSCT) (Tefferi et al.Leukemia 32:1200, 2018). In the current study, we describe our more recent experience, subsequent to the FDA approval of ruxolitinib. Methods: The current study was conducted under an institutional review board approved minimum risk protocol that allowed retrospective collection and analysis of data from patients with BP-MPN who were seen at the Mayo Clinic, Rochester, MN, USA between 12/16/2011 and 5/27/2021. Diagnoses of specific MPN variants and post-MPN AML was according to the 2016 WHO criteria (Arber et al. Blood2016;127:2391) Estimates for chemotherapy-induced complete remission (CR), CR with incomplete blood count recovery (CRi), and morphologic leukemia-free state (MLFS) rates were according to conventional criteria (Dohner et al. Blood 2017;129:424). Clinical and laboratory data, including cytogenetic and molecular information, were collected from patients at the time of leukemic transformation. Conventional statistical methods were applied using JMP Pro 16.0.0 software (SAS Institute, Cary, NC, USA). Results: Among 103 study patients (median age 70 years, range 37-89; 52% males), MPN variant prior to AML transformation was primary MF (PMF) in 35% and post-PV/ET MF in 65%. Karyotype was available in 97 patients and revealed monosomal karyotype or monosomy 7 in 35 (36%), complex karyotype, non-monosomal in 18 (19%), normal karyotype in 17 (18%) and other abnormalities in 27 (28%). Driver mutation distribution ("n” evaluable = 83) was JAK2 67%, CALR 7%, MPL 6% and triple-negative 1%. Median time from MPN diagnosis to leukemic transformation was 7.5 years. Thirty-two (31%) patients had received ruxolitinib and/or other JAK2i ± other cytoreductive drugs, 60 (58%) had received cytoreductive drugs (often hydroxyurea) but not JAK2i, and 11 (10%) had received neither JAK2i or other cytoreductive drugs, prior to leukemic transformation; patients with MPN-BP, developing in the context of the three treatment groups, were similar in their phenotype, karyotype and mutation distribution (Table to be shown at meeting). First-line MPN-BP therapy included intensive chemotherapy (n=35), hypomethylating agents (HMA) with (n=12) or without (n=21) venetoclax, imetelestat (n=6) or supportive care in the remaining. AHSCT was documented in 11 patients. 71 patients were evaluable for response and included 11 (15%) with CR/CRi and 7 (10%) with MLFS. At the time of this writing, 96 (93%) deaths were documented. Among the 7 patients censored alive, 5 had received AHSCT, 4 of whom had persistent bone marrow blasts (8-16%) at time of transplant. There was no significant difference (p=0.09) in survival, based on pre-AML exposure to JAKi ± other cytoreductive drugs vs cytoreductive drugs not including JAKi vs neither JAKi or other cytoreductive drugs (Figure 1); the corresponding median survivals (3-year survival rates) were 3.6 months (3%), 5.3 months (5%), and 9 months (21%). By contrast, there was a favorable impact (p<0.01) from AHSCT with median survival (3-year survival rate of 28 months (36%) vs 4 months (3%) without transplant (Figure 1). In multivariable analysis, absence of AHSCT (p<0.01), older age (p=0.03) and thrombocytopenia (p<0.01) were associated with inferior survival. Conclusions: Pre-AML exposure to ruxolitinib or other JAKi might not modify the phenotype, mutational landscape or the dismal prognosis associated with MPN-BP. AHSCT was able to secure long-term survival in some patients with MPN-BP and should thus be aggressively pursued, even in the absence of CR/CRi/MLFS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Management of Myelofibrosis during Treatment with Ruxolitinib: A Real-World Perspective in Case of Resistance and/or Intolerance.

The development and approval of ruxolitinib, the first JAK1/2 inhibitor indicated to treat myelofibrosis, has improved patient outcomes, with higher spleen and symptoms responses, improved quality of life, and overall survival. Despite this, several unmet needs remain, including the absence of resistance criteria, suboptimal response, the timing of allogeneic transplant, and the management of patients in case of intolerance. Here, we report the results of the second survey led by the “MPN Lab” collaboration, which aimed to report physicians’ perspectives on these topics. As in our first survey, physicians were selected throughout Italy, and we included those with extensive experience in treating myeloproliferative neoplasms and those with less experience representing clinical practice in the real world. The results presented here, summarized using descriptive analyses, highlight the need for a clear definition of response to ruxolitinib as well as recommendations to guide the management of ruxolitinib under specific conditions including anemia, thrombocytopenia, infections, and non-melanoma skin cancers.

Risk of mortality and second malignancies in primary myelofibrosis before and after ruxolitinib approval

BackgroundPrimary myelofibrosis (PMF) is associated with morbidity and mortality. Ruxolitinib gained US FDA approval for treatment of intermediate/high-risk PMF in November 2011. We evaluated differences in survival and second primary malignancy (SPM) incidence among US PMF patients in the years before and after ruxolitinib approval. MethodsWe conducted a retrospective study utilizing the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER)-18 database for PMF patients. We divided patients into five-year cohorts pre- (2007−2011) and post-ruxolitinib (2012−2016) approval and compared relative survival rates (RSRs) to the standard population and standardized incidence rates (SIRs) of SPMs between cohorts. ResultsWe included 2020 patients diagnosed with PMF from 2007−2016 in this study. There was no difference in the four-year RSRs between cohorts (54 % vs. 57 %, p = 0.776). More patients developed SPMs in the post-ruxolitinib cohort (8% vs. 6%, p = 0.041). The majority of SPMs were hematologic with higher incidence of AML transformation in the post-ruxolitinib cohort (SIR 125.29 vs. 70.55). ConclusionsPMF prognosis remains poor in the years following ruxolitinib’s approval. SPM incidence including AML transformation is higher in the years after approval. Further studies are needed to determine the true impact of ruxolitnib on population outcomes.

Real-world survival of US patients with intermediate- to high-risk myelofibrosis: impact of ruxolitinib approval

The Janus kinase inhibitor ruxolitinib is approved for the treatment of myelofibrosis (MF) and improved overall survival (OS) versus control therapy in the phase 3 COMFORT trials. The aim of this retrospective analysis was to examine the real-world impact of ruxolitinib on OS in patients with MF. The US Medicare Fee-for-Service claims database (parts A/B/D) was used to identify patients with ≥ 1 inpatient or ≥ 2 outpatient claims with an MF diagnosis (January 2010–December 2017). Eligible patients with MF were ≥ 65 years old (intermediate-1 or higher risk based on age). Patients were divided into 3 groups based on ruxolitinib approval status at diagnosis and ruxolitinib exposure: (1) preapproval, ruxolitinib-unexposed; (2) post-approval, ruxolitinib-unexposed; and (3) post-approval, ruxolitinib-exposed. In total, 1677 patients with MF were included (preapproval [all ruxolitinib-unexposed], n = 278; post-approval, n = 1399 [ruxolitinib-unexposed, n = 1127; ruxolitinib-exposed, n = 272]). Overall, median age was 78 years, and 39.8% were male. Among patients with valid death dates (preapproval, n = 119 [42.8%]; post-approval, ruxolitinib-unexposed, n = 382 [33.9%]; post-approval ruxolitinib-exposed, n = 54 [19.9%]), 1-year survival rates were 55.6%, 72.5%, and 82.3%, and median OS was 13.2 months, 44.4 months, and not reached, respectively. Risk of mortality was significantly lower post- versus preapproval regardless of exposure to ruxolitinib (ruxolitinib-unexposed: adjusted hazard ratio [HR], 0.67; ruxolitinib-exposed: adjusted HR, 0.36; P < 0.001 for both); post-approval, mortality risk was significantly lower in ruxolitinib-exposed versus ruxolitinib-unexposed patients (adjusted HR, 0.61; P = 0.002). Findings from this study complement clinical data of ruxolitinib in MF by demonstrating a survival benefit in a real-world setting.

Patterns of Care for Older Patients With Myelofibrosis: A Population-based Study

BackgroundCurrent treatments for myelofibrosis (MF) are largely palliative, with the JAK inhibitor ruxolitinib being the breakthrough approved for higher-risk patients by the United States Food and Drug Administration in November 2011. There are limited data on the “real-world” clinical experiences among patients with MF who are treated in the JAK inhibitor era. Patients and MethodsWe evaluated patterns of care for older patients with MF before and after ruxolitinib approval, using the Surveillance, Epidemiology, and End Results-Medicare database. Treatment patterns were assessed using Medicare part B and D claims. ResultsThis study included 528 patients diagnosed during 2007 to 2015, with a median age at diagnosis of 76 years. Among 298 patients diagnosed in the ruxolitinib era (2012-2015), 113 (37.9%) were ruxolitinib users. Similar numbers of users started ruxolitinib at 5, 10, 15, or 20 milligrams twice a day (BID). Among 31 patients starting at 5 milligrams BID or less, 48.4% were unable to escalate the dose, and < 11 users could increase the dose to the maximum 25 mg BID. Approximately one-half of ruxolitinib users took hydroxyurea and/or prednisone simultaneously with ruxolitinib. The median time on ruxolitinib was 11.9 months (interquartile range, 4.2-21.7 months). ConclusionIt would be important to optimize the use of ruxolitinib and develop new drugs that may be administered together with or after ruxolitinib to accomplish better outcomes in older patients with MF.

Risk of Mortality and Leukemic Transformation in Primary Myelofibrosis before and after Ruxolitinib Approval

Background: Primary myelofibrosis (PMF) has the worst prognosis of the classical BCR-ABL1 negative myeloproliferative neoplasms, with a median overall survival of six years. Factors affecting survival include age, symptom burden, cytopenias, mutation profile, and development of second malignancies including transformation to acute myeloid leukemia (AML). Ruxolitinib, a selective JAK1 and JAK2 inhibitor, was granted approval by the United States (US) Food and Drug Administration for treatment of intermediate and high-risk PMF in November 2011 based on reduction in spleen volume and demonstration of symptom improvement. The impact of ruxolitinib on PMF survival is unknown. In this study, we aimed to evaluate whether there has been a change in survival and patterns of second primary malignancies (SPMs) including AML transformation among PMF population in US after ruxolitinib approval. Methods: Using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)-18 survival and Multiple Primary Standardized Incidence Ratio (MP-SIR) registries, we conducted a retrospective study with patients diagnosed with PMF between the years of 2007 and 2016. We divided these patients into two five-year cohorts, pre-ruxolitinib approval (2007-2011) and post-ruxolitinib approval (2012-2016), and compared relative survival rates (RSRs) and standardized incidence ratios (SIRs) of SPMs between the cohorts. SIRs were calculated as the ratio of observed to expected malignancy cases over the specified time periods. Median follow-up duration was five years for each cohort. RSRs and SIRs were compared between cohorts using two-proportion Z-tests. Results: We included 2164 patients diagnosed with PMF between 2007 and 2016 with data available in the SEER-18 survival and MP-SIR registries. Of these, 1051 (49%) patients were included in the pre-ruxolitinib cohort and 1113 (51%) patients were included in the post-ruxolitinib cohort. There was no significant difference in the four-year RSRs between the pre-ruxolitinib and post-ruxolitinib cohorts (55% vs. 56%, p = 0.719). A higher proportion of SPMs occurred in the post-ruxolitinib cohort when compared with the pre-ruxolitinib cohort (60% vs. 40%, p &amp;lt; 0.001). Hematologic malignancies comprised a majority of all SPMs (AML 39% and non-Hodgkin lymphoma 16%). A higher incidence of AML transformation occurred in the post-ruxolitinib cohort when compared with the pre-ruxolitinib cohort (SIR 121.48 vs. 72.22, p = 0.037). Non-hematologic malignancies were also more common in the post-ruxolitinib cohort when compared with the pre-ruxolitinib cohort (SIR 1.09 vs. 0.94, p &amp;lt; 0.001). The most common non-hematologic malignancies were cancers of the respiratory tract, urinary tract, and prostate gland, though their SIRs were not significant in either cohort. Conclusions: Our study results suggest that despite improvements in prognostication and the approval of ruxolitinib, the prognosis of PMF remains poor in the US. These results may be due to low uptake of ruxolitinib in practice or a lack of benefit from the drug itself. Additionally, for reasons that are unclear, SPM incidence has increased in the five years following the approval of this drug. Further studies should be conducted to determine the cause of these findings. Figure Disclosures Shah: Dren Bio: Consultancy. Vachhani:astellas: Speakers Bureau; agios, blueprint medicines, jazz pharmaceuticals, daiichi sankyo: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Real-World Survival Among Patients with Intermediate- to High-Risk Myelofibrosis in the United States: Impact of Ruxolitinib Approval

Real-World Survival Among Patients with Intermediate- to High-Risk Myelofibrosis in the United States: Impact of Ruxolitinib Approval

Patterns of Care and Outcomes Among Older Patients with Myelofibrosis: A Population-Based Study

Background: Myelofibrosis (MF) is a Philadelphia chromosome negative myeloproliferative neoplasm associated with systemic and splenomegaly-related symptoms, cytopenias and decreased survival. Approval of ruxolitinib, an oral janus kinase (JAK)-inhibitor, for higher-risk MF patients (pts) by the Food and Drug Administration in 11/ 2011 opened a new era of targeted treatment for this disease. There are limited data on the "real-world" clinical experiences and outcomes of pts with MF treated in the JAK inhibitor era. MF became reportable to population-based cancer registries including the Surveillance, Epidemiology and End Results (SEER) program in 2001, making its investigation possible at the population level. The objective of this study was to assess the patterns of care and outcomes of older MF pts in the ruxolitinib era. Methods: Using the linked SEER-Medicare database, we identified a cohort of older pts diagnosed with MF from 2007 through 2015 who fulfilled the following eligibility criteria: 1) aged 66-99 years at diagnosis; 2) had known month of diagnosis; 3) were not identified from death certificate or autopsy only; 4) had continuous enrollment in Medicare Parts A, B and no enrollment in health maintenance organizations from 1 year before diagnosis until the end of follow-up (death or 12/31/2016, whichever came first); 5) had continuous enrollment in Medicare Part D from diagnosis until the end of follow-up; and 6) bone marrow biopsy claim from 1 year before diagnosis to end of follow up. Treatments were assessed via Medicare parts B&amp;D claims. Kaplan-Meier curves and log-rank tests were used to compare survival between patient groups. Multivariable cox proportional hazards regression models were used to assess the effect of ruxolitinib use on survival in MF pts. Aside from treatment, we considered the influence of several characteristics on survival, including age at diagnosis, sex, race/ethnicity, marital status, comorbidities, SEER region and percentage living in poverty at the census tract level. Results: Among 528 MF pts, median age at diagnosis was 76 (interquartile range [IQR], 71- 80) years with 88.8% white and 56.1% male. 230 pts were diagnosed in the early era (2007-2011), and 298 in the late era (2012-2015), of which 113 (37.9%) were ruxolitinib users. There was no difference among any evaluated characteristics between two eras and by ruxolitinib status in the late era. The median duration of ruxolitinib use was 11.9 months. Similar number of pts started at 5, 10, 15 and 20 mg twice a day (BID) (Figure 1). Among 31 pts who started at ≤5 mg BID, 15 (48.4%) never had their dose of ruxolitinib escalated. While on ruxolitinib treatment, nearly half of the pts received additional medications for symptom management including hydroxyurea (22.6%), prednisone (17.9%) or both (10.4%). &amp;lt; 11 users were able to go up to the highest dose of 25 mg BID. Ruxolitinib was interrupted &amp;gt; 30 days for 31 times by 20 of 113 (17.7%) pts with median interruption duration of 43 (IQR 34-71) days. The median survival was 2.70 (95% confidence interval [CI]: 1.87-3.41) years and 2.62 (95% CI: 2.15-3.07) for the early and late era pts, respectively (p for log-rank 0.91). The multivariable analysis showed no impact of diagnosis era on survival (late vs early era hazard ratio (HR) of 1.08, 95% CI 0.83-1.40; p= 0.57). There was no difference in survival by ruxolitinib status (log-rank test, p=0.31), with a median survival of 2.76 (95% CI: 2.01-4.15) years and 2.53 (95% CI: 1.92-3.07) years among users and non-users, respectively (Figure 3). In the multivariable analysis, the risk of death among ruxolitinib users compared to non-users was not statistically significant with HR of 0.82 (95% CI 0. 59-1.16; p= 0.26). Conclusions: Older MF pts treated with ruxolitinib had similar survival when compared to pts who did not receive this medication, but the choice of ruxolitinib might have been influenced by disease risk which we were unable to assess. For many ruxolitinib users, the drug was interrupted, the dose was not escalated, additional medications were used concurrently (possibly to help control disease manifestation), and treatment was discontinued quickly after initiation. Optimization of ruxolitinib use may be necessary to accomplish better outcomes. Furthermore, development of new drugs which may be used together with ruxolitinib or after its discontinuation is needed. The work was supported by The Frederick A. Deluca Foundation. Disclosures Wang: Celgene/BMS: Research Funding. Ma:Celgene/BMS: Research Funding; BMS: Consultancy. Podoltsev:Jazz Pharmaceuticals: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Agios Pharmaceuticals: Consultancy, Honoraria; Sunesis Pharmaceuticals: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Blueprint Medicines: Consultancy, Honoraria; Bristol-Myers Squib: Consultancy, Honoraria; Genentech: Research Funding; AI Therapeutics: Research Funding; Samus Therapeutics: Research Funding; Astellas Pharma: Research Funding; Kartos Therapeutics: Research Funding; CTI biopharma: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Novartis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Astex Pharmaceuticals: Research Funding; Daiichi Sankyo: Research Funding; Arog Pharmaceuticals: Research Funding.

Combination of Cord Blood T Regulatory Cells with Ruxolitinib Decreases Side Effects and Improves Survival in Xenogenic Graft Vs. Host Disease

Background: Recent approval of ruxolitinib (rux) for steroid refractory graft versus host disease (GvHD) has revolutionized the field and provided tremendous choice for the patients. However, the side effects including thrombocytopenia leads to dug discontinuation and intolerance. We have previously shown that adoptive therapy with cord blood (CB) derived T regulatory (Treg) cells can prevent and treat GvHD. We hypothesized that the addition of CB Treg therapy to rux based therapy can augment overall efficacy. Methods: CellTrace Violet suppression assay was performed to evaluate the suppressor function of CB Treg cells in the presence or absence of rux. Xenogenic GvHD mouse model was utilized where the NSG mice underwent sublethal irradiation on day -1 followed by injection of 1x107 donor peripheral blood (PB) mononuclear cells (MNCs) on day 0. Oral rux at 1 mg daily was fed continuously to the mice in the presence or absence of 1x107 CB Treg cells, tagged with CellTrace Violet dye, administered on days +4, +7, +11, +18. Mice were followed every other day for weight, GvHD score and survival. Serial blood draws were performed to analyze for cell compartment and cytokine assays. Results: We examine whether the addition of rux impacts the suppressor function of CB Treg cells. Varying concentration of rux including 0.01, 0.05, 0.1 and 0.5 µM were added at 24, 48 and 96 hours of the cell suppression assay. The addition of rux 0.05 µM at 48 hours of the cell suppression culture led to a restoration of poor cell function (Figure A). Lowest GVHD score was reported in the rux+CB Treg combination arms at day +14 when compared to rux alone or CB Treg alone arm which (Figure B) translated into a superior survival in the rux +CB Treg arm (Figure C). Furthermore, an increase in the hemoglobin level (Figure D) and the platelet count (Figure E) was demonstrated in the rux+CB Treg arm. Addition of rux led to longer persistence of the injected CB Treg cells on day 14 (data not shown) which correlated with the increase in the plasma level of the pro-Treg cell signaling markers including IL-7 (Figure F) and IL-15 (Figure G). A decrease in the IL-4 production supported the increased Treg cell function (Figure H). A synergistic suppression of inflammatory cytokines including IL-17 (Figure I) and IL1A (Figure J) was evident in the rux+CB Treg arm. Conclusion: The combination of CB Tregs with ruxolitinib leads to improved overall survival, decreased inflammatory cytokines and improved hematologic parameters. Such combination should be explored in a clinical setting Figure Disclosures Sadeghi: Cellenkos Inc.: Current Employment. Parmar:Cellenkos Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents &amp; Royalties, Research Funding.

JAK Inhibition for the Treatment of Myelofibrosis: Limitations and Future Perspectives.

The 2011 approval of ruxolitinib ushered in the Janus kinase (JAK) inhibitor era in the treatment of myelofibrosis (MF), and 2019 saw the US approval of fedratinib. The first therapeutic agents approved by regulatory authorities for MF, these drugs attenuate the overactive JAK-signal transducer and activator of transcription (STAT) signaling universally present in these patients, translating into major clinical benefits in terms of spleen shrinkage and symptom improvement. These, in turn, confer a survival advantage on patients with advanced disease, demonstrated in the case of ruxolitinib, for which long-term follow-up data are available. However, JAK inhibitors do not improve cytopenias in most patients, have relatively modest effects on bone marrow fibrosis and driver mutation allele burden, and clinical resistance eventually develops. Furthermore, they do not modify the risk of transformation to blast phase; indeed, their mechanism of action may be more anti-inflammatory than truly disease-modifying. This has spurred interest in rational combinations of JAK inhibitors with other agents that may improve cytopenias and drugs that could potentially modify the natural history of MF. Newer JAK inhibitors that are distinguished from ruxolitinib and fedratinib by their ability to improve anemia (eg, momelotinib) or safety and efficacy in severely thrombocytopenic patients (eg, pacritinib) are in phase 3 clinical trials. There is also interest in developing inhibitors that are highly selective for mutant JAK2, as well as “type II” JAK2 inhibitors. Overall, although current JAK inhibitors have limitations, they will likely continue to form the backbone of MF therapy for the foreseeable future.

The role of fedratinib for the treatment of patients with primary or secondary myelofibrosis.

Myelofibrosis (MF) is a chronic myeloid neoplasm characterized by either primary myelofibrosis, or secondary MF following essential thrombocythemia or polycythemia vera. Historically, therapy has been symptom directed; however, in 2011, the first janus kinase inhibitor (JAK-i) – ruxolitinib – was approved for treatment. This medication was found to be effective in reduction of symptom burden and spleen size; however, the median duration of response is about 3 years. In addition, many patients are intolerant or develop toxicities to ruxolitinib, including patients with anemia, as well as thrombocytopenia. Therefore, there is a critical need for alternate therapeutic options for patients with MF. Additional JAK-i have been developed over the last 8 years, including fedratinib, momelotinib, and pacritinib. Fedratinib recently received approval for treatment of MF both in the first-line and second-line setting. It has shown efficacy in the first-line setting, as well as in 30% of patients who are refractory/intolerant of ruxolitinib. This review covers the trials that have led to the approval of ruxolitinib as well as fedratinib, as well as reviews of two JAK inhibitors that are still under clinical investigation: momelotinib and pacritinib.

Persistence of Ruxolitinib Treatment in Patients with Myelofibrosis at Community Oncology Practices in the United States-Contemporary Data

Introduction Myelofibrosis (MF) is a chronic myeloproliferative neoplasm frequently associated with debilitating disease-related symptoms and shortened overall survival (OS). Ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, was approved on November 16, 2011 for patients with intermediate- and high-risk MF. The phase 3 COMFORT trials demonstrated that ruxolitinib reduced spleen volume, improved MF-related symptoms, and prolonged OS. In the COMFORT trials, the median duration of ruxolitinib treatment was 2.8 years (5-year pooled analysis). The objective of this real-world chart review study is to describe persistence of ruxolitinib treatment early on in the treatment course in patients with MF at community hematology/oncology practices in the United States. Methods Medical charts from community hematology/oncology practices in Cardinal Health Oncology Provider Extended Network (OPEN) were reviewed and abstracted into electronic case report forms by physicians. Physicans were instructed to abstract data from the earliest eligible patients and then chronologically, thereafter. This analysis included adult patients diagnosed with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF between 01/2012 and 12/2016. Patients were required to have intermediate- or high-risk MF (based on a data-derived International Prognostic Scoring System [IPSS] risk categorization), have platelet count &gt;50 × 109/L at the time of diagnosis, have received ruxolitinib as first-line treatment, and have ≥6 months of follow up after the initiation of ruxolitinib; patients who died within 6 months of initiation of ruxolitinib were considered as discontinued patients and were included in the analysis. Three- and 6-month persistence rates are reported. Results A total of 141 patients from 22 community hematology/oncology practices were included in the analysis; 3 patients who were still on ruxolitinib at the end of the study period, but with less than 6 months of follow up, were excluded from the analysis. Mean (SD) age at diagnosis was 69.8 (10.2) years, 61.7% were male, 71.6% had primary MF, and 56.7% were high-risk at diagnosis. Median time from diagnosis to ruxolitinib initiation was 36 (interquartile range [IQR], 20-91) days. The majority of patients initiated ruxolitinib in 2016 or later (Figure). The starting dose of ruxolitinib was 5 mg twice daily [BID] in 7.8%, 10 mg BID in 9.9%, 15 mg BID in 39.7%, 20 mg BID in 34.8%, and 25 mg BID in 7.8%. Three- and 6-month persistence rates were 97.2% and 91.5%, respectively (Table). Discussion A previous retrospective chart review of prescription claims and patient level data evaluated a cohort of patients with MF prescribed ruxolitinib just prior to and shortly after its approval (November 1, 2011 to August 31, 2012); in that study, 3- and 6-month persistence rates of 39.1% and 27.0%, respectively, were reported (Blood. 2013[122]:2833). In the current study, the 3- and 6-month persistence rates were notably higher at 97.2% and 91.5%, respectively. These higher rates are likely attributable to a number of factors. The current analysis was limited to patients treated first-line with ruxolitinib. Furthermore, the index period in the current analysis extended almost 5 years beyond ruxolitinib approval; in this 5-year period, there were a number of publications in support of ruxolitinib dose optimization with particular focus on the first 8-12 weeks of treatment (J Hematol Oncol. 2013[6]:79; Int J Hematol. 2016[104]4:420-9). The 3- and 6-month persistence rates reported here demonstrate that only a small proportion of patients with myelofibrosis treated with first-line ruxolitinib discontinued the drug early on in their treatment course. Conclusion This contemporary analysis demonstrates high rates of 3- and 6-month persistence of first-line ruxolitinib in patients with MF treated in community practices. Proper monitoring and management of the expected mechanism-based toxicity of a JAK inhibitor and proper dose titration for insufficient response, early in the treatment course, may help patients derive maximum, long-term benefits from ruxolitinib. Disclosures Yu: Incyte: Employment, Equity Ownership. Kish:Cardinal Health: Employment. Paranagama:Incyte: Employment, Equity Ownership. Colucci:Incyte: Employment, Equity Ownership.

Allogeneic stem-cell transplantation for myelofibrosis.

Allogeneic hematopoietic stem-cell transplantation (HSCT) remains the only curative therapy for myelofibrosis. The number of HSCTs performed for this indication has been steadily increasing over the past years, even after the approval of the Janus kinase (JAK) inhibitor, ruxolitinib. This increase may be attributed to improved patient selection based on new prognostic molecular markers, more frequent use of matched unrelated donors, secondary to better (high-resolution) human leukocyte antigen typing and supportive care. Ruxolitinib approval raises new questions regarding the role of JAK inhibitors in the transplant setting. The current review summarizes recent updates on HSCT in myelofibrosis. Predictors for transplant outcomes, and specific considerations related to myelofibrosis patient selection for HSCT (e.g. molecular risk stratification) are reviewed. In addition, this review will consider management of myelofibrosis patients in the peritransplant period, including the role of ruxolitinib in the pretransplant period, pre and posttransplant splenomegaly, transplant protocols, posttransplant follow-up of minimal residual disease and interventions in the event of poor engraftment. HSCT remains a highly relevant treatment option for myelofibrosis in the era of JAK inhibitors. Recent advances may contribute to a refined definition of HSCT eligibility and identification of the optimal transplantation time, conditioning protocols and posttransplant management.

The Treatment Landscape of Myelofibrosis Before and After Ruxolitinib Approval.

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm that presents with a heterogeneous clinical phenotype and prognosis. Before the US Food and Drug Administration approval of ruxolitinib, treatment options were varied and had limited effect. The increased use of ruxolitinib has drastically altered the MF treatment landscape. In this study, we aimed to clarify the clinical situations in which ruxolitinib is being used and analyze its effect on this landscape. We retrospectively assessed treatment choices for MF patients treated at our institution (n= 309). This population was divided into 2 cohorts on the basis of a diagnosis before (cohort BR: n= 174) or after (cohort AR: n= 135) ruxolitinib approval. Cohorts were further stratified for comparison according to presenting clinical factors. Expectedly, the first-line use of ruxolitinib markedly increased after its approval. AR patients were less likely to receive erythropoiesis-stimulating agents (ESAs; P= .0003) and thalidomide (P= .003) than BR patients. In patients with MF-related symptoms and/or splenomegaly, increased use of ruxolitinib was associated with decreased use of first-line ESA (P= .03) or thalidomide (P= .03). In anemic patients, increased use of first-line ruxolitinib was associated with a decreased use of thalidomide (P= .007). In patients with severe leukocytosis, ruxolitinib use did not significantly increase and hydroxyurea was the preferred first-line agent. Overall, the increased use of ruxolitinib appears to have come predominantly at the expense of thalidomide and ESAs, while not having a large effect on the first-line use of hydroxyurea.

Comparing Eras: Assessing Treatment Trends before and after Ruxolitinib Approval

Background: Ruxolitinib is a JAK1/2 inhibitor that gained FDA approval for treatment of intermediate and high-risk myelofibrosis (MF) in 2011. Prior to ruxolitinib, a variety of treatments were used for myelofibrosis, with variable efficacy. Even in the ruxolitinib era, treatment decisions are primarily focused on symptom management, as no treatment, other than allogeneic hematopoietic stem-cell transplant (allo-HSCT) has shown to have a strong disease-modifying effect. Ruxolitinib significantly improves splenomegaly and constitutional symptoms associated with MF. Here, we aim to compare MF treatments before and after ruxolitinib approval to assess treatment patterns and impact on clinical outcomes. We hypothesized that an increased use of ruxolitinib after its FDA-approval would affect those with constitutional symptoms and/or splenomegaly and correlate with decreased use of other treatments aimed at these symptoms.Methods: This was a single institution, retrospective study of all patients with a diagnosis of MF who were seen at our center between 2/2001 and 6/2016. The World Health Organization 2016 definition of primary myelofibrosis (PMF) was used for confirmation of diagnosis. Initial treatment was defined as first treatment after diagnosis of MF. Specific phenotypes were assigned retrospectively based on chart review reflecting the patient's initial complaints which led to diagnosis.Results: We identified 312 eligible patients. This group was divided into two cohorts: those diagnosed prior to the ruxolitinib era (cohort PRE, n = 177) and those diagnosed in the ruxolitinib era (cohort POST, n = 135). Demographics (gender, race, age at diagnosis) and presenting features were comparable between the cohorts. In the PRE cohort, JAK2 inhibitor use occurred in the setting of a clinical trial as well as in patients who were diagnosed prior to ruxolitinib approval, but first received treatment after its approval. In this cohort, 25% of patients received a JAK2 inhibitor, with 36% of these patients receiving it as frontline therapy (see figure 1). This compared to 44% of POST patients who received a JAK-2 inhibitor, with 69% receiving it in the frontline setting. POST patients were, more likely to receive ruxolitinib overall (OR 2.28, p = 0.001) and as first-line therapy (OR 4.49, p < 0.0001). POST patients were less likely to receive an erythropoiesis-stimulating agent (ESA) overall (OR 0.40, p = 0.0003) and as first line therapy (OR 0.51, p = 0.02). Thalidomide was also less commonly used in the POST patients (OR 0.34, P = 0.003). The use of hydroxyurea was similar between cohorts.When stratified based on the presence of constitutional symptoms (CS) and/or splenomegaly (S), patients most commonly received an ESA, JAK-2 inhibitor, or hydroxyurea as frontline therapy (see figure 2). When both CS and S were present, patients more commonly received the latter two options. Patients presenting with CS and S were more likely to receive ruxolitinib as first line therapy in the POST cohort compared to the PRE (OR 5.5, p = 0.0004); however, the use of first line hydroxyurea was not significantly different between the PRE and POST cohorts (p = 0.28). In all, ten separate frontline treatments were used in the symptomatic PRE cohort while only five were utilized in POST patients.In patients presenting without constitutional symptoms or splenomegaly, there was no difference in initial treatment strategy in the PRE and POST cohorts, and ruxolitinib was rarely utilized in this patient population.No difference in overall survival (OS) was noted between the two cohorts.Conclusion:After FDA-approval, ruxolitinib has emerged as the most common first-line treatment option for MF, specifically in patients with constitutional symptoms and splenomegaly, with decreased up-front use of thalidomide, ESAs and hydroxyurea. Patients presenting without constitutional symptoms or splenomegaly were no more likely to received ruxolitinib in the post-approval era, indicating a preference for alternative treatment options in this group. Longer follow up is needed to assess survival impact of frontline ruxolitinib use in our patient population. [Display omitted] [Display omitted] DisclosuresSweet:Karyopharm: Honoraria, Research Funding; Ariad: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Incyte Corporation: Research Funding. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.