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Purpose Patients with advanced pancreatic adenocarcinoma have a poor prognosis and limited second-line treatment options. Evidence suggests a role for the Janus kinase (JAK)/signal transducer and activator of transcription pathway in the pathogenesis and clinical course of pancreatic cancer. Patients and Methods In this double-blind, phase II study, patients with metastatic pancreatic cancer who had experienced treatment failure with gemcitabine were randomly assigned 1:1 to the JAK1/JAK2 inhibitor ruxolitinib (15 mg twice daily) plus capecitabine (1,000 mg/m2 twice daily) or placebo plus capecitabine. The primary end point was overall survival (OS); secondary end points included progression-free survival, clinical benefit response, objective response rate, and safety. Prespecified subgroup analyses evaluated treatment heterogeneity and efficacy in patients with evidence of inflammation. Results In the intent-to-treat population (ruxolitinib, n = 64; placebo, n = 63), the hazard ratio was 0.79 (95% CI, 0.53 to 1.18; P = .25) for OS and was 0.75 (95% CI, 0.52 to 1.10; P = .14) for progression-free survival. In a prespecified subgroup analysis of patients with inflammation, defined by serum C-reactive protein levels greater than the study population median (ie, 13 mg/L), OS was significantly greater with ruxolitinib than with placebo (hazard ratio, 0.47; 95% CI, 0.26 to 0.85; P = .011). Prolonged survival in this subgroup was supported by post hoc analyses of OS that categorized patients by the modified Glasgow Prognostic Score, a systemic inflammation–based prognostic system. Grade 3 or greater adverse events were observed with similar frequency in the ruxolitinib (74.6%) and placebo (81.7%) groups. Grade 3 or greater anemia was more frequent with ruxolitinib (15.3%; placebo, 1.7%). Conclusion Ruxolitinib plus capecitabine was generally well tolerated and may improve survival in patients with metastatic pancreatic cancer and evidence of systemic inflammation.

Patients with myelofibrosis (MF) have significant debilitating symptoms, physical disabilities, and poor health-related quality of life (HRQoL). Here, we report post-hoc analyses of the impact of ruxolitinib, a potent and selective JAK1 and JAK2 inhibitor, on disease-related symptoms and HRQoL in MF patients from the large phase 3 COMFORT-II study (N = 219). During the follow-up period of 48 weeks, HRQoL and MF-associated symptoms improved from baseline for ruxolitinib-treated patients but remained the same or worsened for best available therapy (BAT)-treated patients. Based on the European Organization for Research and Treatment of Cancer QoL Questionnaire core 30 items (EORTC QLQ-C30), treatment-induced differences in physical and role functioning, fatigue, and appetite loss significantly favoured ruxolitinib versus BAT from week 8 (P < 0·05) up to week 48 (P < 0·05). Ruxolitinib resulted in significantly higher response rates in global health status/QoL and Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) summary scores versus BAT at most time points (P < 0·05). Significant improvements in the Lymphoma subscale (including symptoms of pain, fever, itching, fatigue, weight loss, loss of appetite, and other patient concerns), FACT-General, FACT-Lym trial outcome index, and FACT-Lym total were also observed with ruxolitinib versus BAT starting at week 8 and continuing thereafter. Overall, these data demonstrated that ruxolitinib improved HRQoL in MF patients and further support the use of ruxolitinib for the treatment of symptomatic MF.

Combined Janus kinase 1 (JAK1) and JAK2 inhibition therapy effectively reduces splenomegaly and symptom burden related to myelofibrosis but is associated with dose-dependent anemia and thrombocytopenia. In this open-label phase II study, we evaluated the efficacy and safety of three dose levels of INCB039110, a potent and selective oral JAK1 inhibitor, in patients with intermediate- or high-risk myelofibrosis and a platelet count ≥50×109/L. Of 10, 45, and 32 patients enrolled in the 100 mg twice-daily, 200 mg twice-daily, and 600 mg once-daily cohorts, respectively, 50.0%, 64.4%, and 68.8% completed week 24. A ≥50% reduction in total symptom score was achieved by 35.7% and 28.6% of patients in the 200 mg twice-daily cohort and 32.3% and 35.5% in the 600 mg once-daily cohort at week 12 (primary end point) and 24, respectively. By contrast, two patients (20%) in the 100 mg twice-daily cohort had ≥50% total symptom score reduction at weeks 12 and 24. For the 200 mg twice-daily and 600 mg once-daily cohorts, the median spleen volume reductions at week 12 were 14.2% and 17.4%, respectively. Furthermore, 21/39 (53.8%) patients who required red blood cell transfusions during the 12 weeks preceding treatment initiation achieved a ≥50% reduction in the number of red blood cell units transfused during study weeks 1-24. Only one patient discontinued for grade 3 thrombocytopenia. Non-hematologic adverse events were largely grade 1 or 2; the most common was fatigue. Treatment with INCB039110 resulted in clinically meaningful symptom relief, modest spleen volume reduction, and limited myelosuppression.

British journal of haematology 176(1), 76-85 (2017). doi:10.1111/bjh.14382, Published by Wiley-Blackwell, Oxford [u.a.]

Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype occurring in 15-30% of older children and adolescents/young adults (AYAs) with B-ALL. Ph-like ALL is associated with high relapse rates and poor survival despite intensive multi-agent cytotoxic chemotherapy. Development of successful treatment strategies to decrease relapse and improve cure rates in patients with Ph-like ALL remains a major therapeutic gap. Rearrangements of cytokine receptor-like factor 2 (CRLF2-R) with frequent concomitant JAK2 point mutations occur in 50% of Ph-like ALL cases and induce constitutive JAK/STAT and other kinase signaling. An additional 15-20% of Ph-like ALL harbors other JAK pathway alterations, such as JAK2 or EPOR rearrangements, that similarly activate JAK/STAT signaling. Ruxolitinib is a potent, selective JAK1/JAK2 inhibitor with demonstrated activity in preclinical Ph-like ALL models and clinical safety as monotherapy in children with relapsed/refractory cancers. We report the initial safety of ruxolitinib in combination with post-induction chemotherapy in children and AYAs with newly-diagnosed high-risk (HR) Ph-like ALL with CRLF2-R or other JAK pathway alterations treated on the non-randomized, 2-part phase 2 study INCB18424-269 (AALL1521; NCT02723994). Methods: Patients aged 1-21 years at time of diagnosis with HR B-ALL and eligible Ph-like genetic lesions who had completed 4-drug induction chemotherapy as per the Children's Oncology Group (COG) AALL1131 study (NCT02883049) were eligible to participate. Patients were stratified into 4 cohorts by genetic alterations and end-induction flow cytometric minimal residual disease (MRD) status: cohort A = CRLF2-R JAK-mutant, MRD+; B = CRLF2-R JAK-wild-type, MRD+; C = other JAK pathway alterations, MRD+, D = any CRLF2-R or JAK pathway alteration, MRD-. Patients commenced treatment on the INCB18424-269/AALL1521 study at consolidation with ruxolitinib orally twice daily in combination with augmented Berlin-Frankfurt-Münster (aBFM) post-induction chemotherapy as per AALL1131. Five discontinuous dose levels (10-50 mg/m2/dose 14-days-on/14-days-off per cycle [DL-2 to DL2]) and one continuous DL1b (40 mg/m2/dose × 28 days per cycle) of ruxolitinib with aBFM chemotherapy were explored via a standard rolling 6 design. Dose-limiting toxicities (DLTs) were assessed through Day 29 of delayed intensification (DI) and defined as hematologic and non-hematologic toxicity with higher grade or more prolonged duration than observed in children with treated with identical chemotherapy (without ruxolitinib) on other COG HR B-ALL trials. Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted using serial blood samples obtained from patients during consolidation therapy. Results: Forty patients (pts) were enrolled in Part 1 (cohort A, n=10; B, n=9; C, n=5; D, n=16). Four patients discontinued study treatment before the Day 29 DI timepoint, 3 of whom were replaced. Patients had a median age of 14 years, and 67.5% were male. Treatment-emergent adverse events occurred in all patients and included anemia (75%), platelet count decrease and/or thrombocytopenia (65%), febrile neutropenia (72.5%), and AST or ALT increase (57.5%). Thirty-three patients had Grade 3/4 events deemed possibly related to ruxolitinib without identified DLTs. Eleven patients in Part 1 (27.5%) discontinued study therapy for various reasons: CNS relapse (2 pts), end-consolidation MRD+ (4 pts), multi-system organ dysfunction (MSOD; 2 pts), elective MRD- stem cell transplantation (1 pt), psychosocial/compliance issues (2 pts). One patient died of septic shock and MSOD not attributed to ruxolitinib. Preliminary analysis of plasma drug levels at 4 hours post-dose was consistent with the known PK profile of ruxolitinib. PD studies demonstrated dose-dependent inhibition of target phosphoproteins and, importantly, sustained inhibition of phosphorylated STAT5 with continuous ruxolitinib dosing at DL1b. Discussion: These findings demonstrate safety and tolerability of ruxolitinib in combination with intensive multi-agent chemotherapy in children and AYAs with newly-diagnosed HR CRLF2-R/JAK pathway-mutant Ph-like ALL and support continued investigation of treatment efficacy in Part 2 of this trial. Disclosures Tasian: Aleta Biopharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding; Incyte Corporation: Research Funding. Assad:Incyte Corporation: Employment, Equity Ownership. Hunter:Incyte Corporation: Employment. Du:Incyte Corporation: Employment.

Xenoestrogens with endocrine disrupting activity have been associated with the dysregulation of reproductive function and promotion of malignancies in experimental animals and human populations. The high incidence of uterine leiomyomas, a benign estrogen-responsive neoplasm of the uterine myometrium, calls into question the potential influence of xenoestrogens in the pathogenesis of these tumors. An in vivo/in vitro animal model, the Eker rat, that can be used to assess the estrogen-like agonist activity of potential endocrine disruptors in the uterine myometrium is discussed. Using this model, several in vitro assays are developed that demonstrate that compounds from three major classes of xenoestrogens can mimic the effect of estrogen on leiomyoma cells and act as estrogen receptor (ER) agonists: phytoestrogens, organochlorine pesticides and pharmacologic agents. These compounds can stimulate transcription via the ER and upregulate the expression of an estrogen-responsive gene in uterine leiomyoma cells. The use of these in vitro assays has also advanced our ability to predict the agonist activity of potential therapeutic agents in the uterine myometrium. Selective estrogen receptor modulators (SERMs), while able to act as agonists in some tissues such as the bone and uterine endometrium, act as antagonists in vivo in the uterine myometrium and in our in vitro assays. This antagonist activity in the uterine myometrium suggests that SERMs may be useful in the treatment of uterine leiomyoma.

Eker rats carry a defect in the Tsc-2 tumor suppressor gene and female Eker rats develop uterine leiomyoma with a high frequency. The presentation, response to hormones and molecular alterations in these mesenchymal smooth muscle tumors, closely resembles their cognate human disease. Female rats and tumor-derived cell lines from Eker rat leiomyomas (ELT lines) have been developed as an in vivo/in vitro model system for preclinical studies to identify novel therapeutic agents for this disease and for studying disease pathogenesis. In addition to serving as a model for uterine leiomyoma, Eker rats have proven valuable for studying lymphangioleiomyomatosis, a related proliferative smooth muscle disease of women.

Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome characterized by seizures, mental retardation, autism, and tumors of the brain, kidney, heart, retina, and skin. TSC is caused by mutations in either TSC1 or TSC2, both of which are tumor suppressor genes. Hamartin, the protein product of TSC1, was found to interact with the ezrin-radixin-moesin family of cytoskeletal proteins and to activate the small GTPase Rho. To determine whether tuberin, the TSC2 product, can also activate Rho, we stably expressed full-length human tuberin in two cell types: MDCK cells and ELT3 cells. ELT3 cells lack endogenous tuberin expression. We found that expression of human tuberin in both MDCK and ELT3 cells was associated with an increase in the amount of Rho-GTP, but not in Rac1-GTP or cdc42-GTP. Tuberin expression increased cell adhesion in both cell types, and decreased chemotactic cell migration in ELT3 cells. In MDCK cells, there was a decrease in the amount of total Focal Adhesion Kinase (FAK) and an increase in the fraction of phosphorylated FAK. These findings demonstrate for the first time that tuberin activates Rho and regulates cell adhesion and migration. Pathways involving Rho activation may have relevance to the clinical manifestations of TSC, including pulmonary lymphangioleiomyomatosis.

Uterine leiomyomas develop in reproductive-age women with high frequency and are dependent on the production of ovarian hormones. While it is generally accepted that these tumors are estrogen (E(2))-responsive, the role of progesterone (P(4)) in modulating tumor growth is less clear. In the present study, an in vivo/in vitro rat model was used to characterize progesterone receptor (PR) isoform expression in uterine leiomyoma and investigate PR signaling using progestins and antiprogestins in the leiomyoma-derived cell line ELT-3. PR-A was the predominant isoform expressed in normal myometrium, leiomyomas and ELT3 cells. In the normal myometrium, PR-A and PR-B levels varied during the estrous cycle with low ratios of PR-A relative to PR-B (PR-A/PR-B) coinciding with times of cell proliferation. Although PR ligands had no effect on basal levels of uterine leiomyoma cell proliferation in vitro, both progestins and antiprogestins inhibited E(2)-stimulated cell proliferation. In addition, E(2)-stimulated transactivation of an estrogen-response-element reporter gene as well as E(2)-induced upregulation of the PR were also inhibited by PR ligands. These data indicate that PR ligands can transdominantly suppress estrogen receptor signaling and stimulation of uterine leiomyoma cell growth.

Although the cellular functions ofTSC2 and its protein product, tuberin, are not known, somatic mutations in the TSC2 tumor suppressor gene are associated with tumor development in lymphangioleiomyomatosis (LAM). We found that ribosomal protein S6 (S6), which exerts translational control of protein synthesis and is required for cell growth, is hyperphosphorylated in the smooth muscle-like cell lesions of LAM patients compared with smooth muscle cells from normal human blood vessels and trachea. Smooth muscle (SM) cells derived from these lesions (LAMD-SM) also exhibited S6 hyperphosphorylation, constitutive activation of p70 S6 kinase (p70S6K), and increased basal DNA synthesis. In parallel, TSC2−/− smooth muscle cells (ELT3) and TSC2−/− epithelial cells (ERC15) also exhibited hyperphosphorylation of S6, constitutive activation of p70S6K, and increased basal DNA synthesis. Re-introduction of wild type tuberin into LAMD-SM, ELT3, and ERC15 cells abolished phosphorylation of S6 and significantly inhibited p70S6K activity and DNA synthesis. Rapamycin, an immunosuppressant, inhibited hyperphosphorylation of S6, p70S6K activation, and DNA synthesis in LAMD-SM cells. Interestingly, the basal levels of phosphatidylinositol 3-kinase, Akt/protein kinase B, and p42/p44 MAPK activation were unchanged in LAMD-SM and ELT3 cells relative to levels in normal human tracheal and vascular SM. These data demonstrate that tuberin negatively regulates the activity of S6 and p70S6K specifically, and suggest a potential mechanism for abnormal cell growth in LAM.

Background Treatment options for myelofibrosis are limited. We evaluated the efficacy and safety of ruxolitinib, a potent and selective Janus kinase (JAK) 1 and 2 inhibitor, as compared with the best available therapy, in patients with myelofibrosis. Methods We assigned 219 patients with intermediate-2 or high-risk primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofi brosis to receive oral ruxolitinib or the best available therapy. The primary end point and key secondary end point of the study were the percentage of patients with at least a 35% reduction in spleen volume at week 48 and at week 24, respectively, as assessed with the use of magnetic resonance imaging or computed tomography. Results A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen volume at week 48, as compared with 0% in the group receiving the best available therapy (P

Mechanisms that regulate the growth response to estrogen (17β-estradiol, E2) are poorly understood. Recently, loss of function of the tuberous sclerosis complex 2 ( TSC2) gene has been associated with E2-related conditions that are characterized by benign cellular proliferation. We examined the growth response to E2in vascular smooth muscle cells (VSMCs) that possess wild-type TSC2 and compared them with ELT-3 smooth muscle cells that do not express TSC2.In TSC2-expressing VSMCs, growth inhibition in response to E2was associated with downregulation of platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), and limited activation of extracellular signal-regulated kinase (ERK). In contrast, the growth-promoting effect of E2in TSC2-null ELT-3 cells was associated with induction of PDGF, robust phosphorylation of PDGFR, and sustained activation of ERK. Furthermore, in ELT-3 cells, cellular growth and ERK activation by E2were inhibited by the PDGFR inhibitor tyrphostin AG 17 and by PDGF-neutralizing antibody. These results demonstrate that autocrine production of PDGF and augmentation of the ERK pathway leads to estrogen-induced cellular proliferation in TSC2-null cells, a pathway that was downregulated in cells that express TSC2. Understanding the mechanisms that regulate the diverse responses to the steroid hormone estrogen could lead to novel approaches to the treatment of estrogen-related diseases that are characterized by aberrant cell proliferation.

Unregulated proliferation of mesenchymal cells in leiomyomas, lipomas, hamartomas,and other diseases has been linked to the high mobility group (HMGA) family of DNA architectural proteins. HMGA genes are primarily expressed during embryonal development and silenced in adult tissues but can become reactivated in neoplasia as a result of chromosomal rearrangements. Although the genetic data suggesting a role for HMGA proteins in tumorigenesis are compelling, the biological role of these proteins in mesenchymal proliferation and differentiation is incompletely defined. Uterine myometria and spontaneous leiomyomas from the Eker rat, which carries a germ-line mutation in the tuberous sclerosis complex-2 (Tsc2) tumor suppressor gene, were analyzed for genetic defects in and expression of the Tsc2 and HMGA proteins. Eker leiomyomas exhibited a 50% incidence of loss of the wild-type Tsc2 allele and an almost uniform loss of protein expression, implicating loss of function of the Tsc2 gene in these tumors. Concomitantly, HMGA2 protein, which was completely absent in normal myometria, was expressed in 16 of 19 Eker leiomyomas. HMGA1 was expressed in both leiomyoma and normal myometria. No structural alterations were observed at the HMGA2 locus in either primary rat leiomyomas or leiomyoma-derived cell lines that expressed HMGA2. These data support a role for HMGA2 in the development of smooth muscle neoplasms and suggest HMGA2 expression is a point of convergence between the human disease and the Eker rat model. Furthermore, these data indicate that aberrant HMGA2 expression can result from dysfunction of the Tsc2 tumor suppressor gene, in the absence of structural alterations involving the HMGA2 locus.

Background: Janus kinases (JAKs), including JAK1 and JAK2, mediate the signaling of cytokines and growth factors implicated in the pathogenesis of myelofibrosis (MF). Suppression of JAK2 leads to cytopenias due to its involvement in the signaling pathways of thrombopoietin and erythropoietin. Purpose: The objective of this ongoing study is to evaluate the efficacy and safety of INCB039110, a selective JAK1 inhibitor, in patients with MF with the goal of improving MF-related symptoms with less myelosuppression than seen with JAK1/JAK2 inhibition. Here, we report the 12- and 24-week efficacy and safety of INCB039110 in a phase II trial. Methods: Adults with intermediate-1 or higher (per Dynamic International Prognostic Scoring System [DIPSS]) primary MF (PMF), post–polycythemia vera MF (PPV-MF), or post–essential thrombocythemia MF (PET-MF) were eligible regardless of JAK2 V617F mutation status. A platelet count of ≥ 50 × 109/L, hemoglobin ≥ 8.0 g/dL (transfusions permitted), and a palpable spleen or prior splenectomy were required. Patients assessed the severity of 19 disease-related symptoms daily using the modified Myelofibrosis Symptom Assessment Form v3.0 electronic diary. Spleen volume (SV) was evaluated by magnetic resonance imaging or computed tomography at baseline, week 12, and week 24. The primary endpoint was the proportion of patients with a ≥ 50% reduction from baseline in total symptom score (TSS, consisting of the sum of 6 individual symptom scores: night sweats, itchiness, abdominal discomfort, pain under left ribs, early satiety, and bone/muscle pain) at week 12. Other endpoints included the proportion of patients with a ≥ 50% reduction from baseline in TSS at week 24, percentage change from baseline in TSS at week 12 and 24, percentage change from baseline in SV at week 12 and 24, and safety. The study used a Simon 2-stage design to assess 3 separate dose cohorts (100 mg twice daily [BID], 200 mg BID, and 600 mg once daily [QD]). A dose cohort could be expanded if ≥ 3 of the first 10 patients met the primary endpoint (intent-to-treat method). Results: Enrollment is complete and 87 patients have been treated with INCB039110: 10 in the 100 mg BID, 45 in the 200 mg BID, and 32 in the 600 mg QD groups; 10, 42, and 31 patients, respectively, were evaluable for the primary endpoint. The 200 mg BID and 600 mg QD cohorts met criteria for expansion. Enrolled patients (mean age, 64 years) had PMF (55%), PPV-MF (26%), or PET-MF (18%), and most had intermediate-1 (37%) or intermediate-2 (47%) risk by DIPSS. Mean SV at baseline was 2442.7 cm3, mean hemoglobin was 10.2 g/dL, and mean platelet count was 246.7 × 109/L. Reductions in TSS were similar between the 200 mg BID and 600 mg QD groups, and largely maintained through week 24 (Table). Modest reductions in spleen volume were attained in the 200 mg BID and 600 mg QD groups. | | INCB039110 Dose | || | 100 mg BID | 200 mg BID | 600 mg QD | | Patients with ≥ 50% improvement in TSS,* n/N (%) | | Week 12 | 2/10 (20) | 15/42 (36) | 10/31 (32) | | Week 24 | 2/10 (20) | 12/42 (29) | 11/31 (35) | | Median change from baseline in TSS,† % | | Week 12 | −28.5 | −45.8 | −37.2 | | Week 24 | −57.2 | −48.6 | −46.7 | | Median change in SV,† % | | | | | Week 12 | −0.5 | −14.1 | −14.5 | | Week 24 | −31.1 | −17.4 | −17.1 | | * Patients who discontinued prior to the week 12 or 24 visit were considered nonresponders at that time point. † Only patients with baseline and week 12 or 24 data were included. Negative change = improvement. | Table Mean platelet count is shown in [Figure 1][1]. Mean hemoglobin levels in patients who entered the study without transfusion requirements and did not receive post-baseline blood transfusions are shown in [Figure 2][2]. In these patients, the mean percent change from baseline in hemoglobin at week 24 increased by 5.6% in the 200 mg BID group and 8.6% in the 600 mg QD group. The most common nonhematologic adverse events (occurring in > 15% of enrolled patients overall regardless of causality) were fatigue (29%), nausea (21%), upper respiratory tract infection (18%), constipation (17%), diarrhea (17%), and cough (16%); most of these events were grade 1 or 2 and did not appear to be dose dependent. New or worsening grade 3 or 4 anemia occurred in 33% and 0% of patients, respectively, and thrombocytopenia in 24% and 5% of patients, respectively. Conclusions: Patients with MF treated with the JAK1 inhibitor INCB039110 (200 mg BID or 600 mg QD) continued to show meaningful improvements in MF-related symptoms and modest decreases in spleen size, while preserving mean hemoglobin levels over time through week 24. ![Figure 1][3] Figure 1 ![Figure 2][3] Figure 2 Disclosures Mascarenhas: Incyte Corporation: Consultancy. Talpaz: ARIAD, BMS, Sanofi. Incyte, Pfizer: Research Funding. Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Foltz: Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Janssen: Consultancy. Savona: Karyopharm: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Gilead : Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Celgene : Membership on an entity's Board of Directors or advisory committees. Paquette: Incyte Corporation: Speakers Bureau. Coughlin: Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eastern Health: Employment. Winton: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hunter: Incyte Corporation: Employment. Assad: Incyte Corporation: Employment. Clark: Incyte Corporation: Employment. O'Neill: Incyte Corporation: Employment. Hoffman: All Cells LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees. Verstovsek: Incyte Corporation: Research Funding. [1]: #F1 [2]: #F2 [3]: pending:yes

Background: Polycythemia vera (PV) is characterized by erythrocytosis, thrombocytosis, and/or leukocytosis and a broad range of disease-related symptoms. In high-risk patients, the most common first-line treatment is hydroxyurea (HU). The open-label RESPONSE trial demonstrated that ruxolitinib (RUX), a JAK1/JAK2 inhibitor, provided superior efficacy compared with best available therapy in patients with PV who were resistant to or intolerant of HU according to modified European LeukemiaNet (ELN) criteria. This study (RELIEF) was conducted in patients receiving a stable dose of HU and who were generally well controlled but reporting disease-associated symptoms, comparing the change in PV-related symptom burden in patients continuing their HU therapy with those switching to RUX treatment. Methods: RELIEF was a randomized, multicenter, double-blind, double-dummy, phase 3b study of patients with PV aged ≥18 years on a stable dose of HU monotherapy and reporting PV-related symptoms. Patients were required to be receiving HU for ≥12 weeks prior to enrollment and on the same dose level for the last 4 weeks, and have a score ≥8 on the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) cytokine total symptom score (TSS-C). The TSS-C comprised symptoms of itching, tiredness, muscle ache, night sweats, and sweats while awake; each symptom was rated on a scale of 0=absent to 10=worst imaginable, with a maximum TSS-C score of 50. Patients also had to meet one of the following: ≤1 phlebotomy in the previous 6 months or no palpable splenomegaly. Those eligible were randomized 1:1 to receive RUX 10 mg BID and HU-placebo, or HU at the same dose/schedule and RUX-placebo. Dose adjustments were permitted for safety and efficacy. After Week 16, patients could receive open-label RUX until Week 48. The primary endpoint was the proportion of patients with a ≥50% reduction in TSS-C at Week 16; secondary endpoints included proportion of patients with a ≥50% reduction in individual TSS-C symptoms and safety. Results: Overall, 54 and 56 patients were randomized to RUX and HU, respectively; 87.0% and 89.3% remained on treatment through Week 16. At baseline, the median age (range) was 64 (36-87) in the RUX group and 66 (19-85) in the HU group; 44% and 61% were men. The majority of patients in the RUX and HU groups did not have baseline platelet counts or WBC above ELN thresholds: platelets >400 and ≤600 x 109/L (RUX 31.5%, HU 28.6%), >600 x 109/L (3.7%, 8.9%); WBC >10 and ≤15 x 109/L (16.7%, 16.1%), >15 x 109/L (11.1%, 14.3%). In the RUX and HU groups, the mean TSS-C at screening (22.4, 23.1) was higher than that at baseline (16.7, 18.0); the ratio of screening to baseline TSS-C was 1.7 and 1.6. The proportion of patients achieving a ≥50% reduction from baseline in TSS-C at Week 16 (primary endpoint) was 43.4% in the RUX group and 29.6% in the HU group (P=0.139; OR, 1.82; 95% CI, 0.82-4.04). The proportions of patients in the RUX vs HU groups achieving a ≥50% reduction in scores for itching and tiredness at Week 16 were 40.0% vs 26.4% and 54.2% vs 32.0%, respectively. Median percentage changes in individual TSS-C symptoms are shown in Table 1. Additional analyses found no correlation between individual changes in HU dose from baseline to Weeks 13-16 and percentage change in TSS-C in the HU arm (r2=0.030). Even patients maintaining the same HU dose from prior to study entry through Week 16 reported symptom improvement: 12/35 (34.3%) with no dose change, 4/12 (33.3%) with a dose increase, and 0/9 (0%) with a dose decrease had a ≥50% reduction in TSS-C. The most common nonhematologic adverse events in the RUX arm on randomized treatment were fatigue (20.4% RUX vs 10.7% HU), headache (16.7% vs 5.4%), and dizziness (13.0% vs 8.9%). The most common adverse events on HU were diarrhea (9.3% RUX vs 19.6% HU) and constipation (7.4% vs 12.5%); most events were grade 1 or 2. Grade 3 or 4 anemia or thrombocytopenia (lab values) were not reported in the RUX group; two patients in the RUX group had grade 3 or 4 neutropenia. Conclusion: In generally well controlled PV patients receiving a stable dose of HU, there was a positive trend in symptom improvement for patients switched to RUX therapy versus those continuing on HU therapy, although this was not statistically significant. The 34% response rate among patients who continued to receive a stable HU dose suggests a placebo effect that led to an underpowered study. Further analyses are required to better interpret these findings. Disclosures Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yacoub:Alexion Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees. Koschmieder:Novartis Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Byrne:Novartis Pharmaceuticals: Honoraria. Verstovsek:Incyte Corporation: Research Funding. Hunter:Incyte Corporation: Employment, Equity Ownership. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Morozov:Novartis Pharmaceuticals: Employment, Equity Ownership.

4000 Background: Local and systemic inflammation (INFL) are hallmarks of cancer, including PC, that adversely impact prognosis. Given the role of JAK-STAT signaling in cancer INFL, the efficacy and...

Uterine leiomyomas, also called fi broids, are the most common reproductive tract neoplasm and the leading indication for hysterectomy in premenopausal women. The discovery and development of medicinal therapies for uterine leiomyoma have been hampered by a lack of understanding regarding the etiology and molecular mechanisms underlying the development of these lesions. Although the estrogen responsiveness of uterine leiomyoma is well established, the impact of environmental estrogens and their contribution to the development of these tumors is currently unknown. The Eker rat model of uterine leiomyoma has proven useful for addressing these issues and understanding the pathophysiology of this disease. The Eker rat is the only animal model that develops spontaneous uterine leiomyomas, and these tumors share many characteristics with those found in humans. The availability of tumor-derived cell lines from these rats has made this a valuable in vitro/in vivo model system for experimental studies to investigate molecular mechanisms of disease and to design interventional and preventative strategies for this clinically relevant tumor.

Abstract 801 Background: Ruxolitinib is a potent JAK1 & 2 inhibitor that has demonstrated superiority over traditional therapies for the treatment of MF. In the two phase 3 COMFORT studies, ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life. COMFORT-II is a randomized, open-label study evaluating ruxolitinib versus BAT in patients (pts) with MF. The primary and key secondary endpoints were both met: the proportion of pts achieving a response (defined as a ≥ 35% reduction in spleen volume) at wk 48 (ruxolitinib, 28.5%; BAT, 0%; P < .0001) and 24 (31.9% and 0%; P < .0001), respectively. The present analyses update the efficacy and safety findings of COMFORT-II (median follow-up, 112 wk). Methods: In COMFORT-II, 219 pts with intermediate-2 or high-risk MF and splenomegaly were randomized (2:1) to receive ruxolitinib (15 or 20 mg bid, based on baseline platelet count [100-200 × 109/L or > 200 × 109/L, respectively]) or BAT. Efficacy results are based on an intention-to-treat analysis; a loss of spleen response was defined as a > 25% increase in spleen volume over on-study nadir that is no longer a ≥ 35% reduction from baseline. Overall survival was estimated using the Kaplan-Meier method. Results: The median follow-up was 112 wk (ruxolitinib, 113; BAT, 108), and the median duration of exposure 83.3 wk (ruxolitinib, 111.4 [randomized and extension phases]; BAT, 45.1 [randomized treatment only]). Because the core study has completed, all pts have either entered the extension phase or discontinued from the study. The primary reasons for discontinuation were adverse events (AEs; ruxolitinib, 11.6%; BAT, 6.8%), consent withdrawal (4.1% and 12.3%), and disease progression (2.7% and 5.5%). Overall, 72.6% of pts (106/146) in the ruxolitinib arm and 61.6% (45/73) in the BAT arm entered the extension phase to receive ruxolitinib, and 55.5% (81/146) of those originally randomized to ruxolitinib remained on treatment at the time of this analysis. The primary reasons for discontinuation from the extension phase were progressive disease (8.2%), AEs (2.1%), and other (4.1%). Overall, 70 pts (48.3%) treated with ruxolitinib achieved a ≥ 35% reduction from baseline in spleen volume at any time during the study, and 97.1% of pts (132/136) with postbaseline assessments experienced a clinical benefit with some degree of reduction in spleen volume. Spleen reductions of ≥ 35% were sustained with continued ruxolitinib therapy (median duration not yet reached); the probabilities of maintaining the spleen response at wk 48 and 84 are 75% (95% CI, 61%-84%) and 58% (95% CI, 35%-76%), respectively (Figure). Since the last report (median 61.1 wk), an additional 9 and 12 deaths were reported in the ruxolitinib and BAT arms, respectively, resulting in a total of 20 (14%) and 16 (22%) deaths overall. Although there was no inferential statistical testing at this unplanned analysis, pts randomized to ruxolitinib showed longer survival than those randomized to BAT (HR = 0.52; 95% CI, 0.27–1.00). As expected, given the mechanism of action of ruxolitinib as a JAK1 & 2 inhibitor, the most common new or worsened grade 3/4 hematologic abnormalities during randomized treatment were anemia (ruxolitinib, 40.4%; BAT, 23.3%), lymphopenia (22.6%; 31.5%), and thrombocytopenia (9.6%; 9.6%). In the ruxolitinib arm, mean hemoglobin levels decreased over the first 12 wk of treatment and then recovered to levels similar to BAT from wk 24 onward; there was no difference in the mean monthly red blood cell transfusion rate among the ruxolitinib and BAT groups (0.834 vs 0.956 units, respectively). Nonhematologic AEs were primarily grade 1/2. Including the extension phase, there were no new nonhematologic AEs in the ruxolitinib group that were not observed previously (in ≥ 10% of pts), and only 1 pt had a new grade 3/4 AE (epistaxis). Conclusion: In COMFORT-II, ruxolitinib provided rapid and durable reductions in splenomegaly; this analysis demonstrates that these reductions are sustained over 2 years of treatment in the majority of pts. Ruxolitinib-treated pts showed longer survival than those receiving BAT, consistent with the survival advantage observed in previous (Verstovsek et al. NEJM. 2012) and current analyses of COMFORT-I, as well as with the comparison of pts of the phase 1/2 study with matched historical controls (Verstovsek et al. Blood. 2012). Disclosures: Cervantes: Sanofi-Aventis: Advisory Board, Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Pfizer: Advisory Board, Advisory Board Other; Teva Pharmaceuticals: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Speakers Bureau; Novartis: AdvisoryBoard Other, Speakers Bureau. Kiladjian:Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment, Equity Ownership. Stalbovskaya:Novartis: Employment, Equity Ownership. McQuity:Novartis: Employment, Equity Ownership. Hunter:Incyte: Employment. Levy:Incyte: Employment, stock options Other. Passamonti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Barbui:Novartis: Honoraria. Gisslinger:AOP Orphan Pharma AG: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Knoops:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

6514^ Background: Ruxolitinib is a potent and selective JAK1/2 inhibitor approved for the treatment of myelofibrosis (MF) based on results of the phase 3 COMFORT studies. Ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life of patients (pts) with MF. Since one measure of efficacy is molecular response, this analysis correlates changes in mutant allele burden (%V617F) with spleen size reduction in COMFORT-II. Methods: COMFORT-II is a randomized, open-label, phase 3 study comparing ruxolitinib 15 or 20 mg twice daily (BID) with BAT. The primary endpoint was a ≥ 35% reduction in spleen volume from baseline (BL) at week 48. Change in %V617F was measured by allele specific qPCR. Pts were stratified by reduction in %V617F (< 10%, 10-20%, > 20%) and results were correlated with achievement of the primary endpoint. Results: More pts in the ruxolitinib arm had ≥ 10% V617F reductions compared with BAT (41% vs 5%; P = .01; Table). The majority of reductions > 20% were gradual and progressive over the course of the study; 2 pts had rapid reductions from 48% to 1% and 45% to 9% over 48 weeks. In the ruxolitinib arm, significantly more pts with a > 20% V617F reduction achieved the primary endpoint compared with pts with a < 10% reduction (79% vs 30%; P = .004); in each group, gender did not affect spleen response. For pts with < 10% reductions (15 mg BID, n = 16; 20 mg BID, n = 24), the average total daily dose (TDD) was ruxolitinib 29.6 mg; pts with > 20% reductions (15 mg BID, n = 3; 20 mg BID, n = 11) had a TDD of 35.3 mg. Conclusions: Pts who received ruxolitinib had larger reductions in JAK2V617F allele burden compared with BAT. %V617F reductions were gradual over the course of the 48-week study; longer follow-up is needed to determine the extent of allele burden reduction. [Table: see text]

Abstract 795FN2 Background: Ruxolitinib (INC424), a potent and selective oral JAK1 and JAK2 inhibitor, demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms, role functioning, and quality of life (QoL) in 2 phase 3 studies in patients with myelofibrosis (MF) (the COMFORT studies). Per-protocol, patient-reported, health-related QoL (HRQoL) and symptoms analyses in the COMFORT-II study are limited. Here we report on additional post hoc analyses of these outcomes. The COMFORT-II study includes 219 patients (ruxolitinib, n=146; best available therapy [BAT], n=73). At entry, all patients were classified into intermediate 2-risk or high-risk prognostic groups (Cervantes F, et al. Blood, 2009;113(13):2895-2901) and had palpable splenomegaly ≥5 cm below the costal margin. Patients could have received prior therapy for MF. On BAT, doses and schedules or no therapy were selected by the investigator; therapy adjustments were permitted during the randomized treatment phase at the investigator's discretion. Patients in both arms continued in the randomized treatment phase as long as there was no protocol-defined disease progression. Methods: The European Organisation for the Research and Treatment of Cancer (EORTC) QoL Questionnaire–Core 30 (QLQ-C30) and Functional Assessment of Cancer Therapy–Lymphoma (FACT-Lym) questionnaires were assessed at baseline and weeks 8, 16, 24, and 48. EORTC QLQ-C30 consists of 30 items combined into 15 subscales (Global Health Status/QoL, 5 functioning subscales, and 9 symptom subscales; scores range from 0 to 100, and higher scores indicate better HRQoL and functioning but a worsening of symptoms). FACT-Lym consists of 42 items combined into 8 subscales (4 well-being subscales; 1 symptom subscale [LymS]; and 3 total scale scores: FACT-General [G], FACT-Lym trial outcome index [TOI], and FACT-Lym total; scores for the different subscales vary from 0–28 to 0–168, and higher scores indicate better outcomes). This analysis includes evaluable patients in the randomized treatment phase and assesses changes from baseline in HRQoL and MF symptom scores, including the EORTC subscales, LymS, and FACT total scores, which incorporate well-being and/or symptom subscales. Mixed-model analyses, adjusted for age, sex, baseline score, and prognostic risk category, are used to evaluate treatment differences at each time point and overall across time. Results: HRQoL and MF symptoms, on average, improved compared with baseline for patients receiving ruxolitinib, but remained the same or worsened for patients receiving BAT. Based on the EORTC QLQ-C30, the treatment differences in physical functioning, role functioning, fatigue, and appetite loss significantly favored ruxolitinib starting at week 8 (P Scores on the LymS, which includes symptoms of pain, swelling, fever, night sweats, itching, trouble sleeping, fatigue, weight loss, loss of appetite, trouble concentrating, and other patient concerns, also improved significantly during treatment (Figure). Additionally, FACT-G, FACT-Lym TOI, and FACT-Lym total scores were all significantly (P Most EORTC QLQ-C30 and FACT-Lym scores improved significantly on ruxolitinib compared with BAT. The treatment effect between the high-risk and intermediate 2-risk prognostic groups was not significantly different based on an analysis of the risk group–by–treatment interaction. Conclusions: These additional analyses from the COMFORT-II study further support that ruxolitinib significantly improves overall HRQoL and MF symptoms compared with BAT. Disclosures: Harrison: Novartis: Honoraria; Incyte: Honoraria; S*Bio: Honoraria; Celgene: Honoraria; Sanofi Aventis: Honoraria. Kiladjian:Novartis: Honoraria; Celgene: Honoraria. Gisslinger:Novartis: Speakers Bureau; Celgene Austria: Research Funding, Speakers Bureau; Aop-Orphan: Speakers Bureau. Knoops:Novartis: Consultancy. Waltzman:Novartis: Employment. Mendelson:Novartis: Employment, Equity Ownership. Zhou:RTI-HS: Employment; Novartis: Research Funding. Copley-Merriman:RTI-HS: Employment; Novartis: Research Funding. Hunter:Incyte Corporation: Employment, Equity Ownership. Levy:Incyte Corporation: Employment, Equity Ownership. Cervantes:Bristol-Myers-Squibb: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Passamonti:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vannucchi:Novartis: Honoraria. Barosi:Novartis: Consultancy.

Abstract 279 Background: COMFORT-II is a randomized, open-label, phase 3 study evaluating the safety and efficacy of ruxolitinib, a potent and selective oral inhibitor of JAK1 and JAK2, in patients with primary myelofibrosis (PMF), post-polycythemia vera-MF (PPV-MF), or post-essential thrombocythemia-MF (PET-MF). Patients who received ruxolitinib had significantly greater reductions in spleen volume compared with those who received best available therapy (BAT). The primary and key secondary endpoints of the study were both met: the proportion of patients achieving ≥35% reduction in spleen volume at week 48 (28.5%, ruxolitinib; 0%, BAT; P Methods: In the COMFORT-II study, 219 patients were randomized (2:1) to receive ruxolitinib (15 or 20 mg twice daily [bid] based on the baseline platelet count [100– 200 × 109/L or >200 × 109/L, respectively]) or BAT of the investigator's choice. The proportions of ruxolitinib-treated patients achieving the primary and key secondary endpoints were analyzed by subgroup for gender (male or female), age (≤65 or >65 years), starting dose (15 or 20 mg bid), baseline MF type (PMF, PPV-MF, or PET-MF), previous hydroxyurea (hydroxycarbamide) use (yes or no), baseline palpable spleen length (≤10 or >10 cm), baseline spleen volume (>median or ≤median), JAK2V617F mutation (presence or absence), and International Prognostic Scoring System (IPSS) risk category (intermediate-2 or high) (Cervantes F, et al, Blood, 2009;113(13):2895–2901). In addition, the relationships between these factors and spleen volume reduction were investigated by multivariate logistic regression. Results: The proportion of patients in each subgroup with ≥ 35% reduction in spleen volume from baseline at week 48 is shown below (Figure). BL, baseline; HU, hydroxyurea. The response rate was higher in patients receiving ruxolitinib than in patients receiving BAT in all subgroups; no patients in the BAT group reached a ≥35% reduction in spleen volume at week 48. All subgroups receiving ruxolitinib responded and all subgroup comparisons had overlapping 95% confidence intervals. At week 24, a trend for a higher response rate was observed in patients who received a starting dose of 20 mg bid compared with those who received a starting dose of 15 mg bid; however, the response rates among these patients at week 48 were not different. No significant difference in response rates was observed between patients with the JAK2V617F mutation compared with those without the mutation. Results of the subgroup analysis were confirmed by the multivariate models. A significant effect of the ruxolitinib starting dose was seen when response rates were modeled at week 24 but not when modeled at week 48. Conclusions: Recent findings from the COMFORT-II study show that patients who received ruxolitinib had significantly greater reductions in splenomegaly than did patients who received BAT. In this analysis, ruxolitinib was shown to be more effective than BAT at reducing spleen volume in all patient subgroups regardless of gender, age, mutation status, IPSS risk category, baseline spleen size, MF subtype, or ruxolitinib starting dose. Disclosures: Harrison: Novartis: Honoraria; Incyte: Honoraria; S*Bio: Honoraria; Celgene: Honoraria; Sanofi Aventis: Honoraria. Kiladjian:Novartis: Honoraria; Celgene: Honoraria. Gisslinger:Novartis: Speakers Bureau; Celgene Austria: Research Funding, Speakers Bureau; Aop-Orphan: Speakers Bureau. Niederwieser:Novartis: Speakers Bureau. Passamonti:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Waltzman:Novartis: Employment. Hollaender:Novartis Pharma AG: Employment. Hunter:Incyte Corporation: Employment, Equity Ownership. Levy:Incyte Corporation: Employment, Equity Ownership. Knoops:Novartis: Consultancy. Cervantes:Bristol-Myers-Squibb: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vannucchi:Novartis: Honoraria. Barosi:Novartis: Consultancy.

LBA6501 Background: MF, a myeloproliferative neoplasm characterized by dysregulation of the JAK pathway, is associated with splenomegaly, constitutional symptoms and reduced lifespan. Ruxolitinib is a potent and selective JAK1 and JAK2 inhibitor. Methods: COMFORT-II, a randomized (2:1) phase III study, compared the efficacy and safety of ruxolitinib PO BID with BAT (other agents or no therapy) in adults with intermediate-2 or high-risk (Cervantes et al, Blood 2009) PMF, PPV-MF or PET-MF and palpable splenomegaly. The primary endpoint was the proportion of patients (pts), stratified by baseline risk category, achieving ≥ 35% reduction in spleen volume at week (wk) 48 determined by MRI or CT. The key secondary endpoint was the proportion achieving ≥ 35% reduction in spleen volume at wk 24. Results: 219 pts were randomized: 146 to ruxolitinib and 73 to BAT. Both arms included 49% high- and 51% intermediate-2 risk pts. The wk 48 response rate was 28.5% vs 0% (ruxolitinib vs BAT, P < .0001). The wk 24 response rate was 31.9% vs 0% (ruxolitinib vs BAT, P < .0001). Median duration of response to ruxolitinib was 48 wks. The most common (> 20%) adverse events (AEs) of any grade were (ruxolitinib vs BAT) thrombocytopenia (44.5% vs 9.6%), anemia (40.4% vs 12.3%), diarrhea (24.0% vs 11.0%), and peripheral edema (21.9% vs 26.0%). Grade 3-4 AEs occurring in ≥ 5% of pts in the ruxolitinib arm were: anemia (11%) and thrombocytopenia (7.5%). The most frequent grade 3-4 AEs in the BAT arm were anemia, thrombocytopenia, pneumonia and dyspnea (each 4.1%). Seven deaths occurred on treatment or within 28 days after end of treatment: 4 (2.7%) ruxolitinib and 3 (4.1%) BAT. Disposition of discontinuations were (ruxolitinib vs BAT) 8.2% vs 5.5% due to AEs and 1.4% vs 12.3% due to withdrawn consent. Conclusions: The COMFORT-II study demonstrates that ruxolitinib provides marked and sustained clinical benefit in spleen size and an acceptable safety profile relative to BAT, extends the positive results of COMFORT-I which compared ruxolitinib with placebo, and may result in a new standard of care for a large number of patients with MF.

The remarkable frequency of uterine leiomyoma in the human population calls into question the potential for the participation of environmental factors in tumor etiology. Having been implicated in the dramatic rise in hormone-related cancers in recent years, endocrine disruptors are salient suspects in this pathogenesis, although the mechanism by which they might participate is unclear. Investigations using the Eker rat model show that uterine leiomyoma may have an enhanced sensitivity to modulation via the estrogen receptor. This sensitivity could make these tumors a target for disruption by exogenous estrogen receptor ligands. Direct evidence for a pathogenic role of exogenous compounds in leiomyomas is lacking; however, it can be demonstrated that such diverse agents as organochlorine pesticides, dietary flavonoids, botanical extracts, and therapeutic antiestrogens have either estrogen agonist or antagonist function in myometrial tissues. The use of this model will help define the impact of exogenous estrogen receptor modulators on uterine leiomyoma and will permit the evaluation of strategies for therapeutic intervention.

Prior to Janus kinase inhibitors, available therapies for myelofibrosis were generally supportive and did not improve survival. This analysis compares efficacy outcomes of patients with myelofibrosis in the control arms (placebo [n=154] and best available therapy [n=73]) from the two phase 3 COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (COMFORT) studies. Spleen volume was assessed by magnetic resonance imaging/computed tomography at baseline and every 12 weeks through week 72; spleen length was assessed by palpation at each study visit. Health-related quality of life and symptoms were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items at baseline and in weeks 4, 8, 12, 16 and 24 in COMFORT-I and in weeks 8, 16, 24 and 48 in COMFORT-II. The demographic and baseline characteristics were similar between the control arms of the two studies. One patient who received placebo and no patients who received best available therapy had a ≥35% reduction in spleen volume from baseline at week 24. At 24 weeks, neither placebo nor best available therapy had produced clinically meaningful changes in global quality of life or symptom scales. Non-hematologic adverse events were mostly grade 1/2; the most frequently reported adverse events in each group were abdominal pain, fatigue, peripheral edema and diarrhea. These data suggest that non-Janus kinase inhibitor therapies provide little improvement in splenomegaly, symptoms or quality of life as compared with placebo. Both COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) studies have been appropriately registered with clinicaltrials.gov.