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Frontiers in Oncology 2023Knowledge on the myeloproliferative neoplasms (MPNs) - polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) - has accumulated since the... (Review)
Review
Knowledge on the myeloproliferative neoplasms (MPNs) - polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) - has accumulated since the discovery of the JAK/STAT-activating mutations associated with MPNs: V617F, observed in PV, ET and PMF; and the and mutations, found in ET and PMF. The intriguing lack of disease specificity of these mutations, and of the chronic inflammation associated with MPNs, triggered a quest for finding what precisely determines that MPN patients develop a PV, ET or PMF phenoptype. The mechanisms of action of MPN-driving mutations, and concomitant mutations (, others), have been extensively studied, as well as the role played by these mutations in inflammation, and several pathogenic models have been proposed. In parallel, different types of drugs have been tested in MPNs (JAK inhibitors, interferons, hydroxyurea, anagrelide, azacytidine, combinations of those), some acting on both JAK2 and inflammation. Yet MPNs remain incurable diseases. This review aims to present current, detailed knowledge on the pathogenic mechanisms specifically associated with PV, ET or PMF that may pave the way for the development of novel, curative therapies.
PubMed: 37284191
DOI: 10.3389/fonc.2023.1196817 -
Clinical Case Reports Apr 2023Pericardial effusion leading to cardiac tamponade can occur due to a multitude of etiologies, one of which is medication adverse effects. In patients with comorbid...
Pericardial effusion leading to cardiac tamponade can occur due to a multitude of etiologies, one of which is medication adverse effects. In patients with comorbid conditions, this can prove to be a challenge in its co-management along with the primary disease. We present a rare case of anagrelide-induced pericardial effusion that is presented with tamponade physiology in a patient with essential thrombocythemia. After cautiously weighing the risks and benefits of further invasive interventions following an unsuccessful pericardiocentesis, the decision was to stop anagrelide while managing the pericardial effusion medically. Therefore, managing pericardial effusion should be tailored to each patient individually through shared decision-making.
PubMed: 37102091
DOI: 10.1002/ccr3.7246 -
ACS Medicinal Chemistry Letters Apr 2023The mode of action by which the orphan drug anagrelide (), a potent cAMP phosphodiesterase 3A inhibitor, reduces blood platelet count in humans is not well understood....
The mode of action by which the orphan drug anagrelide (), a potent cAMP phosphodiesterase 3A inhibitor, reduces blood platelet count in humans is not well understood. Recent studies indicate that stabilizes a complex between PDE3A and Schlafen 12, protecting it from degradation while activating its RNase activity.
PubMed: 37077378
DOI: 10.1021/acsmedchemlett.3c00092 -
Journal of Clinical and Experimental... 2023TAFRO syndrome is a rare systemic inflammatory disease characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly. We encountered a case of...
TAFRO syndrome is a rare systemic inflammatory disease characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly. We encountered a case of calreticulin mutation-positive essential thrombocythemia (ET) with TAFRO syndrome-like features, followed by a rapid fatal course. The patient had been on anagrelide therapy for approximately three years for management of ET; however, she suddenly stopped going for follow-up and discontinued the medicine for a year. She presented with fever and hypotension, suggestive of septic shock, and was transferred to our hospital. The platelet count at the time of admission to another hospital was 50 × 10 / μL; however, it decreased to 25 × 10 / μL upon transfer to our hospital and further decreased to 5 × 10 / μL on the day of her death. In addition, the patient showed remarkable systemic edema and progression of organomegaly. Her condition suddenly worsened and led to her death on the 7th day of hospitalization. Postmortem, serum and pleural effusion interleukin (IL)-6 and vascular endothelial growth factor (VEGF) levels were significantly increased. Consequently, a diagnosis of TAFRO syndrome, since she met the diagnostic criteria for clinical findings and had high cytokine concentrations. Dysregulation of cytokine networks has also been reported in ET. Therefore, concurrent ET and TAFRO syndrome may have further triggered cytokine storms and contributed to the aggravation of the disease on development of TAFRO syndrome. To the best of our knowledge, this is the first report of complications seen in a patient with TAFRO syndrome due to ET.
Topics: Female; Humans; Thrombocythemia, Essential; Vascular Endothelial Growth Factor A; Castleman Disease; Edema; Fever; Cytokines
PubMed: 36990774
DOI: 10.3960/jslrt.22029 -
Journal of Pharmaceutical and... May 2023Anagrelide (ANG) is a widely used drug for the treatment of essential thrombocytosis and myeloproliferative neoplasms. Recently, a new oxidative degradant was identified...
Anagrelide (ANG) is a widely used drug for the treatment of essential thrombocytosis and myeloproliferative neoplasms. Recently, a new oxidative degradant was identified when the drug product capsule underwent stress testing. Full structural characterization of this previously unidentified degradant was conducted. Preliminary LC-MS analysis indicated the targeted degradant as a mono-oxygenated product of ANG. For the purpose of facile isolation and purification, various forced degradation conditions were screened to enrich the desired degradant, among which, pyridinium chlorochromate (PCC)-treatment effectively afforded a yield of 55 % unknown degradant. Following isolation by prep-HPLC, 1D and 2D NMR studies and HRMS characterization assigned the products as a pair of 5-hydroxy-Anagrelide (5-OH-ANG) enantiomers. A plausible mechanism of formation is proposed.
Topics: Chromatography, High Pressure Liquid; Chromatography, Liquid; Mass Spectrometry; Quinazolines
PubMed: 36989665
DOI: 10.1016/j.jpba.2023.115352 -
Hematology Reports Mar 2023Myeloproliferative neoplasms (MPN) such as essential thrombocythemia (ET) and polycythemia vera (PV) are rare during pregnancy. However, they are harmful because they...
Myeloproliferative neoplasms (MPN) such as essential thrombocythemia (ET) and polycythemia vera (PV) are rare during pregnancy. However, they are harmful because they are associated with an increased risk of thromboembolic, hemorrhagic, or microcirculatory disturbances or placental dysfunction leading to fetal growth restriction or loss. Low-dose aspirin and low-molecular-weight heparin (LMWH) are recommended to reduce pregnancy complications, and interferon (IFN) is the only treatment option for cytoreductive therapy based on the likelihood of live birth in pregnant women with MPN. Since ropeginterferon alfa-2b is the only available IFN in South Korea, we present a case report of ropeginterferon alfa-2b use during pregnancy in an MPN patient. A 40-year-old woman who had been diagnosed with low-risk PV in 2017 and had been maintained on phlebotomy, hydroxyurea (HU), and anagrelide (ANA) for 4 years was confirmed as 5 weeks pregnant on 9 December 2021. After stopping treatment with HU and ANA, the patient showed a rapid increase in platelet count (1113 × 10/L to 2074 × 10/L, normal range, 150-450 × 10/L) and white blood cell count (21.93 × 10/L to 35.55 × 10/L, normal range, 4.0-10.0 × 10/L). Considering the high risk of complications, aggressive cytoreductive treatment was required, for which we chose ropeginterferon alfa-2b, as it is the only available IFN agent in South Korea. The patient underwent 8 cycles of ropeginterferon alfa-2b over 6 months during pregnancy and delivered without any neonatal or maternal complications. This case report highlights the importance of considering treatment options for MPN patients who are pregnant or planning a pregnancy, as well as the need for further investigation into the safety and efficacy of ropeginterferon alfa-2b in this population.
PubMed: 36975731
DOI: 10.3390/hematolrep15010018 -
Case Reports in Hematology 2023VEXAS syndrome stands for vacuoles, E1 enzyme, -linked, autoinflammatory, somatic syndrome. The syndrome is a combined hematological and rheumatological condition caused...
VEXAS syndrome stands for vacuoles, E1 enzyme, -linked, autoinflammatory, somatic syndrome. The syndrome is a combined hematological and rheumatological condition caused by a somatic mutation in the . There is an association between VEXAS and hematological conditions such as myelodysplastic syndrome (MDS), monoclonal gammopathies of uncertain conditions (MGUS), multiple myeloma (MM), and monoclonal B-cell lymphoproliferative conditions. There are not many descriptions of patients having VEXAS in combination with myeloproliferative neoplasm (MPN). With this article, we want to present a case history of a man in his sixties with a V617F mutated essential thrombocythemia (ET) developing VEXAS syndrome. The inflammatory symptoms occurred three and a half years after the ET diagnosis. He started to experience symptoms of autoinflammation and an overall worsening of his health, and blood work showed high inflammatory markers, leading to repeated hospitalizations. His major complaint was stiffness and pain, and high dosages of prednisolone were necessary to obtain pain relief. He subsequently developed anemia and significantly variable levels of thrombocytes, which previously were at a steady level. To evaluate his ET, we made a bone marrow smear demonstrating vacuolated myeloid and erythroid cells. Having VEXAS syndrome in mind, genetic testing identifying the gene mutation was performed, thus confirming our suspicion. The work-up with myeloid panel on his bone marrow identified genetic mutation in the too. After developing VEXAS syndrome, he experienced thromboembolic events with both cerebral infarction and pulmonary embolism. Thromboembolic events are also common in mutated patients, but in his case, they presented first after VEXAS had developed. Throughout the course of his condition, several attempts with prednisolone tapering and steroid sparing drugs were tried. He could not get pain relief unless the combination of medications included a relatively high dose of prednisolone. Currently, the patient uses prednisolone, anagrelide, and ruxolitinib, with partial remission and fewer hospitalizations and more stabilized hemoglobin and thrombocytes.
PubMed: 36879894
DOI: 10.1155/2023/6551544 -
Frontiers in Oncology 2022As the discussion of first-line anagrelide treatment is ongoing, we aimed to prospectively examine the efficacy and safety of anagrelide in cytoreduction therapy-naïve...
A multicenter, open-label study for efficacy and safety evaluation of anagrelide in patients with treatment-naïve, high-risk essential thrombocythemia as a primary treatment.
As the discussion of first-line anagrelide treatment is ongoing, we aimed to prospectively examine the efficacy and safety of anagrelide in cytoreduction therapy-naïve high risk essential thrombocythemia (ET) patients in Korea. Seventy patients from 12 centers were treated with anagrelide monotherapy for up to 8 weeks, followed up until 24 months. At week 8, 50.0% of the patients were able to achieve platelet < 600 x 10/L, and by 12 months, 55/70 (78.6%) patients stayed on anagrelide, and 40.0% patients showed platelet normalization. 14 patients required additional hydroxyurea (HU) for cytoreduction. The median daily dose of needed HU was 500mg (range 250mg - 1500mg). The efficacy was independent of the somatic mutation status. There were 4 thromboembolic events and 7 bleeding events during the follow-up period. The most common adverse events associated with anagrelide use were headache, followed by palpitation/chest discomfort, edema and generalized weakness/fatigue. 7 patients wished to discontinue anagrelide treatment due to adverse events (3 due to headache; 2 due to edema; 1 due to palpitation and 1 due to skin eruption). All in all, first-line anagrelide treatment showed a favorable response with tolerable safety profiles regardless of somatic mutation status.
PubMed: 36505839
DOI: 10.3389/fonc.2022.989984 -
Cancer Medicine Feb 2023Conventional cytoreductive therapy for patients with chronic Philadelphia-negative myeloproliferative neoplasms (MPNs) includes hydroxyurea (HU), interferon-alpha2...
BACKGROUND
Conventional cytoreductive therapy for patients with chronic Philadelphia-negative myeloproliferative neoplasms (MPNs) includes hydroxyurea (HU), interferon-alpha2 (IFN), and anagrelide. HU is worldwide the most used cytoreductive agent, which lowers elevated blood cell counts within days in the large majority of patients. However, some patients may experience rebound cytosis when HU is reduced due to cytopenia, thereby potentially giving rise to fluctuating cell counts during therapy. Such rapid oscillations may be harmful and potentially elicit thrombosis. Treatment with IFN gradually lowers elevated cell counts within weeks and when the dosage is reduced, the cell counts do not rapidly increase but are sustained within the normal range in the large majority of patients. Conventional hematological response criteria are among others based upon single absolute cell count values and do not take into account the relative decreases toward normal for each cell count.
MATERIALS, METHODS & RESULTS
Using serial data from the Danish DALIAH trial, we herein describe a novel integrated biomarker index for the assessment of hematological and molecular (JAK2V617F) responses in patients with MPNs during treatment with IFN or HU.
DISCUSSION
This novel tool convincingly displays the superiority of IFN versus HU in normalizing elevated cell counts. Our results need to be validated in larger studies but already now call for studies of the safety and efficacy of combination therapy during the initial treatment of patients with MPNs.
Topics: Humans; Hydroxyurea; Polycythemia Vera; Interferon-alpha; Myeloproliferative Disorders; Biomarkers
PubMed: 36254099
DOI: 10.1002/cam4.5285 -
Cureus Sep 2022Essential thrombocythemia (ET) is a myeloproliferative neoplasm involving the clonal proliferation of platelets. It is Philadelphia negative and is associated with...
Essential thrombocythemia (ET) is a myeloproliferative neoplasm involving the clonal proliferation of platelets. It is Philadelphia negative and is associated with Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL) mutations. The resultant platelets have quantitative and qualitative defects, making them more sticky and prone to thromboembolism. However, ET does not only affect platelet survival, it also has a low leukemogenic potential. It's more common in the elderly, 60 years or more, but can be seen in all age groups, including children. Patients with ET have an increased risk of vascular events like hemorrhage and thromboses like cerebrovascular events, myocardial infarction, superficial thrombophlebitis, deep vein thrombosis, and pulmonary embolism. Cardiovascular risk factors like hypertension, diabetes, and smoking can lead to increased thromboembolism and atherosclerosis. The management of ET focuses primarily on the prevention of thrombosis and hemorrhage. It involves cardiovascular risk management and antiplatelet and cytoreductive therapy according to the risk stratification. Low-risk ET patients are treated with low-dose aspirin, and high-risk ET patients are treated with cytoreductive therapy with hydroxyurea. Interferon (IFN) and anagrelide are reserved for young patients or pregnant women. This case report discusses a 40-year-old male, a known smoker presenting with myocardial infarction and left anterior descending artery (LAD) blockage without any prior history. His high platelets and the relative absence of cardiovascular risk factors helped reach the diagnosis, and bone marrow analysis and mutation analysis confirmed the diagnosis. The patient was started on hydroxyurea, which decreased the total platelet count.
PubMed: 36225436
DOI: 10.7759/cureus.28883