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International Journal of Hematology May 2022Myelofibrosis is a chronic hematologic malignancy characterized by constitutional symptoms, bone marrow fibrosis, extramedullary hematopoiesis resulting in splenomegaly... (Review)
Review
Myelofibrosis is a chronic hematologic malignancy characterized by constitutional symptoms, bone marrow fibrosis, extramedullary hematopoiesis resulting in splenomegaly and a propensity toward leukemic progression. Given the central role of the JAK-STAT pathway in the pathobiology of myelofibrosis, JAK inhibitors are the mainstay of current pharmacologic management. Although these therapies have produced meaningful improvements in splenomegaly and symptom burden, JAK inhibitors do not significantly impact disease progression. In addition, many patients are ineligible because of disease-related cytopenias, which are exacerbated by JAK inhibitors. Therefore, there is a continued effort to identify targets outside the JAK-STAT pathway. In this review, we discuss novel therapies in development for myelofibrosis. We focus on the preclinical rationale, efficacy and safety data for non-JAK inhibitor therapies that have published or presented clinical data. Specifically, we discuss agents that target epigenetic modification (pelabresib, bomedemstat), apoptosis (navitoclax, navtemdalin), signaling pathways (parsaclisib), bone marrow fibrosis (AVID200, PRM-151), in addition to other targets including telomerase (imetelstat), selective inhibitor of nuclear transport (selinexor), CD123 (tagraxofusp) and erythroid maturation (luspatercept). We end by providing commentary on the ongoing and future therapeutic development in myelofibrosis.
Topics: Humans; Janus Kinase Inhibitors; Janus Kinases; Primary Myelofibrosis; Protein Kinase Inhibitors; STAT Transcription Factors; Signal Transduction; Splenomegaly
PubMed: 35182376
DOI: 10.1007/s12185-022-03299-8 -
Balkan Medical Journal Aug 2020
Topics: Castleman Disease; Female; Fever; Humans; Middle Aged; Splenomegaly; Tomography, X-Ray Computed
PubMed: 32208567
DOI: 10.4274/balkanmedj.galenos.2020.2020.3.30 -
The New England Journal of Medicine Aug 2019
Topics: Adult; Fatal Outcome; Humans; Lymphoma, T-Cell; Male; Spleen; Splenomegaly; Tomography, X-Ray Computed
PubMed: 31390503
DOI: 10.1056/NEJMicm1901064 -
The Lancet. Haematology Jul 2022The phase 3b, randomised, open-label RESPONSE-2 study in patients with inadequately controlled polycythaemia vera without splenomegaly showed superiority of the Janus... (Randomized Controlled Trial)
Randomized Controlled Trial
Ruxolitinib versus best available therapy in inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): 5-year follow up of a randomised, phase 3b study.
BACKGROUND
The phase 3b, randomised, open-label RESPONSE-2 study in patients with inadequately controlled polycythaemia vera without splenomegaly showed superiority of the Janus kinase (JAK) 1 and JAK2 inhibitor ruxolitinib versus best available therapy for the primary endpoint of haematocrit control at week 28. Here, we present secondary endpoints of the RESPONSE-2 study after 5 years of follow-up.
METHODS
RESPONSE-2 was an open-label, randomised, phase 3b study done at 48 hospitals or clinics across 12 countries in Asia, Australia, Europe, and Canada. Patients (aged ≥18 years) with polycythaemia vera without splenomegaly, who were intolerant of, or resistant to hydroxyurea, with an Eastern Cooperative Oncology Group performance status of 2 or less were randomly assigned (1:1) to receive ruxolitinib or best available therapy for up to 80 weeks. Patients received oral ruxolitinib at a starting dose of 10 mg twice a day or best available therapy. Patients assigned to best available therapy could cross over to ruxolitinib at week 28 if the primary endpoint was not met, or after week 28 and up to week 80 if best available therapy was ineffective or not tolerated. Patients receiving ruxolitinib at week 80, including crossover patients, could continue ruxolitinib treatment up to week 260. We assessed secondary endpoints at week 260, including durable haematocrit control, median duration of haematocrit control, median haematocrit level over time, number of phlebotomies, and overall survival. Analyses were based on the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT02038036 and was completed on April 7, 2020.
FINDINGS
Patients were enrolled between March 25, 2014 and Feb 11, 2015. 149 patients were randomly assigned to ruxolitinib (n=74) or best available therapy (n=75). The median follow-up was 67 months (IQR 65-70). At randomisation, best available therapy regimens included hydroxyurea (n=38), interferon or pegylated interferon (n=9), pipobroman (n=5), lenalidomide (n=1), or no treatment (n=22). Between weeks 28 and 80, 58 (77%) of 75 patients in the best available therapy group crossed over to ruxolitinib; no patients continued best available therapy after week 80 per protocol. 97 patients received ruxolitinib until week 260, including 59 (80%) of 74 patients in the ruxolitinib group and 38 (66%) of 58 patients in the crossover groups. At week 260, 16 (22%; 95% CI 13-33) of 74 patients in the ruxolitinib group had achieved durable haematocrit control, with estimated median duration not reached (NR; 95% CI 144 to NR). Median duration of haematocrit control was not reported for patients in the best available therapy group due to the small number of responders by week 80. During the 5-year follow-up, median haematocrit level among patients in the ruxolitinib group remained below 45%. 60 phlebotomies were required among 74 patients in the ruxolitinib group in 260 weeks, and 106 phlebotomies among 75 patients in the best available therapy group in 80 weeks. 5-year overall survival was 96% (95% CI 87-99) in the ruxolitinib group and 91% (80-96) in the best available therapy group. The most common grade 3-4 adverse events (exposure-adjusted per 100 patient-years) in the ruxolitinib group (n=74) and best available therapy group (n=75) were hypertension (eight [2·4%] vs three [5·6%]), thrombocytopenia (one [0·3%] vs three [5·6%]), and thrombocytosis (0 vs four [7·5%]). Exposure-adjusted rates of any-grade thromboembolic events were 1·5% per 100 person-years (five of 74 patients) in the ruxolitinib group and 3·7% per 100 person-years (two of 75 patients) in the best available therapy group. No treatment-related deaths occurred during the study.
INTERPRETATION
5-year results from the RESPONSE-2 study support the use of ruxolitinib as a second-line therapy of choice for patients with inadequately controlled polycythaemia vera without splenomegaly.
FUNDING
Novartis.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Follow-Up Studies; Humans; Hydroxyurea; Interferons; Nitriles; Polycythemia Vera; Pyrazoles; Pyrimidines; Splenomegaly
PubMed: 35597252
DOI: 10.1016/S2352-3026(22)00102-8 -
Autoimmunity Reviews Nov 2023Autoimmune Lymphoproliferative Syndrome (ALPS) is an autoimmune disease that has been reported in over 2200 patients. It is a rare, genetic disease where pathogenic... (Review)
Review
Autoimmune Lymphoproliferative Syndrome (ALPS) is an autoimmune disease that has been reported in over 2200 patients. It is a rare, genetic disease where pathogenic variants occur in the extrinsic pathway of apoptosis. Various mutations in different genes, such as FAS, FASL, and CASP10, can result in ALPS. Most commonly, pathogenic variants occur in the FAS receptor. This malfunctioning pathway allows for the abnormal accumulation of lymphocytes, namely CD3 + TCRαβ+CD4 - CD8- (double negative (DN) T) cells, which are a hallmark of the disease. This disease usually presents in childhood with lymphadenopathy and splenomegaly as a result of lymphoproliferation. Over time, these patients may develop cytopenias or lymphomas because of irregularities in the immune system. Current treatments include glucocorticoids, mycophenolate mofetil, sirolimus, immunoglobulin G, and rituximab. These medications serve to manage the symptoms and there are no standardized recommendations for the management of ALPS. The only curative therapy is a bone marrow transplant, but this is rarely done because of the complications. This review serves to broaden the understanding of ALPS by discussing the mechanism of immune dysregulation, how the symptoms manifest, and the mechanisms of treatment. Additionally, we discuss the epidemiology, comorbidities, and medications relating to ALPS patients across the United States using data from Cosmos.
Topics: Humans; Autoimmune Lymphoproliferative Syndrome; Autoimmune Diseases; fas Receptor; Splenomegaly; Mutation; Sirolimus; Lymphoproliferative Disorders
PubMed: 37683818
DOI: 10.1016/j.autrev.2023.103442 -
Disease Markers 2023Patients with cirrhosis and splenomegaly often have coagulation dysfunction which affects treatment and prognosis. This study explores the status, grading, and treatment...
OBJECTIVE
Patients with cirrhosis and splenomegaly often have coagulation dysfunction which affects treatment and prognosis. This study explores the status, grading, and treatment strategies of coagulation dysfunction in patients with liver cirrhosis and splenomegaly.
METHODS
A retrospective cohort study was conducted on the clinical data on consecutive patients with cirrhosis and splenomegaly treated at Hainan General Hospital, China, from January 2000 to December 2020. Starting research in January 2022.
RESULTS
Among 1522 patients included into this study, 297 (19.5%) patients had normal results in all five coagulation tests (prothrombin time, prothrombin activity, activated partial thromboplastin time, thrombin time, and fibrinogen), and 1225 (80.5%) had coagulation dysfunction in at least one of these tests. There were significant differences ( < 0.05) in treatment efficacy on these patients for three of these five coagulation tests, with the exception of prothrombin activity and thrombin time. When coagulation dysfunction was classified into grades I, II, and III based on scores from the three significant coagulation tests, prothrombin time, activated partial thromboplastin time, and fibrinogen, significant differences in surgical outcomes were found among the three grades of coagulation dysfunction and between grades I and III ( < 0.05). The operative mortality rate in patients with grade III in treating liver cancer, portal hypersplenism, and/or splenomegaly was 6.5%. There was no significant difference between patients with grades I and II ( > 0.05).
CONCLUSIONS
Approximately, 80% of patients with liver cirrhosis and splenomegaly had coagulation dysfunction. Surgery is feasible for grade I and II patients. For grade III patients, nonsurgical treatment should be given first, and surgery should only be considered when the coagulation function returns to normal or near-normal levels after treatment. This trial is registered with MR-46-22-009299.
Topics: Humans; Retrospective Studies; Splenomegaly; Prothrombin; Liver Cirrhosis; Fibrinogen; Blood Coagulation Disorders
PubMed: 37325552
DOI: 10.1155/2023/5560560 -
Pathology Jun 2023
Topics: Pregnancy; Female; Humans; Splenomegaly; Anemia; Thrombocytopenia; Leukopenia; Splenectomy
PubMed: 36503637
DOI: 10.1016/j.pathol.2022.09.006 -
Annals of Hematology Apr 2023Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by mutations (most frequently in JAK2, CALR, or MPL), burdensome symptoms, splenomegaly, cytopenia, and... (Review)
Review
Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by mutations (most frequently in JAK2, CALR, or MPL), burdensome symptoms, splenomegaly, cytopenia, and shortened life expectancy. In addition to other clinical manifestations, patients with MF often develop anemia, which can either be directly related to MF pathogenesis or a result of MF treatment with Janus kinase (JAK) inhibitors, such as ruxolitinib and fedratinib. Although symptoms and clinical manifestations can be similar between the 2 anemia types, only MF-related anemia is prognostic of reduced survival. In this review, I detail treatment and patient management approaches for both types of anemia presentations and provide recommendations for the treatment of MF in the presence of anemia.
Topics: Humans; Primary Myelofibrosis; Janus Kinase 2; Splenomegaly; Nitriles; Anemia; Pyrrolidines; Sulfonamides
PubMed: 36786879
DOI: 10.1007/s00277-023-05126-4 -
Journal of Korean Medical Science Mar 2022Non-palpable splenomegaly in patients with polycythemia vera (PV) has seldom been addressed. In this retrospective study, we evaluated non-palpable, volumetric...
BACKGROUND
Non-palpable splenomegaly in patients with polycythemia vera (PV) has seldom been addressed. In this retrospective study, we evaluated non-palpable, volumetric splenomegaly defined based on age- and body surface area (BSA)-matched criteria in patients with PV diagnosed according to the 2016 World Health Organization diagnostic criteria.
METHODS
Patients with PV who underwent abdominal computed tomography (CT) and who had palpable splenomegaly at diagnosis from January 1991 to December 2020 at Chungnam National University Hospital were enrolled. The spleen volume of each patient was determined by volumetric analysis of abdominal CT and adjusted for the patient's age and BSA. Then the degree of splenomegaly was classified as no splenomegaly, borderline volumetric splenomegaly, overt volumetric splenomegaly, or palpable splenomegaly.
RESULTS
Of the 87 PV patients enrolled, 15 (17.2%) had no splenomegaly, whereas 17 (19.5%), 45 (51.7%), and 10 (11.5%) had borderline volumetric, overt volumetric, and palpable splenomegaly, respectively. The degree of splenomegaly did not affect the cumulative incidence of thrombotic vascular events (10-year incidence: 7.7%, 0%, 22.3%, and 50.7%, respectively, = 0.414). By contrast, splenomegaly tended to adversely affect myelofibrotic transformation (10-year cumulative incidence: 0%, 0%, 7.1%, and 30.3%, respectively, = 0.062). Moreover, the cumulative incidence of myelofibrotic transformation was significantly higher in patients with overt volumetric or palpable splenomegaly than those with no or borderline volumetric splenomegaly (10-year incidence: 0% vs. 10.3%, respectively; 15-year incidence: 0% vs. 26.3%, respectively, = 0.020). Overall survival (OS) differed among patients with different degrees of splenomegaly (15-year OS: 100%, 78.6%, 71.7%, and 51.9%, respectively, = 0.021).
CONCLUSION
The degree of splenomegaly, including volumetric splenomegaly, based on age- and BSA-matched reference spleen volumes at diagnosis reflects disease progression in PV patients. Therefore, volumetric splenomegaly should be evaluated at the time of diagnosis and taken into consideration when predicting the prognosis of patients with PV.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Polycythemia Vera; Predictive Value of Tests; Prognosis; Republic of Korea; Retrospective Studies; Splenomegaly; Young Adult
PubMed: 35315598
DOI: 10.3346/jkms.2022.37.e87 -
Minerva Pediatrica Oct 2020As improvements in nutritional and pulmonary care increase the life expectancy of cystic fibrosis (CF) patients, CF-associated liver disease (CFLD) is emerging as a... (Review)
Review
As improvements in nutritional and pulmonary care increase the life expectancy of cystic fibrosis (CF) patients, CF-associated liver disease (CFLD) is emerging as a cause of mortality. CFLD is the third leading cause of death in CF patients. We performed a search on PubMed and Google Scholar for published articles on CFLD. We reviewed the articles found in the literature search and gave priority to recent publications and studies with larger sample sizes. The prevalence of CFLD in the CF population is around 23% with a range of 2-62% and that prevalence increases linearly with age from 3.7% at age 5 to 32.2% at age 30. CFLD can present clinically in various ways such as hepatomegaly, variceal hemorrhage, persistent elevation of liver enzymes, and micro-gallbladder. Due to the focal nature of fibrosis in majority cases of CFLD, liver biopsies are sparsely performed for diagnosis or the marker of liver fibrosis. Although the mechanism of CFLD development is still unknown, many potential factors are reported. Some mutations of CFTR such as having a homozygous F508del mutation has been reported to increase the risk of developing CFLD and its severity. Having the SERPINA1 Z allele, a history of pancreatic insufficiency, a history meconium ileus, CF-related diabetes, or being male increases the risk of developing CFLD. Environmental factors do not appear to have significant effect on modulating CFLD development. Ursodeoxycholic acid is commonly used to treat or prevent CFLD, but the efficacy of this treatment is questionable.
Topics: Adolescent; Adult; Age Factors; Alleles; Cause of Death; Child; Child, Preschool; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Esophageal and Gastric Varices; Female; Hepatomegaly; Homozygote; Humans; Hypertension, Portal; Liver; Male; Mutation; Prevalence; Primary Prevention; Sex Factors; Splenomegaly; Ursodeoxycholic Acid; Young Adult; alpha 1-Antitrypsin
PubMed: 32418413
DOI: 10.23736/S0026-4946.20.05895-8