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Krisstina L Gowin, Ruben A Mesa Division of Hematology and Medical Oncology, Mayo Clinic Arizona, Scottsdale, AZ, USA Abstract: Myelofibrosis, a Philadelphia-negative myeloproliferative neoplasm, is in a new treatment era after the discovery of the JAK2V617F mutation in 2005. JAK inhibitors boast improvements in disease-related symptoms, splenomegaly, and overall survival; however, treatment of myelofibrosis remains a challenge, given the lack of improvement in cytopenias with these agents. Second-generation immunomodulatory agents, such as pomalidomide, have shown efficacy in myelofibrosis-associated anemia within multiple clinical trials. Five major pomalidomide clinical trials have been completed to date, and demonstrate tolerability and efficacy with low-dose pomalidomide (0.5 mg/day) in the treatment of myelofibrosis, and no clinical benefit of elevated dosing regimens (≥2.5 mg/day). Anemia responses ranged from 17% to 36% as per the International Working Group for Myelofibrosis Research and Treatment consensus guidelines, while improvements in splenomegaly were rare, and observed in

Srdan Verstovsek,1 Jason Gotlib,2 Vikas Gupta,3 Ehab Atallah,4 John Mascarenhas,5 Alfonso Quintas-Cardama,1 William Sun,6 Nicholas J Sarlis,6 Victor Sandor,6 Richard S Levy,6 Hagop M Kantarjian,1 Ruben A Mesa71University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Stanford Cancer Institute, Stanford, CA, USA; 3Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada; 4Medical College of Wisconsin, Milwaukee, WI, USA; 5Mount Sinai School of Medicine, New York, NY, USA; 6Incyte Corporation, Wilmington, DE, USA; 7Mayo Clinic, Scottsdale, AZ, USAPurpose: Ruxolitinib is an oral Janus kinase (JAK) 1/JAK2 inhibitor approved in the US for the treatment of intermediate- or high-risk myelofibrosis (MF). Because thrombopoietin and erythropoietin signal through JAK2, dose-dependent cytopenias are expected with treatment. In the COMFORT-I (COntrolled Myelofibrosis study with Oral JAK inhibitor Treatment I) trial, these cytopenias were effectively managed with dose adjustments. These analyses were conducted to evaluate the relationship between ruxolitinib titrated doses and changes in platelet count and hemoglobin level as well as efficacy measures.Patients and methods: COMFORT-I was a randomized, placebo-controlled trial in 309 patients with intermediate-2 or high-risk MF and a platelet count ≥100 × 109/L. Ruxolitinib starting doses were 15 and 20 mg twice daily (bis in die [BID]) for patients with baseline platelet counts of 100–200 × 109/L and >200 × 109/L, respectively. Percentage changes from baseline to week 24 in spleen volume and MF-related symptoms were assessed in subgroups defined by final titrated dose (average daily dose during weeks 21 to 24).Results: The median final titrated doses for patients starting at doses of 15 and 20 mg BID were 10 and 20 mg BID, respectively, at week 24. Most dose reductions occurred in the first 8–12 weeks of treatment and coincided with decreases in platelet count and hemoglobin level. Subsequently, platelet counts stabilized and hemoglobin levels gradually returned to near baseline levels (red blood cell transfusion rates followed a similar trend). Final titrated doses of ≥10 mg BID were associated with clinically meaningful improvements in MF-related symptoms that were comparable across doses, while marginally greater reductions in spleen volume were observed at higher doses.Conclusion: This COMFORT-I analysis shows that dose-dependent cytopenias were effectively managed with ruxolitinib dose adjustments, and titrated doses of ≥10 mg BID were associated with clinically meaningful reductions in spleen volume and symptom improvement at week 24.Keywords: COMFORT-I, dose titration, JAK2 inhibitor, myelofibrosis, ruxolitinib, treatment-related cytopenias

Robyn M Emanuel,1 Holly L Geyer,1 Ruben A Mesa2 1Department of Internal Medicine, 2Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA Abstract: Essential thrombocythemia, polycythemia vera, and myelofibrosis belong to the class of Bcr-Abl negative hematologic neoplasms, which arise in part from varying Janus kinase-2 (JAK2) cellular deregulation. With the development of novel tyrosine kinase inhibitors capable of successfully inhibiting JAK in vivo, an influx of JAK2 inhibitors has come under clinical investigation. Ruxolitinib (Jakafi®; Incyte Corporation, Wilmington, DE, USA) was the first of these compounds to gain US Food and Drug Administration approval in late 2011 for the treatment of intermediate- and high-risk myelofibrosis. Two Phase III clinical trials – Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment-I and -II (COMFORT-I and -II) – played key roles in the US Food and Drug Administration approval of ruxolitinib with successful demonstration of spleen reduction and symptom palliation. Well tolerated in most patients, common side effects include cytopenias and gastrointestinal toxicities. The majority of preliminary data appears to suggest that if administered in a dose-titrated fashion, ruxolitinib can be used safely in a clinical practice setting. Additionally, patients most likely to benefit from ruxolitinib treatment are those with moderate to severe constitutional symptoms or splenomegaly. Future studies are ongoing in applying ruxolitinib to other hematologic and solid tumor malignancies. More clinical experience is recommended before the utility of this medication in a routine clinical practice setting can be fully determined. Keywords: myeloproliferative neoplasms, myelofibrosis, ruxolitinib, JAK2 inhibitors, INCB018424

Raoul Tibes, James M Bogenberger, Ruben A MesaDivision of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USAAbstract: The myeloproliferative neoplasm of myelofibrosis (MF) is clinically constituted by individuals both with primary MF, as well as those that evolved from an antecedent polycythemia vera or essential thrombocythemia. Individuals presenting with MF have a heterogeneous phenotype which can involve significant constitutional symptoms (night sweats, fevers, weight loss, fatigue, variable but frequently problematic splenomegaly, and multifactorial cytopenias). These individuals clearly have decreased survival. Refinement of MF prognostic scores can distinguish from survival as poor as 16 months, to a median survival of 185 months. Sadly, although curative, allogeneic stem cell transplant still has sobering success rates for individuals of the standard ages for MF. Recent reports suggest less than half of patients will be alive at 3 years after allotransplant above the age of 60 years. The most important recent advancement in MF therapy has been the development of Janus kinase 2 (JAK2) inhibitors led by ruxolitinib, now Food and Drug Administration approved in the United States, and several other JAK2 inhibitors (in testing) including SAR302503, CYT387, and SB1518. In randomized, placebo-controlled studies, ruxolitinib was demonstrated to be superior for the improvement of splenomegaly and symptoms. These benefits are mirrored across other JAK2 inhibitors. Improving anemia remains an unmet need in MF and is currently being evaluated by clinical trials utilizing the JAK2 inhibitor CYT387, as well as pomalidomide. Additional areas of interest for MF therapy include the inhibition of histone/lysine deacetylases, hedgehog pathway inhibition, as well as combination strategies with JAK2 inhibitors.Keywords: myeloproliferative neoplasm, myelofibrosis, JAK2 inhibitors

BackgroundPatients with cancer may be at high risk of adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We analyzed a cohort of patients with cancer and coronavirus 2019 (COVID-19) reported to the COVID-19 and Cancer Consortium (CCC19) to identify prognostic clinical factors, including laboratory measurements and anticancer therapies.Patients and methodsPatients with active or historical cancer and a laboratory-confirmed SARS-CoV-2 diagnosis recorded between 17 March and 18 November 2020 were included. The primary outcome was COVID-19 severity measured on an ordinal scale (uncomplicated, hospitalized, admitted to intensive care unit, mechanically ventilated, died within 30 days). Multivariable regression models included demographics, cancer status, anticancer therapy and timing, COVID-19-directed therapies, and laboratory measurements (among hospitalized patients).ResultsA total of 4966 patients were included (median age 66 years, 51% female, 50% non-Hispanic white); 2872 (58%) were hospitalized and 695 (14%) died; 61% had cancer that was present, diagnosed, or treated within the year prior to COVID-19 diagnosis. Older age, male sex, obesity, cardiovascular and pulmonary comorbidities, renal disease, diabetes mellitus, non-Hispanic black race, Hispanic ethnicity, worse Eastern Cooperative Oncology Group performance status, recent cytotoxic chemotherapy, and hematologic malignancy were associated with higher COVID-19 severity. Among hospitalized patients, low or high absolute lymphocyte count; high absolute neutrophil count; low platelet count; abnormal creatinine; troponin; lactate dehydrogenase; and C-reactive protein were associated with higher COVID-19 severity. Patients diagnosed early in the COVID-19 pandemic (January-April 2020) had worse outcomes than those diagnosed later. Specific anticancer therapies (e.g. R-CHOP, platinum combined with etoposide, and DNA methyltransferase inhibitors) were associated with high 30-day all-cause mortality.ConclusionsClinical factors (e.g. older age, hematological malignancy, recent chemotherapy) and laboratory measurements were associated with poor outcomes among patients with cancer and COVID-19. Although further studies are needed, caution may be required in utilizing particular anticancer therapies.Clinical trial identifierNCT04354701.

A character is a crystallization form of the habituation process carried out by individuals during their life spans. Character building is carried out firstly in the family environment and can be instilled through formal and informal educational institutions. Currently, the government is promoting character education and Pancasila students in schools because it is believed to shape child character effectively. This study aimed to improve elementary school students' gotong royong character, known as the mutual assistance character, through traditional games using Socratic method-based learning. This research is an experimental research using pre-experimental (single group designs). The participants were 37 elementary school students aged 9-11 years. The mutual assistance character was measured using a questionnaire instrument adapted from the Permendikbud and integrated with Krathwohl affective domain indicators. Data were analyzed using SPSS 21 employing paired sample T-test processing. The results show a significant increase from the pretest to post-test results (16.6% on mutual assistance, 18.1% on cooperation, and 15.1% on communication). It implies that traditional games through Socratic Method-based learning can be used as an alternative to developing the mutual assistance character as an effort to promote the profile of Pancasila students in elementary schools.

In Indonesia, physical literacy has not developed as rapidly as in developed countries. There are only a few of studies examining physical literacy in Indonesia. This study was aimed to scientifically reveal the focus of physical literacy studies in Indonesia by using an article review approach. The search for articles was limited to the latest 10-year publications and articles published in accredited National/International Journals and National/International Seminars provided with ISBN. A total of 7 articles were selected for further analysis using synthesis techniques. The results of the study revealed that there were only six studies on Physical Literacy in Indonesia published in National Journals and National/International Seminars. The focus of the study on physical literacy research in Indonesia included the lead to the measurement of physical literacy and the development of physical literacy instruments in elementary schools (three studies), using learning approach to improve physical literacy (two studies), and the concept of physical literacy in Physical Education (one study). This study is limited to an article review. For further research, it is hoped that new research focusing on physical literacy studies, using a research method approach adapted to the research objectives, will emerge to develop concepts, measurements, and implementations of physical literacy programs in Indonesia.

Physical Education class is one of the solutions taken by regional schools to improve achievements in sports. The process of recruiting physical education class students has mostly conducted by using the talent scouting test method which consists of physical test and skill test. However, the implementation of sport injury detection test using Functional Movement Screening (FMS) is still insignificant. The purpose of this study was to identify the student risk of injury in physical education class by using the FMS test. The research was an ex-post-facto method. The research samples were 32 students of class VIII in the physical education class at SMPN 1 Baturaden (20 males and 12 females) aged 14 years in average. The research instrument used was the Functional Movement Screening (FMS) test with the validity and reliability of 0.81. Data processing and analysis employed the Benchmark Reference (PAN) with the help of Ms. Excel. The results showed that 56.25% of physical education class students at SMPN 1 Baturaden were identified at risk of sports injuries. The results also showed an imbalance of strength between the right and left body muscles. The study concludes that the use of Functional Movement Screening (FMS) test is important to minimize the high likelihood of injury of the students in physical education class.

A child motor development and body mass index are determinant aspects yet important predictors for other aspect of development. However, both of them are also influenced by other factors, including the parents’ socioeconomic status. Therefore, this study was aimed at finding out the relationship between parents’ socioeconomic status with the children’ motor development and body mass index, especially for the children living in rural area. The study was an ex-post facto study. The study used Ages and Stages Questionnaire (ASQ) 3rd Edition to measure the children motor development and Instrument (Scale) for Measuring the Socioeconomic Status of a Family Questionnaire to measure the socioeconomic status of the parents. The children body mass index were calculated from the height and weight. The study involved 64 children as the participants. However, only 53 data of the children that were eligible to be analyzed after the data cleaning process was conducted. The data were analyzed by using statistic calculation by the help of SPSS application. The results of the study found that most of the children were coming from upper middle and lower middle status. Their body mass index were mostly in thin category. However, their motor development seems to be on the schedule. Only a small number of the children who need more activities or further professional assessment. Moreover, there was no significant relationship between the parents’ socioeconomic status and the children motor development and body mass index was found. The study indicates that the children weight status were alarming and need further attention. However, the data were taken from a small number of participant, thus it cannot be generalized to summarize a general depiction of all children in rural area.

This study aims to look at differences in motivation and physical intensity in junior high school students through tactical and technical learning models in invasion games. This study used an experimental method with a post-test control group design. Sample selection using cluster random sampling was chosen to determine the experimental group and the control group. Each class consists of 24 students. From each class 8 students were taken (4 men; 4 women) because of the limited availability of the Polar Global Positioning System (GPS) instrument. Student motivation is measured using a questionnaire. Data is processed using independent sample t-test. The results showed that there were differences in the motivation and intensity of student movements in the tactical and technical learning model groups. The intensity and motivation of students in the tactical learning model group is higher than the technical learning model. The implications of this study can be used as empirical data related to motivation and intensity of movement influenced by tactical learning models in invasion games. So that the achievement of physical fitness can be obtained by taking into account the intensity of student movement during the Physical Education learning objectively.

This study was aimed at determining the relationship between early childhood motor development and the level of socio-economic status (SES) of parents. The research method used was Ex-post Facto comparative study. The population of the study involved children aged 4-5 year from early childhood education schools in urban areas. 50 samples were selected (male = 27; female = 23). Overall sample participation was 78%. So that the representative sample were 39 participants. Children motor development was measured by using the Ages and Stages Questionnaire (ASQ) 3rd Edition. To measure the Socio-Economic Status (SES), an Instrument for Measuring the Socioeconomic Status of a family was used. The results showed that the early childhood motor development was not only influenced by parents' socioeconomic status, it was also influenced by playgrounds available in schools and the playing space at home. This study shows that parents today understand the importance of early childhood education in optimizing children development. Schools and neighborhoods are two best investments for a better children' future. Abstrak Studi ini bertujuan untuk mengetahui keterkaitan perkembangan motorik anak usia dini dengan tingkat status sosial ekonomi (SES) orang tua. Metodologi penelitian menggunakan studi komparasi Ex-post Facto. Populasi penelitian melibatkan anak usia 4-5 tahun berasal dari sekolah pendidikan anak usia dini yang berada di daerah perkotaan. Sampel dipilih sebanyak 50 (laki-laki = 27; perempuan = 23). Partisipasi sampel keseluruhan sebesar 78%. Sehingga sampel yang representatif sebanyak 39. Perkembangan Motorik anak diukur menggunakan Ages and Stages Questionaire (ASQ) 3rd Edition. Sedangkan untuk mengukur Status Sosial Ekonomi (SES) menggunakan Instrument (Scale) for Measuring the Socioeconomic Status of a family. Hasil penelitian menunjukkan bahwa perkembangan motorik anak usia dini tidak hanya dipengaruhi faktor status sosial ekonomi orang tua, juga dipengaruhi oleh tempat bermain yang tersedia di sekolah dan lingkungan bermain di rumah. Penelitian ini menunjukkan bahwa orang tua saat ini semakin memahami pentingnya pendidikan anak sejak dini dalam mengoptimalkan perkembangan anak. Sekolah dan lingkungan tempat tinggal merupakan salah satu wujud investasi terbaik untuk masa depan anak yang lebih baik.

Background: Symptomatic burden from constitutional symptoms, anemia, and splenomegaly-related symptoms are common and morbidity inducing in patients with myelofibrosis (MF). The authors previously developed a MF-specific instrument for capturing the burden of MF-associated disease-related symptoms, the Myelofibrosis Symptom Assessment Form.Methods: The authors evaluated the usefulness of serial administration of the Myelofibrosis Symptom Assessment Form as an instrument for the assessment of symptomatic burden and improvement in conjunction with the therapeutic clinical trial of the open label phase 2 trial of the JAK1 and JAK2 inhibitor INCB018424 in patients with MF.Results: The analysis cohort of 87 patients treated in this trial demonstrated that the instrument was comprehensive and sensitive to symptoms present at trial enrollment. In addition, baseline Myelofibrosis Symptom Assessment Form symptom scores correlated well with objective parameters such as splenomegaly and impaired performance status assessed by the 6-minute walk test. Serial administration while on therapy with INCB018424 demonstrated the instrument to be sensitive to symptomatic change, and that improvements in symptoms correlated well with objective improvements in both weight loss and performance status (6-minute walk test).Conclusions: The use of the Myelofibrosis Symptom Assessment Form in this phase 2 trial helped characterize the symptomatic improvements observed with use of INCB018424 in MF patients. In an era of many targeted therapies undergoing testing for MF with potential symptomatic benefit, the Myelofibrosis Symptom Assessment Form may provide a useful tool for objective symptomatic assessment and potentially allow some nonrandomized comparison between therapeutic agents. [ABSTRACT FROM AUTHOR]

Objective: To present the results of a long-term analysis of 2 sequential phase 2 trials of thalidomide (alone or in combination) for palliation of myelofibrosis with myeloid metaplasia (MMM).Patients and Methods: We analyzed (March 1999 to August 2003) initial and long-term outcomes from 36 patients with symptomatic MMM who had enrolled in either our thalidomide single-agent trial (n=15) or our trial of low-dose thalidomide (50 mg/d) combined with prednisone (n=21).Results: Among the 36 study patients, 20 (56%) showed some improvement in their clinical course. Response rates for specific end points included improvements in anemia (15 of 36 [42%]), thrombocytopenia (10 of 13 [77%]), or splenomegaly (5 of 30 [17%]). The combination of low-dose thalidomide and prednisone, as opposed to single-agent thalidomide, was better tolerated and more efficacious. After a median follow-up of 25 months (range, 20-56 months), 10 of 36 patients (28%) showed an ongoing response, including 8 patients in whom protocol treatment has been discontinued for a median of 21 months (range, 16-31 months). Durable treatment responses were documented for only anemia and thrombocytopenia. Treatment response was not affected by the baseline status of bone marrow fibrosis, angiogenesis, osteosclerosis, cytogenetics, or circulating myeloid progenitor (CD34) cell count. Unusual drug effects, all reversible, included leukocytosis (8 patients) and/or thrombocytosis (6 patients).Conclusions: Thalidomide (alone or combined with prednisone) is an effective first-line treatment of symptomatic anemia or thrombocytopenia in MMM. Thalidomide-based therapy has the potential to produce durable responses in MMM-associated cytopenias, even after discontinuation of the drug. [ABSTRACT FROM AUTHOR]

Artikel ini disajikan melalui kajian literatur yang berusaha memaparkan bagaimana proses kemampuan berpikir kritis dapat distimulasi melalui pembelajaran berbasis masalah pada pembelajaran penjas. Penulis mencoba memaparkan proses stimulasi berpikir kritis dari berbagai perspektif, diantaranya perspektif neurologi, sosiokultural, dan keadaan awal siswa serta berbagai hasil penelitian terkait berpikir kritis pada konteks pendidikan jasmani. Para guru penjas dapat mengimprovisasi kemampuan berpikir kritis melalui pembelajaran penjas berbasis masalah, dengan memperhatikan faktor-faktor pendukung lainnya seperti keadaan awal peserta didik meliputi IQ, gaya belajar, dsb. Serta aspek sosiokultural tempat peserta didik berinteraksi perlu menjadi pertimbangan dan perhatian, agar pembelajaran dapat berkualitas dan berdampak terhadap perkembangan peserta didik secara holistik.

This article is presented through a study of literature to explain the association of guided-discovery teaching styles with an effort to increase higher-order thinking that can also be said to be the level of critical thinking. In the guided-discovery teaching style, the teacher guides the student into discovery learning situations on movement problem. Movement problem solved is based on discovery results, from the process of knowing, understanding, applying, analyzing, synthesizing, and evaluating. Keywords: Guided-Discovery Teaching Style Higher-Order Thinking. ABSTRAK Artikel ini disajikan melalui kajian teoritis yang berupaya memaparkan keterkaitan gaya mengajar guided-discovery dengan upaya peningkatan higher-order thinking yang dapat pula dikatakan tingkat berpikir kritis. Pada gaya mengajar guided-discovery, guru membimbing siswa ke dalam situasi pembelajaran discovery tentang pemecahan masalah gerak. Pemecahan masalah gerak dilakukan berdasarkan hasil discovery, mulai dari proses mengetahui, memahami, menerapkan, menganalisis, mensintesis, dan mengevaluasi. Kata kunci: Gaya Mengajar Guided-Discovery Higher-Order Thinking.

IntroducciónEn los últimos años se ha producido un notable interés por la vitamina D, no sólo por su importancia crucial en el metabolismo mineral óseo, sino también por los efectos extraóseos, cada vez mejor conocidos. Asi mismo, se ha constatado la existencia de valores séricos bajos de vitamina D, por debajo de lo deseable, en diferentes poblaciones, tanto sanas como enfermas, y se discute cuáles serían los niveles óptimos de vitamina D en sangre. Por todo ello, la Sociedad Española de Investigación Ósea y Metabolismo Mineral (SEIOMM), conjuntamente con todas las Sociedades Científicas implicadas en el estudio del metabolismo óseo, han elaborado el presente documento de posición sobre las necesidades y niveles óptimos de vitamina D.

OBJECTIVE: To define associated clinical conditions, pathology, natural history, and treatment outcome of nonhepatosplenic extramedullary hematopoiesis (NHS-EMH). PATIENTS AND METHODS: We retrospectively reviewed the medical charts of all patients identified as having NHS-EMH from 1975 to 2002. Diagnosis was made by tissue biopsy, fine-needle aspiration biopsy, or radionuclide bone marrow scanning. RESULTS: We identified 27 patients with antemortem diagnosis of NHS-EMH. The most common associated condition and disease site were myelofibrosis with myeloid metaplasia (MMM) (in 18 patients [67%]) and the vertebral column (in 7 patients [26%]; all involving the thoracic region), respectively. At the time of diagnosis of NHS-EMH, concurrent splenic EMH (in 22 patients [82%]; 15 [56%] had undergone splenectomy) and red blood cell transfusion dependency (in 12 patients [44%]) were prevalent. Of the 27 patients, 9 (33%) required no specific therapy. Specific therapy was radiation (in 7 patients with a 71% response rate) and surgical excision (in 6 patients with a 67% response). Treatment-associated complications were limited to surgery. Radiation therapy was not used in the non-MMM group, but low-dose radiation therapy was used in the MMM group for paraspinal or intraspinal EMH (median dose, 1 Gy; range, 1-10 Gy), pleural or pulmonary disease (median dose, 1.25 Gy; range, 1.00-1.50 Gy), and abdominal or pelvic disease (median dose, 2.02 Gy; range, 150-4.50 Gy). Median survival after the diagnosis of NHS-EMH was 13 months in the MMM group and 21 months in the non-MMM group. CONCLUSIONS: This retrospective study suggests that NHS-EMH is rare, is often associated with MMM, and preferentially affects the thoracic spinal region. Asymptomatic disease may require no specific treatment, whereas symptomatic disease is best managed with low-dose radiation therapy. [ABSTRACT FROM AUTHOR]

Advances in anticancer therapies have provided crucial benefits for millions of patients who are living long and fulfilling lives. Although these successes should be celebrated, there is certainly room to continue improving cancer care. Increased long-term survival presents additional challenges for determining whether new therapies further extend patients' lives through clinical trials, commonly known as the gold standard endpoint of overall survival (OS). As a result, an increasing reliance is observed on earlier efficacy endpoints, which may or may not correlate with OS, to continue the timely pace of translating innovation into novel therapies available for patients. Even when not powered as an efficacy endpoint, OS remains a critical indication of safety for regulatory decisions and is a key aspect of the FDA's Project Endpoint. Unfortunately, in the pursuit of earlier endpoints, many registrational clinical trials lack adequate planning, collection, and analysis of OS data, which complicates interpretation of a net clinical benefit or harm. This article shares best practices, proposes novel statistical methodologies, and provides detailed recommendations to improve the rigor of using OS data to inform benefit-risk assessments, including incorporating the following in clinical trials intending to demonstrate the safety and effectiveness of cancer therapy: prospective collection of OS data, establishment of fit-for-purpose definitions of OS detriment, and prespecification of analysis plans for using OS data to evaluate for potential harm. These improvements hold promise to help regulators, patients, and providers better understand the benefits and risks of novel therapies., (©2024 American Association for Cancer Research.)

The phase 3b FREEDOM trial (ClinicalTrials.gov: NCT03755518) evaluates efficacy/safety of fedratinib in intermediate- or high-risk myelofibrosis patients with platelet count ≥50 × 10 9 /L, previously treated with ruxolitinib. The trial design included protocol specified strategies to mitigate the risk for gastrointestinal (GI) adverse events (AEs), thiamine supplementation, and encephalopathy surveillance. Due to COVID-19, accrual was cut short with 38 patients enrolled. In the efficacy evaluable population ( n  = 35), nine (25.7%; 95% confidence interval 12.5-43.3) patients achieved primary endpoint of ≥35% spleen volume reduction (SVR) at end of cycle (EOC) 6; and 22 (62.9%) patients showed best overall response of ≥35% SVR up to end of treatment. Sixteen (44.4%) patients showed ≥50% reduction in total symptom score at EOC6 ( n  = 36). Compared to previously reported JAKARTA-2 trial, rates of GI AEs were lower, and no patient developed encephalopathy. Overall, FREEDOM study showed clinically relevant spleen and symptom responses with fedratinib, and effective mitigation of GI AEs.

There has been remarkable progress in the development of novel therapeutic approaches for patients with polycythemia vera (PV). Historically, therapy goals in PV were to mitigate thrombotic risks and control blood counts and symptoms. There is now increased focus on disease modification through progressive attrition of JAK2 -mutant stem/progenitor cells. The approval of ropeginterferon, a novel monoPEGylated interferon, coupled with findings from LOW-PV and longer-term data from CONTINUATION-PV that strongly support a disease-modifying effect for interferon therapy, have transformed the treatment paradigm for this disorder. Results from MAJIC-PV demonstrate that disease modification can also be induced with JAK inhibitors, suggesting an urgent need to incorporate prospective molecular monitoring into PV trials. Novel agents, such as hepcidin mimetics, aim to help patients with PV restore normal hematocrit levels and become phlebotomy-free. In this review, we will summarize past, current and future approaches to PV management and highlight findings from key clinical studies.

Introduction: Distinct, disease-associated intracellular miRNA (miR) expression profiles have been observed in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematous (SLE) patients. Additionally, we have identified novel estrogenic responses in PBMCs from SLE patients and demonstrated that estrogen upregulates toll-like receptor (TLR)7 and TLR8 expression. TLR7 and TLR8 bind viral-derived single-stranded RNA to stimulate innate inflammatory responses, but recent studies have shown that miR-21, mir-29a, and miR-29b can also bind and activate these receptors when packaged and secreted in extracellular vesicles (EVs). The objective of this study was to evaluate the association of EV-encapsulated small RNA species in SLE and examine the therapeutic approach of miR inhibition in humanized mice., Methods: Plasma-derived EVs were isolated from SLE patients and quantified. RNA was then isolated and bulk RNA-sequencing reads were analyzed. Also, PBMCs from active SLE patients were injected into immunodeficient mice to produce chimeras. Prior to transfer, the PBMCs were incubated with liposomal EVs containing locked nucleic acid (LNA) antagonists to miR-21, mir-29a, and miR-29b. After three weeks, blood was collected for both immunophenotyping and cytokine analysis; tissue was harvested for histopathological examination., Results: EVs were significantly increased in the plasma of SLE patients and differentially expressed EV-derived small RNA profiles were detected compared to healthy controls, including miR-21, mir-29a, and miR-29b. LNA antagonists significantly reduced proinflammatory cytokines and histopathological infiltrates in the small intestine, liver, and kidney, as demonstrated by H&E-stained tissue sections and immunohistochemistry measuring human CD3., Discussion: These data demonstrate distinct EV-derived small RNA signatures representing SLE-associated biomarkers. Moreover, targeting upregulated EV-encapsulated miR signaling by antagonizing miRs that may bind to TLR7 and TLR8 reveals a novel therapeutic opportunity to suppress autoimmune-mediated inflammation and pathogenesis in SLE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Young, Schwarz, Zeno, Bruckner, Mesa, Jablonski, Wu, Roberson and Jarjour.)

Purpose: To determine whether high-sensitivity C-reactive protein (hsCRP) is associated with incident Metabolic Syndrome (MetS) among U.S. Hispanic/Latino adults. Patients and Methods: The Hispanic Community Health Study/Study of Latinos is a longitudinal observational cohort assessing cardiovascular health among diverse U.S. Hispanic/Latino adults. hsCRP was measured at visit 1 (2008-2011) and classified as low, moderate, or high, based on the Centers for Disease Control and Prevention and American Heart Association (CDC/AHA) guidelines. All MetS components [abdominal obesity, triglycerides, high-density lipoprotein (HDL) cholesterol, blood pressure, and fasting glucose] were measured at visit 1 and visit 2 (2014-2017). MetS was defined as the presence of three or more components based on the 2005 definition from the modified Third Report of the National Cholesterol Education Program Adult Treatment Panel (modified NCEP ATP III). Participants free of MetS at visit 1 and with complete data on hsCRP and all MetS components were included ( n  = 6121 participants). We used Poisson regression analysis to determine whether hsCRP was associated with incident MetS after adjusting for demographic, behavioral, and clinical factors. All analyses accounted for the complex survey design of the study. Results: In fully adjusted models, moderate versus low hsCRP was associated with a 33% increased risk of MetS [incidence rate ratio (IRR): 1.33, 95% confidence interval (CI): 1.10-1.61], while high versus low hsCRP was associated with a 89% increased risk of MetS (IRR: 1.89, 95% CI: 1.58-2.25). Conclusions: Greater levels of hsCRP were associated with new onset of MetS in a diverse sample of U.S. Hispanic/Latino adults. Results suggest that hsCRP may be an independent risk factor for MetS.

Objective: To evaluate whether hypertensive disorders of pregnancy, including gestational hypertension, preeclampsia, and eclampsia, are associated with cognitive decline later in life among U.S. Hispanic/Latina individuals., Methods: The HCHS/SOL (Hispanic Community Health Study/Study of Latinos) is a prospective population-based study of Hispanic/Latino individuals aged 18-74 years from four U.S. communities. This analysis included parous individuals aged 45 years or older who participated in the HCHS/SOL clinic study visit 1 (2008-2011) neurocognitive assessment and subsequently completed a repeat neurocognitive assessment as part of the Study of Latinos-Investigation of Neurocognitive Aging ancillary study visit 2 (2015-2018). Hypertensive disorders of pregnancy were assessed retrospectively by self-report of any gestational hypertension, preeclampsia, or eclampsia. Cognitive functioning was measured at both study visits with the Brief Spanish-English Verbal Learning Test, Digit Symbol Substitution, and Word Fluency. A regression-based approach was used to define cognitive decline at visit 2 as a function of cognition at visit 1 after adjustment for age, education, and follow-up time. Linear regression models were used to determine whether hypertensive disorders of pregnancy or their component diagnoses were associated with standardized cognitive decline after adjustment for sociodemographic characteristics, clinical and behavioral risk factors, and follow-up time., Results: Among 3,554 individuals included in analysis, the mean age was 56.2 years, and 467 of individuals (13.4%) reported at least one hypertensive disorder of pregnancy. Individuals with hypertensive disorders of pregnancy compared with those without were more likely to have higher mean systolic blood pressure, fasting glucose, and body mass index. After an average of 7 years of follow-up, in fully adjusted models, gestational hypertension was associated with a 0.17-SD relative decline in Digit Symbol Substitution scores (95% CI, -0.31 to -0.04) but not other cognitive domains (Brief Spanish-English Verbal Learning Test or Word Fluency). Neither preeclampsia nor eclampsia was associated with neurocognitive differences., Conclusion: The presence of preeclampsia or eclampsia was not associated with interval neurocognitive decline. In this cohort of U.S. Hispanic/Latina individuals, gestational hypertension alone was associated with decreased processing speed and executive functioning later in life., Competing Interests: Financial Disclosure Tali Elfassy received support from the NIH/National Institute on Minority Health and Health Disparities (MD014158). Shathiyah Kulandavelu received support from American Heart Association (19CDA34660102). Leah Dodds received support from the NIH/National Heart, Lung, and Blood Institute (HL165894). Krista M. Perreira's institution received payment from the NIH, Russell Sage Foundation, and the Urban Institute. She received an honorarium from the University of Tennessee. Richard B. Lipton received payment from AbbVie, Amgen, and Pfizer. Dr. Lipton is the Edwin S. Lowe Professor of Neurology at the Albert Einstein College of Medicine in New York. He receives research support from the NIH: 2PO1 AG003949 (mPI), 1RF1 AG057531 (site PI), RF1 AG054548 (investigator), 1RO1 AG048642 (investigator), R56 AG057548 (investigator), RO1 AG060933 (investigator), RO1 AG062622 (investigator), 1UG3FD006795 (mPI), 1U24NS113847 (investigator), U01 AT011005 (investigator), 1R01 AG075758 (pending, investigator), 1R01 AG077639 (pending, investigator), and K23 NS107643 (mentor). He also receives support from the Migraine Research Foundation and the National Headache Foundation and research grants from TEVA, Satsuma, and Amgen. He serves on the Editorial Board of Neurology , is a senior advisor to Headache , and is an associate editor for Cephalalgia . He has reviewed for the National Institute on Aging and National Institute of Neurological Disorders and Stroke; holds stock and stock options in Biohaven Holdings as well as stock options in Manistee; and serves as consultant or advisory board member for or has received honoraria from the following: AbbVie (Allergan), American Academy of Neurology, American Headache Society, Amgen, Avanir, Axon, Axsome, Biohaven, Biovision, Boston Scientific, Dr. Reddy's (Promius), Electrocore, Eli Lilly, eNeura Therapeutics, Equinox, GlaxoSmithKline, Grifols, Lundbeck (Alder), Merck, Pernix, Pfizer, Satsuma, Supernus, Teva, Trigemina, Vector, and Vedanta. He receives royalties from Wolff's Headache 7th and 8th editions, Oxford Press University, 2009, Wiley and Informa. The other authors did not report any potential conflicts of interest., (Copyright © 2024 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Patients with myelofibrosis develop symptoms due to bone marrow fibrosis, systemic inflammation, and/or organomegaly. Alleviating symptoms improves overall quality of life. Clinical trials have historically defined symptom response as a reduction of at least 50% in Total Symptom Score at week 24 compared with baseline. Whether 50% constitutes a meaningful benefit has not been established. This study determined the meaningful change threshold (MCT) for 2 momelotinib phase III trials, SIMPLIFY-1 and SIMPLIFY-2., Methods: The absolute and percentage MCT was determined using anchor-based methods applied to the modified Myeloproliferative Neoplasm Symptom Assessment Form v2.0 and Patient Global Impression of Change. MCTs were applied retrospectively to determine responder rates. Generalized estimating equations estimated the treatment-related difference in likelihood of improvement., Results: In SIMPLIFY-1, a Janus kinase inhibitor-naive population, the MCT was 8 points. In SIMPLIFY-2, a previously Janus kinase inhibitor-treated population, the MCT was 6 points. A 32% MCT was determined in both studies, showing that the historic 50% reduction threshold may be a conservative choice. In SIMPLIFY-1, a similar proportion of patients achieved responder status with 24 weeks of momelotinib or ruxolitinib therapy based on the absolute MCT (39% vs 41%, respectively). In SIMPLIFY-2, a significantly greater proportion of patients treated with momelotinib achieved responder states compared with best available therapy based on absolute and percent change MCTs., Conclusions: This study demonstrates that momelotinib provided clinically meaningful symptom benefit for patients with myelofibrosis and provides insight into the appropriateness of the symptom change threshold used in historical studies., Competing Interests: Author Disclosures Author disclosure forms can be accessed in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Social determinants of health (SDOH) are fundamental causes of poor cardiovascular health, yet cardiovascular disease (CVD) risk assessment tools exclude SDOH. Our objective was to determine whether SDOH are independently associated with CVD risk in US adults., Methods: Utilizing the National Health and Nutrition Examination Survey (NHANES), we combined years 1999-2018 and included participants aged 40-79 without history of CVD and with information to calculate CVD risk (n = 21,694). Ten-year risk of atherosclerotic CVD (ASCVD) was calculated using the American Heart Association/American College of Cardiology (AHA/ACC) pooled cohort equations. We used linear regression models to estimate the association between SDOH and ASCVD risk, after adjusting for demographic factors. All analyses accounted for the complex survey design., Results: Mean age was 54.7 years, with 52.7 % female, 73.8 % non-Hispanic White, 9.4 % non-Hispanic Black, and 10.7 % Hispanic. From adjusted models, compared with an income of ≥ $75 K, ASCVD risk was greater by 3.06 (95 % CI: 2.65, 3.47) among those with income < $25 K, by 1.55 (95 % CI: 1.21, 1.89) among those with income $25 K-<$55 K, and by 1.20 (95 % CI: 0.84, 1.56) among those with income $55 K-<$75 K. Compared to college graduates, ASCVD risk was greater by 3.09 (95 % CI: 2.56, 3.62) among those with less than a high school education, by 1.65 (95 % CI: 1.31, 200) among those who were high school graduates, and by 1.41 (95 % CI: 1.11, 1.72) among those with some college education., Conclusion: We found strong graded associations between lower income and lower educational attainment with greater CVD risk., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Inc.)

Purpose: Chronic inflammation is integral to myeloproliferative neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among patients with MPN., Experimental Design: We randomly assigned patients with MPN to either a Mediterranean diet or standard U.S. Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four timepoints during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome., Results: The Mediterranean diet was as easy to follow for patients with MPN as the standard USDA diet. Approximately 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any timepoint. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention., Conclusions: With dietician counseling and written education, patients with MPN can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially incorporated into the management of other hematologic conditions., Significance: Diet is a central tenant of management of chronic conditions characterized by subclinical inflammation, such as cardiovascular disease, but has not entered the treatment algorithm for clonal hematologic disorders. Here, we establish that a Mediterranean diet intervention is feasible in the MPN patient population and can improve symptom burden. These findings warrant large dietary interventions in patients with hematologic disorders to test the impact of diet on clinical outcomes., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Using data from the National Health and Nutrition Examination Survey (2001-2018; N = 19,602), this study examined whether ultra-processed food (UPF) consumption is associated with cardiometabolic health (obesity, hypertension, high cholesterol, and diabetes), among White, Black, Hispanic, and Asian Americans (AA) US adults 50 or older. Diet was assessed using 24 hour dietary recall. NOVA dietary classification system was used to calculate the percentage of caloric intake derived from UPFs. Cardiometabolic information was assessed through physical examination, blood tests, and self-reported medication information. A median of 54% (IQR: 40%, 68%) of caloric intake was attributed to UPFs and was lowest for AAs (34%, IQR: 20%, 49%) and highest for White adults (56%; IQR: 42, 69%). In multivariable adjusted models, UPF consumption was associated with greater odds of obesity, high cholesterol, and diabetes. UPF consumption is associated with poor cardiometabolic health among all US older adults. For AAs, UPFs may be particularly obesogenic., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Among certain immigrant groups, length of time spent living in the United States (LOT) is associated with poor cardiometabolic health. We aimed to evaluate the association between LOT and cardiometabolic outcomes among US Black adults., Methods: The National Health Interview Survey is an annual representative survey of non-institutionalized US civilians. We combined 2016-2018 data and included all Black adults (N = 10,034). LOT was defined as the number of years lived in the US, if foreign-born. Obesity, hypertension, diabetes, and high cholesterol were each self-reported. We used logistic regression models to determine whether LOT was associated with cardiometabolic health factors overall and by origin subgroups-US-born non-Hispanic, Hispanic, African-born, and Caribbean/Central American (CA)-born groups., Results: Our study population was 81% US-born non-Hispanic, 5% Hispanic (both foreign- and US-born), 6% African-born, and 6% Caribbean/CA-born groups. Among Black adults, compared with the US-born, being foreign-born with < 15 years in the US was associated with lower odds of obesity (OR: 0.31, 95%CI: 0.23-0.42) and hypertension (OR: 0.35, 95%CI: 0.24-0.49). In subgroup analyses, Caribbean/CA-born individuals with < 15 years in the US had 64% lower odds of obesity (OR: 0.36, 95%CI 0.15-0.84) and 63% lower odds of hypertension (OR: 0.37, 95%CI 0.15-0.88) compared with those with ≥ 15 years., Conclusion: Shorter LOT was associated with more favorable cardiometabolic health, with differential associations among foreign-born Black adults based on origin. This heterogeneity suggests a need to examine the implications of acculturation in the context of the specific population of interest., (© 2024. W. Montague Cobb-NMA Health Institute.)

Background: Life's Essential 8 (LE8) is a new metric to define cardiovascular health. We aimed to describe LE8 among Hispanics/Latinos and its association with incident hypertension., Methods and Results: The HCHS/SOL (Hispanic Community Health Study/Study of Latinos) is a study of Hispanic/Latino adults aged 18 to 74 years from 4 US communities. At visit 1 (2008-2011), information on behavioral and clinical factors (diet, smoking status, physical activity, sleep duration, body mass index, blood pressure, cholesterol, fasting glucose, and medication use) were measured and used to estimate an LE8 score (range, 0-100) for 14 772 participants. Hypertension was defined as systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥80 mm Hg, or self-reported use of antihypertensive medications. Among the 5667 participants free from hypertension at visit 1, we used Poisson regression models to determine the multivariable adjusted association between LE8 and incident hypertension in 2014 to 2017. All analyses accounted for the complex survey design of the study. Mean population age was 41 years, and 21.6% (SE, 0.7) had high cardiovascular health (LE8 ≥80). Mean LE8 score (68.2; SE, 0.3) varied by Hispanic/Latino background ( P <0.05), ranging from 72.6 (SE, 0.3) among Mexican Americans to 62.2 (SE, 0.4) among Puerto Ricans. Each 10-unit decrement in LE8 score was associated with a 22% increased risk of hypertension over ≈6 years (incident density ratio, 1.22 [95% CI, 1.16-1.29])., Conclusions: Only 1 in 5 Hispanic/Latino adults had high cardiovascular health, and LE8 varied substantially across Hispanic/Latino background groups. Improvements in other components of cardiovascular health may result in a lower risk of developing hypertension.

Background Albuminuria is a known marker of mortality risk. Whether the association between albuminuria and mortality differs by demographic and comorbidity factors remains unclear. Therefore, we sought to determine whether albuminuria is differentially associated with mortality. Methods and Results This study included 49 640 participants from the National Health and Nutrition Examination Survey (1999-2018). All-cause mortality through 2019 was linked from the National Death Index. Multivariable-adjusted Poisson regression models were used to determine whether levels of urine albumin-to-creatinine ratio (ACR) were associated with mortality. Models were adjusted for demographic, socioeconomic, behavioral, and clinical factors. Mean age in the population was 46 years, with 51.3% female, and 30.3% with an ACR ≥10 mg/g. Over a median follow-up of 9.5 years, 6813 deaths occurred. Compared with ACR <10, ACR ≥300 was associated with increased risk of mortality by 132% overall (95% CI, 2.01-2.68), 124% among men (95% CI, 1.84-2.73), 158% among women (95% CI, 2.14-3.11), 130% among non-Hispanic White adults (95% CI: 1.89-2.79), 135% among non-Hispanic Black adults (95% CI, 1.82-3.04), and 114% among Hispanic adults (95% CI, 1.55-2.94). Compared with ACR <10, ACR ≥300 was associated with increased risk of mortality by 148% among individuals with neither hypertension nor hypercholesterolemia (95% CI, 1.69-3.64), 128% among individuals with hypertension alone (95% CI, 1.86-2.79), and 166% among individuals with both hypertension and hypercholesterolemia (95% CI, 2.18-3.26). Conclusions We found strong associations between albuminuria and mortality risk, even at mildly increased levels of albuminuria. Associations persisted across categories of sex, race or ethnicity, and comorbid conditions, with subtle differences.

Summary: Basic and clinical cancer research discoveries stemming from the nation's cancer centers have markedly improved outcomes for many cancer patients. Despite this forward momentum in our progress against this complex disease, cancer in all its forms remains a major public health challenge that touches the lives of nearly every American, either directly or indirectly. The newly formed AACR Cancer Centers Alliance will accelerate the pace of discovery by providing an ongoing mechanism for transferring new knowledge, sharing resources, developing national demonstration projects, and driving innovation that impacts cancer science, cancer care delivery, and science and health policy., (©2023 American Association for Cancer Research.)

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm that typically manifests with debilitating symptoms that progressively worsen, negatively impacting patients' quality of life. Fatigue is a multifactorial and burdensome MF-related symptom due to its severity, persistence, and prevalence, with anemia a contributing factor and major unmet need. Clinical trials of the Janus kinase (JAK)1/JAK2/activin A receptor type 1 inhibitor momelotinib have shown consistent anemia benefits, in addition to improvements in MF-related symptoms. The phase 3 MOMENTUM trial in symptomatic and anemic patients met its primary end point, with a greater proportion having a Myelofibrosis Symptom Assessment Form (MFSAF) Total Symptom Score (TSS) reduction ≥50% at week 24 with momelotinib versus danazol. To support the positive primary end point result, we conducted longitudinal, responder, and time-to-event analyses of patient-reported outcomes from MOMENTUM, as measured by the MFSAF, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and Patient-Reported Outcomes Measurement Information System (PROMIS) assessments. These analyses demonstrated rapid and durable response benefits with momelotinib, with achievement of first TSS response by day 29 and continued improvement over time. Improvements favored momelotinib versus danazol for each MFSAF individual item, and greater improvements were observed for disease- and cancer-related fatigue and physical functioning at week 24, with significant results for multiple items/domains across the 3 assessments. These findings are consistent in demonstrating that momelotinib provides substantial symptom benefit., Competing Interests: RAM has consulted and received honoraria from Novartis, Sierra Oncology, Gentech, Blueprint, Geron, Telios, CTI, Incyte, BMS, AbbVie, GSK and Morphosys. CH has consulted for Galecto DISC and Keros and received compensation; received honoraria from Novartis, CTI, BMS, Sierra, and GSK; participated on an Ad Board for AOP, Telios, Sumitomo, and Keros; and had a leadership role in EHA, HemaSphere, and MPN Voice. VG has consulted for Novartis, BMS Celgene, Sierra Oncology, AbbVie, Constellation Biopharma, Pfizer, GSK Pharma, and CTI Biopharma and received compensation; received honoraria from Novartis and BMS Celgene; and received compensation for participation on an Ad Board for BMS Celgene, Roche, AbbVie, Pfizer, Sierra Oncology, and CTI Biopharma. DPM received a research grant from Imago Biosciences; received honoraria from JAZZ Pharma, AbbVie, and Novartis; participated in the UK ALL RIC TRIAL – DSM board and is an EBMT Scientific Council Member Chair of the EBMT CMWP. MFM received honoraria from Novartis, Abbvie, and AOP; and received compensation for participation on an Ad Board from Novartis, BMS, AbbVie, CTI, Sierra Oncology, and GSK. J-JK received compensation and participated in Ad Boards for Novartis, AbbVie, BMS, GSK, Incyte, and AOP Health. LF received honoraria from Novartis and BMS and participated in Ad Boards for Incyte and GS. MLF has consulted for Novartis, GSK, AbbVie, and Sierra Oncology and received compensation; and received honoraria from Novartis and BMS and attended meetings for AbbVie. DMR has consulted for Keros, and the institution received compensation; received honoraria from Novartis personally and to the institution; received compensation from Novartis to attend a meeting; received compensation to the institution for participation on an Ad Board from Novartis, Menarini, and Takeda. STO has consulted for AbbVie, Constellation, CTI BioPharma, BMS, Geron, Sierra Oncology, Cogent, Protagonist, and Incyte and received compensation. JK owned stock in Sierra Oncology and owns stock in Gilead. SR and RD owned stock in Sierra Oncology. SD is an employee at Sierra Oncology. BG received compensation from GSK for attending meetings and owns stock in GSK. SV received compensation for participation on an Ad Board. UP received honoraria and research support from Geron, GSK, Novartis, Abbvie, and Curis. JMP received honoraria to the institution from CTI; and received compensation to the institution for participation in an Ad Board for Morphosys. AJM received support from Abbvie for the present article; received grants or contracts from Celgene/BMS; received royalties or licenses from Alethiomics; received consulting fees from Celgene/BMS paid to the Sierra Oncology, Novartis paid to Karyopharm, Abbvie paid to Sensyn, and CTI paid to Incyte, Galecto, Pfizer, and Gilead; received honoraria from Celgene/BMS, Novartis, and Abbvie; received support to attend meetings from Celgene/BMS and Novartis; and participated on an Ad Board for Celgene/BMS and Abbvie. All authors received medical writing support for this article funded by Sierra Oncology, a GSK company. All the other authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

In patients with cytopenic myelofibrosis, treatment with the JAK2/IRAK1 inhibitor pacritinib was associated with anemia benefit in the phase 3 PERSIST-2 study. The impact of pacritinib on transfusion independence (TI) has not been previously described, nor has the mechanism by which pacritinib improves anemia been elucidated. Because it has been previously postulated that inhibition of activin A receptor, type 1 (ACVR1)/activin receptor-like kinase-2 improves anemia in patients with myelofibrosis via suppression of hepcidin production, we assessed the relative inhibitory potency of pacritinib compared with other JAK2 inhibitors against ACVR1. Pacritinib inhibited ACVR1 with greater potency (half-maximal inhibitory concentration [IC50] = 16.7 nM; Cmax:IC50 = 12.7) than momelotinib (IC50 = 52.5 nM; Cmax:IC50 = 3.2), fedratinib (IC50 = 273 nM; Cmax:IC50 = 1.0), or ruxolitinib (IC50 > 1000; Cmax:IC50 < 0.01). Pacritinib's inhibitory activity against ACVR1 was corroborated via inhibition of downstream SMAD signaling in conjunction with marked suppression of hepcidin production. Among patients on PERSIST-2 who were not transfusion independent at baseline based on Gale criteria, a significantly greater proportion achieved TI on pacritinib compared with those treated on best available therapy (37% vs 7%, P = .001), and significantly more had a ≥50% reduction in transfusion burden (49% vs 9%, P < .0001). These data indicate that the anemia benefit of the JAK2/IRAK1 inhibitor pacritinib may be a function of potent ACVR1 inhibition., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, anemia, extramedullary hematopoiesis, and splenomegaly. Patients with MF are at risk for reduced survival versus the general population and often experience burdensome signs and symptoms that reduce quality of life. The oral Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib was initially approved by the US Food and Drug Administration in 2011 for the treatment of patients with intermediate or high-risk MF, including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF, based on efficacy and safety findings from the randomized, controlled, phase 3 COMFORT trials. Over a decade later, ruxolitinib continues to be the standard of care in higher-risk MF, and dose optimization and management remain crucial for safely maximizing clinical benefits of ruxolitinib. This review summarizes the safety profile of ruxolitinib in patients with MF in the COMFORT trials leading up to approval and in the subsequent JUMP, ROBUST, EXPAND, and REALISE trials; in pooled analyses; and in postmarketing analyses in the 10 years following approval. There is a focus on the occurrence of common hematologic and nonhematologic adverse events, with guidance provided on the management of patients with anemia or thrombocytopenia, including dosing strategies based on findings from the REALISE and EXPAND trials. Finally, to ensure a greater understanding of the safety profile of ruxolitinib, practical considerations are discussed., (© 2023. The Author(s).)

Purpose: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (MF) or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F-mutant cell lines., Patients and Methods: In a phase I dose-escalation and -expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor, umbralisib, in combination with ruxolitinib in patients with MF who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that MTD at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose-escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas., Results: Thirty-seven patients with MF (median age, 67 years) with prior exposure to ruxolitinib were enrolled. A total of 2 patients treated with 800 mg umbralisib experienced reversible grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved a durable complete response, and 12 patients (32%) met the International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria of clinical improvement. With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up., Conclusions: Adding umbralisib to ruxolitinib in patients was well tolerated and may resensitize patients with MF to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors. Randomized trials testing umbralisib in the treatment of MF should be pursued., (©2023 American Association for Cancer Research.)

Purpose: Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms., Patients and Methods: MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response., Results: One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; P = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; P < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; P = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; P = .03). Serial analysis of JAK2 V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] P = .001, EFS P = .001, overall survival P = .01) and clearance of JAK2 V617F stem/progenitor cells. ASXL 1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; P = .003). The safety profile of ruxolitinib was as previously reported., Conclusion: The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.

Background: In a pooled analysis of the phase 3 Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I (COMFORT-I) and COMFORT-II clinical trials, adult patients with intermediate-2 or high-risk myelofibrosis who received oral ruxolitinib at randomization or after crossover from placebo or best available therapy (BAT) had improved overall survival (OS)., Methods: This post hoc analysis of pooled COMFORT data examined relevant disease outcomes based on the disease duration (≤12 or >12 months from diagnosis) before ruxolitinib initiation., Results: The analysis included 525 patients (ruxolitinib: ≤12 months, n = 84; >12 months, n = 216; placebo/BAT: ≤12 months, n = 66; >12 months, n = 159); the median age was 65.0-70.0 years. Fewer thrombocytopenia and anemia events were observed among patients who initiated ruxolitinib treatment earlier. At Weeks 24 and 48, the spleen volume response (SVR) was higher for patients who initiated ruxolitinib earlier (47.6% vs. 32.9% at Week 24, p = .0610; 44.0% vs. 26.9% at Week 48, p = .0149). In a multivariable analysis of factors associated with spleen volume reduction, a logistic regression model that controlled for confounding factors found that a significantly greater binary reduction was observed among patients with shorter versus longer disease duration (p = .022). At Week 240, OS was significantly improved among patients who initiated ruxolitinib earlier (63% [95% CI, 51%-73%] vs. 57% [95% CI, 49%-64%]; hazard ratio, 1.53; 95% CI, 1.01-2.31; p = .0430). Regardless of disease duration, a longer OS was observed for patients who received ruxolitinib versus those who received placebo/BAT., Conclusions: These findings suggest that earlier ruxolitinib initiation for adult patients with intermediate-2 and high-risk myelofibrosis may improve clinical outcomes, including fewer cytopenia events, durable SVR, and prolonged OS., Plain Language Summary: Patients with myelofibrosis, a bone marrow cancer, often do not live as long as the general population. These patients may also have an enlarged spleen and difficult symptoms such as fatigue. Two large clinical trials showed that patients treated with the drug ruxolitinib lived longer and had improved symptoms compared to those treated with placebo or other standard treatments. Here it was examined whether starting treatment with ruxolitinib earlier (i.e., within a year of diagnosis) provided benefits versus delaying treatment. Patients who received ruxolitinib within a year of diagnosis lived longer and experienced fewer disease symptoms than those whose treatment was delayed., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Introduction: Ruxolitinib has been the cornerstone of pharmacologic therapy for myelofibrosis for over a decade. However, the last several years have witnessed the regulatory approval of other Janus kinase (JAK) inhibitors for myelofibrosis, i.e. fedratinib, pacritinib, and US approval of momelotinib is widely anticipated in 2023., Areas Covered: Due to the multifaceted clinical presentation of myelofibrosis, a watertight definition of ruxolitinib failure has remained elusive, as "progression" on ruxolitinib can take many forms and management is highly nuanced. Yet, the availability of other JAK inhibitors and potential future availability of non-JAK inhibitor agents for myelofibrosis make a consensus on management of ruxolitinib failure critically important. This consensus paper summarizes a discussion between multiple academic and community physician experts, a pharmacist and an advanced practice provider around the issues to be considered for the optimal care of patients with myelofibrosis whose disease is refractory to or does not respond adequately to ruxolitinib, or who exhibit intolerance to ruxolitinib., Expert Opinion: The panel identified several areas of consensus, as well as some areas where more data to inform evidence-based practice are needed. In some situations, maintaining ruxolitinib while adding another agent, e.g. to address anemia, is appropriate, whereas in others, switching to a different drug has merit.

Background: Myelofibrosis (MF)-associated constitutional symptoms can severely impact health-related quality of life. Clinical trials in MF traditionally measure symptom response to treatment as a landmark endpoint of total symptom score (TSS) reduction ≥50% from baseline. However, this dichotomous assessment provides a limited view of clinically relevant symptomatic changes. Herein we evaluated longitudinal change from baseline in TSS over the continuous 24-week period and individual symptom scores to obtain a more comprehensive understanding of symptom benefits experienced by patients with MF receiving therapy., Methods: Longitudinal symptom change was evaluated using mixed-effect model repeated measure (MMRM) methodology with individual item-level analyses to complement the interpretation of the landmark symptom results in the completed phase III SIMPLIFY studies of momelotinib in MF. MMRM compared mean change in TSS from baseline with Week 24 using data from all patient visits. Generalized estimating equations were used to estimate item-level odds ratios using multiple predictive imputations for missing data., Results: Momelotinib and ruxolitinib groups reported similar overall symptom improvements, with a TSS difference of <1.5 points between groups for each post-baseline visit in SIMPLIFY-1. In SIMPLIFY-2, the improvement in TSS observed in momelotinib-treated patients was consistent with that observed in SIMPLIFY-1, whereas progressive TSS deterioration was observed with control. Item-level scores were heterogeneous in both studies. A similar and greater proportion of momelotinib-treated patients were categorized as "improved" or "stable" compared with control in SIMPLIFY-1 and SIMPLIFY-2, respectively. Odds ratios for between-group comparison ranged from 0.75 to 1.21 in SIMPLIFY-1, demonstrating similarity in likelihood of symptom improvement. In SIMPLIFY-2, the likelihood of symptom improvement in each item was higher in the momelotinib arm., Conclusions: These findings suggest that momelotinib provides clinically relevant symptom benefits in the JAK inhibitor-naïve and JAK inhibitor-exposed settings., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)